DeCure for Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 — 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 moduleProgressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 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 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 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.
What the evidence adds up to
In a cohort 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, 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 (odds ratio 8.43, 95% confidence interval 2.24–31.76). Peripheral neuropathy had 91% specificity and 83% negative predictive value for a nuclear DNA defect. The authors suggest that nuclear gene testing may enable more rapid diagnosis and avoid muscle biopsy in patients with progressive external ophthalmoplegia and peripheral neuropathy.
In a separate study of 38 sporadic progressive external ophthalmoplegia patients with multiple mitochondrial DNA deletions, sequencing of POLG1, C10ORF2, and ANT1 identified causative mutations in approximately 10% of cases. Two unrelated individuals had a novel premature stop codon mutation in POLG1 (1356T>G). No mutations were found in C10ORF2 or ANT1. The authors concluded that in the majority of such patients the primary nuclear genetic defect is likely to affect other unknown genes important for mitochondrial DNA maintenance.
A retrospective analysis of 36 chronic progressive external ophthalmoplegia patients (11 male, 25 female; mean age of onset 41.2 years) found single mitochondrial DNA deletions in all patients. The common 4977 bp deletion was detected in 11 patients (30.6%). Its incidence was higher in patients aged 51 years or older (36.36%) than in younger patients (18.18%). The mean age of onset in patients with the common deletion was 27 years. Ptosis was present in 56% of patients. A tendency toward increasing frequency of COX-deficient fibres with age was observed in patients harbouring the common deletion. The authors propose ptosis and the presence of a single deletion as preliminary diagnostic criteria.
A 2023 case report describes a 16-year-old female with progressive external ophthalmoplegia and characteristic histological features, noting that ptosis and ophthalmoplegia are unresponsive to anticholinergics and that there is no effective treatment beyond palliative corrective surgery for ptosis. No drug therapy is mentioned in any of these abstracts. What remains missing is a clear genetic diagnosis for the majority of sporadic patients with multiple deletions, any prospective trial of a treatment, and patient stratification by specific nuclear gene defect rather than by clinical phenotype alone.
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.
<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.
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.
Journal of Clinical Medicine · 2025 · 0 citations · open access
Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions
AbstractIntroduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the ‘common’ 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria.
Digitalen Hochschulbibliothek Sachsen-Anhalt (Universitäts- und Landesbibliothek Sachsen-Anhalt) · 2025 · 0 citations · open access
Clinical ophthalmic outcomes and impact of single large-scale mitochondrial DNA deletions
AbstractIntroduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the ‘common’ 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria.
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.
