Autosomal Dominant Progressive External Ophthalmoplegia: Disease-Characteristics Report

Scope and evidence note

Autosomal dominant progressive external ophthalmoplegia (adPEO; often adCPEO) is a genetically heterogeneous nuclear-genome mitochondrial DNA (mtDNA)-maintenance disorder. It must be distinguished from the broader phenotype “mitochondrial CPEO,” which also includes sporadic single large-scale mtDNA deletions, mtDNA point variants, and recessive nuclear disorders. Statistics from mixed CPEO cohorts are therefore labeled as such rather than attributed directly to adPEO.

The strongest directly applicable human evidence retrieved was a 25-patient TWNK-adPEO cohort published online in December 2021, together with mitochondrial PEO cohorts and 2023–2024 clinical reviews. The following table summarizes the principal knowledge-base fields.

Table: This table summarizes established, citable knowledge for autosomal dominant progressive external ophthalmoplegia, emphasizing what is supported directly for the AD subtype versus broader mitochondrial CPEO. It is useful for populating structured disease fields while preserving important scope caveats and evidence gaps.

1. Disease information

Definition and nomenclature

adPEO is usually a slowly progressive, adult-onset mitochondrial myopathy characterized by bilateral ptosis and limitation of extraocular movements, with secondary accumulation of multiple mtDNA deletions in post-mitotic tissues. “PEO-plus” denotes ophthalmoplegia accompanied by systemic manifestations such as proximal, neck, or bulbar weakness; exercise intolerance; neuropathy; ataxia; hearing loss; cataract; cardiac disease; or parkinsonism. The typical review-level onset range is approximately 20–40 years, although onset and severity vary considerably. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4)

Common names are autosomal dominant progressive external ophthalmoplegia, autosomal dominant chronic progressive external ophthalmoplegia, adPEO, adCPEO, dominant PEO, and, where systemic disease is present, adPEO-plus/CPEO-plus.

Identifiers

• OMIM phenotype: the literature explicitly cites autosomal dominant PEO as OMIM 157640; individual gene-related phenotypes can also have separate OMIM entries.
• MONDO: a stable adPEO-specific MONDO identifier was not confirmed in the retrieved evidence; it should not be populated without direct MONDO verification. A broader progressive external ophthalmoplegia concept may be available.
• Orphanet: CPEO and autosomal-dominant PEO are represented in Orphanet’s mitochondrial-disease hierarchy, but an exact ORPHA number was not confirmed here.
• ICD: there is no highly specific, universally used ICD-10 code for genetically confirmed adPEO. Cases are generally coded under mitochondrial metabolism/myopathy or ophthalmoplegia categories. ICD-11 provides more granular mitochondrial-disease concepts, but local coding should be verified.
• MeSH: relevant concepts include Ophthalmoplegia, Chronic Progressive External and Mitochondrial Myopathies.

The report describes aggregated disease-level evidence, not an individual EHR. The TWNK statistics derive from a specialist laboratory/clinical cohort of individual patients subsequently aggregated for publication. (bermejoguerrero2021clinicalhistologicaland pages 2-4)

2. Etiology, risk, protection, and environment

Primary cause

adPEO is caused by a heterozygous germline pathogenic variant in a nuclear gene required for mtDNA replication, repair, nucleotide balance, or mitochondrial dynamics. Established genes include TWNK, POLG, POLG2, SLC25A4, DNA2, and RRM2B. Dominant OPA1 variants can produce an overlapping syndromic disorder with optic atrophy, PEO, deafness, ataxia, and multiple mtDNA deletions. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4, kierdaszuk2020progressiveexternalophthalmoplegia pages 11-12)

The causal hierarchy is:

1. heterozygous nuclear variant;
2. defective mtDNA replication/maintenance or nucleotide homeostasis;
3. progressive formation and clonal expansion of multiple mtDNA deletions;
4. mosaic respiratory-chain deficiency;
5. ATP failure in high-demand, long-lived cells;
6. extraocular and skeletal-muscle dysfunction, with variable multisystem disease.

