DeCure for Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 — 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 2 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 2 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
ribonuclease H1 (RNASEH1) — RNASEH1 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 16ddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2QK9 · 2.55 Å · ligand HEXANE-1,6-DIAMINE (16D). Experimental structure, not a prediction.
What the evidence adds up to
In four unrelated individuals with chronic progressive external ophthalmoplegia, large mitochondrial DNA deletions were found to have breakpoints occurring within directly repeated sequences of 13–18 base pairs. A consensus sequence of 11 nucleotides emerged, similar to putative recombination signals, suggesting a recombinational event. Partially deleted and normal mitochondrial DNAs were present in all tissues examined but in very different proportions, indicating the mutations originated before the primary cell layers diverged.
Among 38 sporadic progressive external ophthalmoplegia patients with multiple mitochondrial DNA deletions, causative mutations in POLG1 were identified in approximately 10% of cases. Two unrelated individuals harboured a novel premature stop codon mutation (1356T>G). No mutations were found in C10ORF2 or ANT1. The authors concluded that in the majority of patients the primary nuclear genetic defect is likely to affect other unknown genes important for mtDNA maintenance.
In a cohort of 10 Asian patients with chronic progressive external ophthalmoplegia confirmed by mitochondrial DNA deletions, all showed ophthalmoplegia and ptosis, even after eyelid surgeries. Ophthalmoplegia was symmetric between both eyes in nine patients (90%); one patient (10%) showed asymmetric ophthalmoplegia with esotropia and left hypotropia. Among the nine patients with symmetric involvement, four (44%) showed exotropia, three (33%) had exotropia with vertical deviation, and two (22%) showed orthotropia. Five out of 10 patients (50%) complained of diplopia associated with strabismus, four of whom (80%) had vertical deviation. Three out of five patients (60%) without diplopia showed exotropia of 20 to 50 prism diopters. A separate case report of a 16-year-old female noted that ptosis and ophthalmoplegia are unresponsive to anticholinergics, with no effective treatment, and corrective surgery for ptosis is only palliative.
In a retrospective analysis of 36 CPEO patients (11 males, 25 females; mean age of onset 41.2 years), ptosis was identified in 56% of patients. Single mtDNA deletions were reported in all patients, and the common 4977 bp deletion was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) compared to younger patients (18.18%). The mean age of onset in patients harbouring the common deletion was 27 years. A tendency to increase the frequency of COX-deficient fibres with increasing age was observed in patients harbouring the common deletion. What remains missing is any effective pharmacological treatment, a clear understanding of the nuclear genetic defects in the majority of sporadic cases, and prospective trials that stratify patients by deletion type, age, and symptom pattern to test potential interventions.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Proceedings of the National Academy of Sciences · 1989 · 83 citations · open access
Directly repeated sequences associated with pathogenic mitochondrial DNA deletions.
AbstractWe determined the nucleotide sequences of junctional regions associated with large deletions of mitochondrial DNA found in four unrelated individuals with a phenotype of chronic progressive external ophthalmoplegia. In each patient, the deletion breakpoint occurred within a directly repeated sequence of 13-18 base pairs, present in different regions of the normal mitochondrial genome-separated by 4.5-7.7 kilobases. In two patients, the deletions were identical. When all four repeated sequences are compared, a consensus sequence of 11 nucleotides emerges, similar to putative recombination signals, suggesting the involvement of a recombinational event. Partially deleted and normal mitochondrial DNAs were found in all tissues examined, but in very different proportions, indicating that these mutations originated before the primary cell layers diverged.
<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.
Acta Ophthalmologica · 2020 · 1 citations · open access
Strabismus in chronic progressive external ophthalmoplegia
AbstractPURPOSE: To elucidate the patterns of strabismus and ophthalmoplegia associated with chronic progressive external ophthalmoplegia (CPEO) confirmed by mitochondrial DNA (mtDNA) deletions in Asians. METHODS: A total of 10 patients confirmed to have mtDNA deletion associated with CPEO were included. Long-range PCR encompassing the entire mtDNA was carried out. In the cases with mtDNA deletion, the exact deletion ranges of mtDNA were identified by sequencing. A full ophthalmologic examination including prism and alternate cover test in the primary position, evaluation of ductions and versions, and binocularity was performed in 10 patients with confirmed mtDNA deletions associated with CPEO. RESULTS: All of the patients showed ophthalmoplegia as well as ptosis, even after eyelid surgeries. Ophthalmoplegia was symmetric between both eyes in nine patients (90%) while one patient (10%) showed asymmetric ophthalmoplegia with esotropia and left hypotropia. Among the nine patients with symmetric involvement, four patients (44%) showed exotropia, three (33%) had exotropia with vertical deviation, and the remaining two patients (22%) showed orthotropia. Five out of 10 patients (50%) complained of diplopia associated with strabismus, four of whom (80%) had vertical deviation. Three out of five patients (60%) without diplopia showed exotropia of 20 prism diopters (PD) to 50 PD. CONCLUSIONS: Exotropia with/without vertical deviation is the most common form of strabismus in Asian patients with CPEO and only one of them showed a small angle of esotropia. Ophthalmoplegia could be asymmetric in 10% of CPEO patients.
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.
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.
AbstractProgressive external ophthalmoplegia (PEO) is characterized by progressive bilateral ptosis and eye movement disturbances in horizontal and vertical directions and represents a typical symptom of many mitochondrial disorders, but not a separate disease. PEO often occurs together with other systemic manifestations of mitochondrial disfunction. Correct and early diagnosis of PEO is essential for optimal management of these patients. In this review we collected the last data about etiology, spectrum of clinical symptoms, differential diagnosis, diagnostical methods and treatment options for isolated chronic PEO and other PEO-associated mitochondrial syndromes.
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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