DeCure for Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 — 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 5 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 5 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 topoisomerase III alpha (TOP3A) — TOP3A 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 4CGY · 2.85 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Progressive external ophthalmoplegia with mitochondrial DNA deletions is a slowly progressive hereditary mitochondrial myopathy that particularly affects the extraocular muscles, causing ophthalmoplegia and bilateral ptosis unresponsive to anticholinergics, with no effective treatment aside from palliative ptosis surgery (2023 case report). The most common enzyme defect is a combined deficit of complexes I and IV. In a cohort of 36 CPEO patients (11 males, 25 females; mean age of onset 41.2 years), single mtDNA deletions were found in all patients, and the common 4977 bp deletion was detected in 11 patients (30.6%). The incidence of that common deletion was higher in patients aged 51 years or older (36.36%) than in younger patients (18.18%), and the mean age of onset in patients harbouring it 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 with the common deletion (2025 study).
Among 116 genetically-defined mitochondrial disease patients with progressive external ophthalmoplegia, 78 (67%) had a single mtDNA deletion, 12 (10%) had a point mutation of mtDNA, and 26 (22%) had mutations in POLG, C10orf2, or RRM2B, or had multiple mtDNA deletions without an identified nuclear gene defect. Of 77 patients who had neurophysiological studies, 16 (21%) had a large-fibre peripheral neuropathy. Peripheral neuropathy was significantly less prevalent in patients with a single mtDNA deletion (2%) than in those with a point mutation (44%) or a nuclear DNA defect (52%). Binomial logistic regression identified peripheral neuropathy as the only independent predictor of a nuclear DNA defect (odds ratio 8.43, 95% CI 2.24–31.76). Peripheral neuropathy had 91% specificity and 83% negative predictive value for a nuclear DNA defect (2014 study).
In 10 Asian patients with confirmed mtDNA deletions and CPEO, all had ophthalmoplegia and ptosis even after eyelid surgery. Ophthalmoplegia was symmetric between both eyes in nine patients (90%); one patient (10%) had asymmetric ophthalmoplegia with esotropia and left hypotropia. Among the nine symmetric patients, four (44%) showed exotropia, three (33%) had exotropia with vertical deviation, and two (22%) were orthotropic. Five of the 10 patients (50%) complained of diplopia associated with strabismus, and four of those five (80%) had vertical deviation. Three of five patients without diplopia showed exotropia of 20 to 50 prism diopters (2020 study). Heteroplasmic mtDNA populations appear to be present at a very early developmental stage, with no direct maternal transmission of mtDNA heteroplasmy (1990 study).
What is still missing is any proven pharmacological treatment — the 2023 case report states there is no effective treatment. No trial has tested a drug specifically for this autosomal recessive form. Patient stratification by nuclear versus single deletion genotype is not yet standard in clinical practice, and no funding has been committed to a repurposing trial for this precise genetic subgroup.
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 Neurology · 1990 · 98 citations
Tissue distribution and transmission of mitochondrial DNA deletions in mitochondrial myopathies
AbstractBy using a combination of Southern blot hybridization analysis, polymerase-chain reaction amplification, and direct nucleotide sequencing, we studied deletions of mitochondrial DNA (mtDNA) in several nonfamilial patients with progressive external ophthalmoplegia and Kearns-Sayre syndrome, and in some of their direct relatives. Results suggest that the heteroplasmic mtDNA populations are already present at a very early stage of development, and that there is no direct transmission of mtDNA heteroplasmy by maternal inheritance.
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.
Journal of Medical Genetics · 2000 · 5 citations · open access
Further evidence for genetic heterogeneity of autosomal dominant disorders with accumulation of multiple deletions of mitochondrial DNA
AbstractEditor—Disorders of oxidative phosphorylation are highly heterogeneous from both a clinical and a genetic point of view. The nuclear as well as the mitochondrial genomes contain genes that are necessary for respiratory chain function. Consequently, different modes of inheritance are encountered in disorders of oxidative phosphorylation.
Single large scale deletions of mitochondrial DNA (mtDNA) usually occur in sporadic cases.1 However, multiple deletions of mtDNA also occur in autosomal dominant disorders.2 These deletions are generated de novo as somatic mutations in each affected subject. The nuclear gene defects predisposing to secondary mtDNA deletions in these patients remain unknown.
The disorder discovered by Zeviani et al 2 was later found in several families and was called autosomal dominant progressive external ophthalmoplegia (ADPEO),3 as ptosis and external ophthalmoplegia are the major clinical findings.4-7 More generalised weakness of the skeletal muscles and sudden unexpected death are also common clinical features.4-7 Additional features vary among different families.4 6-8
Linkage analysis provided direct evidence for genetic heterogeneity …
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.
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.
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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