Risk factors

• Genetic: an affected parent, a pathogenic heterozygous allele, and increasing age are the major established risk determinants. In the TWNK cohort, 22/25 patients (88%) had a first-degree relative with ptosis and/or ophthalmoplegia. (bermejoguerrero2021clinicalhistologicaland pages 2-4)
• Age: deletion burden and clinical manifestations generally increase with age; presymptomatic carriers may have subclinical biochemical abnormalities. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4)
• Sex: no established biological sex predisposition exists. The TWNK cohort was 64% female, but this small referral cohort cannot establish a sex ratio. (bermejoguerrero2021clinicalhistologicaland pages 2-4)
• Environmental/infectious: no toxin, infection, occupational exposure, diet, smoking behavior, or lifestyle factor is known to cause Mendelian adPEO.

Protective factors and gene–environment interaction

No validated protective variant, diet, drug, or behavioral intervention prevents adPEO. Avoidance of mitochondrial stressors is prudent clinical practice but is not demonstrated primary prevention. Potentially mitochondrion-toxic drugs and prolonged metabolic stress may aggravate mitochondrial symptoms generally, but a quantified adPEO-specific gene–environment interaction has not been established. No infectious trigger is implicated.

3. Phenotypes

Core and systemic manifestations

These percentages are from 25 individuals with TWNK variants and should not be treated as universal frequencies for POLG-, POLG2-, SLC25A4-, DNA2-, RRM2B-, or OPA1-related disease. (bermejoguerrero2021clinicalhistologicaland pages 5-6, bermejoguerrero2021clinicalhistologicaland pages 1-2)

Additional reported adPEO-spectrum manifestations include sensorineural hearing loss, facial weakness, hypogonadism, psychiatric abnormalities, gastrointestinal dysmotility, and cataracts. OPA1-related “DOA-plus” particularly suggests optic atrophy and hearing loss. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4, ali2024mitochondrialchronicprogressive pages 13-14)

Quality of life

Ptosis can obstruct the visual axis, fixed ophthalmoplegia restricts gaze, and weakness, dysphagia, fatigue, neuropathy, or hearing loss can limit mobility, work, communication, and participation. Robust adPEO-specific EQ-5D, SF-36, PROMIS, survival, and disability-transition estimates were not identified. Accordingly, quality-of-life impact is clinically credible but insufficiently quantified by genotype.

4. Genetic and molecular information

Genes and functional classes

• TWNK encodes the mitochondrial replicative helicase. Dominant missense variants impair helicase function, stall replication, and produce multiple mtDNA deletions.
• POLG encodes the catalytic polymerase-γ subunit; dominant variants can alter polymerase, proofreading, or replisome function.
• POLG2 encodes the accessory polymerase-γ subunit.
• SLC25A4/ANT1 encodes the muscle-predominant mitochondrial ADP/ATP carrier and influences nucleotide/energy homeostasis.
• DNA2 participates in mtDNA replication/repair and flap processing.
• RRM2B supports deoxyribonucleotide production in non-dividing cells.
• OPA1 controls inner-membrane fusion/cristae organization and, in dominant syndromic disease, indirectly compromises mtDNA maintenance.

These proteins converge on mtDNA replication/maintenance despite performing different proximal functions. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4)

Variant evidence

In the TWNK cohort, all variants were heterozygous missense substitutions in exons 1–2. Ten variants were found: c.1361T>G (p.Val454Gly) occurred in seven patients from six families; c.1070G>C (p.Arg357Pro) in seven patients from five families; c.1121G>A (p.Arg374Gln) in three patients; and c.1411T>G (p.Tyr471Asp) in two siblings. All 17 tested muscle samples contained multiple mtDNA deletions. (bermejoguerrero2021clinicalhistologicaland pages 7-9)

Variants should be classified individually under ACMG/AMP criteria using ClinVar/ClinGen evidence, segregation, functional data, phenotype specificity, and population frequency. Disease association alone does not make every rare variant pathogenic. Causal alleles are germline; secondary mtDNA deletions arise somatically and clonally in affected tissues. Pathogenic dominant alleles are generally absent or extremely rare in population databases, but no single allele-frequency threshold is valid for every gene or variant.

Modifiers, epigenetics, and chromosome abnormalities

No reproducible modifier gene, protective allele, disease-specific methylation signature, histone alteration, or recurrent chromosomal rearrangement is established for adPEO. Conventional aneuploidy or translocation is not the characteristic lesion. The clinically relevant structural abnormalities are multiple mtDNA deletions, not a nuclear karyotypic defect.

Suggested annotations include SO:0001583 missense_variant, GO:0006260 DNA replication, GO:0006281 DNA repair, GO:0007005 mitochondrion organization, and GO:0006119 oxidative phosphorylation.

5. Environmental information

adPEO is not infectious, contagious, toxic, or environmentally acquired. No causal association with pollution, radiation, smoking, alcohol, occupation, or a specific diet has been demonstrated. Lifestyle measures—adequate nutrition, avoidance of prolonged fasting/dehydration, appropriately paced aerobic activity, and avoidance of unnecessary mitochondrial-toxic exposures—are supportive rather than curative or preventive. Vaccination has no disease-specific etiologic role, although routine immunization is appropriate.

6. Mechanism and pathophysiology

Upstream pathways

The principal upstream modules are mtDNA replication/repair (TWNK, POLG, POLG2, DNA2), nucleotide supply/balance (RRM2B and indirectly SLC25A4), and mitochondrial dynamics/quality control (OPA1). A major review summarizes mtDNA-maintenance disorders as involving “mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control.” (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4)

Downstream cellular injury

Multiple deletions remove mtDNA genes encoding respiratory-chain subunits and RNAs. Deletion burden varies among fibers, producing a mosaic of cytochrome-c-oxidase-negative cells. Respiratory-chain activities may range from normal to approximately 50% of control means, explaining why blood biomarkers can be normal despite muscle disease. Energy failure and compensatory mitochondrial proliferation produce ragged-red fibers; extraocular muscles are particularly vulnerable because of sustained activity and high mitochondrial demand. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4)

Suggested terms:

• GO biological process: GO:0006260 mitochondrial-DNA replication; GO:0006119 oxidative phosphorylation; GO:0007005 mitochondrion organization; GO:0006091 generation of precursor metabolites and energy.
• GO cellular component: GO:0005739 mitochondrion, GO:0005743 mitochondrial inner membrane, GO:0005759 mitochondrial matrix, GO:0005758 mitochondrial intermembrane space.
• Cell Ontology: CL:0000187 skeletal muscle cell; extraocular myofiber-specific annotations may require anatomy plus skeletal-muscle-cell terms.
• Metabolic consequence: impaired ATP production, variable lactate elevation, and compensatory mitochondrial biogenesis.

No primary autoimmune mechanism is established. Oxidative stress may be downstream of respiratory dysfunction, but chronic inflammation is not considered the initiating pathology.

Molecular profiling and advanced technologies

Routine pathology and bulk biochemical/genomic testing dominate the evidence base. No validated adPEO-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or integrated multi-omics diagnostic signature was identified. GDF-15 is promising as a general mitochondrial biomarker but not specific to adPEO: it was elevated in 2/3 tested TWNK patients at 1,454–2,727 pg/mL. (bermejoguerrero2021clinicalhistologicaland pages 6-7)

7. Anatomical structures affected

The primary structures are the extraocular muscles and levator palpebrae superioris, generally bilaterally and relatively symmetrically. Other skeletal muscles—proximal limb, cervical, facial, pharyngeal, and respiratory muscles—can be involved. Secondary sites vary by genotype and can include peripheral nerves, cochlea/auditory pathways, optic nerve, basal ganglia/cerebellar pathways, gastrointestinal smooth muscle/enteric nervous system, and heart. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4)

Suggested anatomy terms include UBERON:0001135 skeletal muscle tissue, UBERON extraocular-muscle and eyelid terms after database verification, and organ-specific terms for heart, peripheral nerve, optic nerve, and cochlea. At the subcellular level, mitochondria—especially matrix replisomes and inner-membrane OXPHOS machinery—are central.

8. Temporal development

adPEO is typically insidious and chronic. Review literature places usual onset around 20–40 years; broader mitochondrial CPEO has a reported mean onset around 29 years. In the TWNK series, 80% began at age ≥18, mean onset was 43 years, and mean molecular diagnosis was 63 years—a roughly 20-year average diagnostic gap. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4, chen2023mitochondriaandthe pages 1-2, bermejoguerrero2021clinicalhistologicaland pages 1-2)

A practical trajectory is:

1. subtle asymmetric or bilateral ptosis;
2. gradually restricted ocular motility, often with limited diplopia because progression is symmetric;
3. neck/proximal weakness or exercise intolerance;
4. variable PEO-plus manifestations later in life.

There are no validated formal stages, predictable annual progression rate, spontaneous remission pattern, or defined end-stage. Disease is lifelong and generally progressive. Critical opportunities are early genetic diagnosis, surveillance before cardiac/respiratory complications, and ptosis management before visual-axis obstruction or compensatory head posture becomes disabling.

9. Inheritance and population

Inheritance is autosomal dominant: an affected heterozygous individual generally has a 50% transmission probability per pregnancy, independent of sex. Expressivity is markedly variable and penetrance is likely age-dependent, but robust gene- and variant-specific penetrance estimates are unavailable. Anticipation is not established. Germline mosaicism is biologically possible but not a defining feature; consanguinity is not relevant to dominant transmission. (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4, kierdaszuk2020progressiveexternalophthalmoplegia pages 11-12)

adPEO-specific incidence, prevalence, carrier frequency, ethnic enrichment, geographic distribution, and sex ratio remain inadequately characterized. Broader CPEO estimates—1–2 per 100,000 incidence, approximately 1 in 30,000 prevalence, or 3.4 per 100,000—must not be interpreted as adPEO-specific. (ali2024mitochondrialchronicprogressive pages 1-3, chen2023mitochondriaandthe pages 1-2)

No universal founder allele was established. Recurrent TWNK variants in a Spanish cohort may reflect referral or ancestry patterns; their cohort frequencies are not population frequencies. (bermejoguerrero2021clinicalhistologicaland pages 7-9)

10. Diagnostics

Clinical and laboratory approach

Clinical suspicion is raised by slowly progressive bilateral ptosis and ophthalmoparesis, especially with an autosomal-dominant pedigree or proximal/bulbar weakness. Examination should document eyelid position, Bell phenomenon, corneal exposure, ocular ductions, diplopia, visual acuity, fundus/optic nerve, hearing, bulbar function, strength, gait, neuropathy, and systemic involvement.

CK and lactate may be normal or mildly elevated. In the TWNK cohort, mild hyperCKemia occurred in 28%; mild hyperlactacidemia in 3/6 tested; EMG was myopathic in 9/15 (60%), neurogenic in 2/15 (13%), and normal in 4/15 (27%). Brain and muscle imaging were often normal or nonspecific. (bermejoguerrero2021clinicalhistologicaland pages 5-6, bermejoguerrero2021clinicalhistologicaland pages 6-7)

Genetic testing strategy

1. Use a mitochondrial disease/PEO nuclear-gene panel including at least TWNK, POLG, POLG2, SLC25A4, DNA2, RRM2B, OPA1 and relevant recessive genes.
2. Concurrently or reflexively assess mtDNA for point variants, single deletions, and multiple deletions.
3. If blood is nondiagnostic, test a clinically affected tissue—usually skeletal muscle—because secondary deletions can be tissue-restricted.
4. Use WES/WGS when panel testing is negative; WGS may improve detection of nuclear structural/noncoding variants and mtDNA abnormalities, but tissue and analytic validation remain important.
5. Perform segregation testing in relatives and interpret variants under ACMG/AMP standards.

CMA, karyotyping, FISH, and repeat-expansion testing have low first-line yield unless another diagnosis is suspected. RNA sequencing may clarify splice variants but is not routine. Prenatal and preimplantation testing require a known familial pathogenic nuclear variant.

Biopsy and pathology

Muscle shows ragged-red fibers, subsarcolemmal mitochondrial accumulation, COX-negative fibers, and sometimes neurogenic changes. All 19 biopsied patients in the TWNK cohort had mitochondrial abnormalities; all 17 tested had multiple mtDNA deletions. In a mixed 89-patient mitochondrial PEO series, biopsy showed mitochondrial changes in 95% and molecular diagnosis was reached in 96%. Those mixed-cohort performance estimates should not be assigned specifically to adPEO. (bermejoguerrero2021clinicalhistologicaland pages 7-9, ali2024mitochondrialchronicprogressive pages 1-3)

Differential diagnosis

Important alternatives are myasthenia gravis, oculopharyngeal muscular dystrophy, congenital myasthenic syndromes, thyroid eye disease, orbital disease, cranial neuropathies, myotonic dystrophy, and other mitochondrial PEO etiologies. In the TWNK cohort, 56% were initially misdiagnosed—36% as myasthenia and 20% as oculopharyngeal muscular dystrophy—showing the real-world value of early molecular testing. (bermejoguerrero2021clinicalhistologicaland pages 1-2)

11. Outcome and prognosis

adPEO commonly causes chronic visual-functional and neuromuscular morbidity but isolated ocular disease is not usually directly fatal. Prognosis depends on PEO-plus involvement, particularly cardiac conduction disease/cardiomyopathy, respiratory weakness, dysphagia/aspiration, severe neuropathy, and central neurologic disease. No reliable adPEO-specific 5- or 10-year survival, mortality rate, or life-expectancy estimate was found.

Recovery of lost extraocular movement is not expected with current care. Ptosis and diplopia can be palliated, and rehabilitation may preserve function, but treatment does not remove the causal nuclear variant or accumulated mtDNA deletions. No validated molecular prognostic biomarker exists; genotype, age, deletion burden in muscle, respiratory-chain deficiency, cardiac involvement, dysphagia, and respiratory function are plausible clinical prognostic variables.

12. Treatment and current implementation

There is no approved disease-modifying therapy specifically for adPEO. The 2024 review states that “No definitive treatment option is available for mitochondrial diseases,” with management focused on lifestyle measures, supplements, and symptomatic relief such as ptosis repair. (ali2024mitochondrialchronicprogressive pages 1-3)

Symptomatic and supportive care

• Ptosis: lubricants and exposure prevention; ptosis crutch or eyelid tape in selected patients; cautious levator advancement or frontalis suspension. Surgery must account for poor Bell phenomenon and risk of exposure keratopathy. Suggested NCIT concepts: Supportive Care, Blepharoplasty/Ptosis Repair.
• Diplopia/ophthalmoplegia: prisms when deviation is suitable; selected strabismus surgery, with counseling that progression can alter alignment.
• Myopathy/fatigue: individualized submaximal aerobic/resistance exercise, physiotherapy, pacing, and fall prevention. NCIT: Physical Therapy, Exercise Therapy.
• Dysphagia: speech/swallow assessment, dietary modification, and aspiration prevention; enteral feeding if severe. In the TWNK cohort, no patient required enteral nutrition despite bulbar involvement. (bermejoguerrero2021clinicalhistologicaland pages 5-6)
• Hearing/vision: hearing aids or cochlear assessment; low-vision support where optic or retinal disease occurs.
• Cardiac/respiratory: ECG, echocardiographic and rhythm surveillance; pulmonary-function and sleep assessment when indicated; standard specialist treatment.

Coenzyme Q10, riboflavin, antioxidants, and other “mitochondrial cocktails” are often used empirically, but no adPEO-specific response rate or high-quality efficacy evidence was identified. Pharmacogenomic dosing guidance is not established.

Trials and advanced therapy

Relevant but nonspecific studies include NCT02161848, an observational MRI study in CPEO (completed; 133 participants); NCT04678115, a completed 16-participant trial of nonsurgical approaches for severe blepharoptosis; and NCT05162768, a completed phase III study of elamipretide in nuclear-DNA primary mitochondrial disease (102 participants). These records do not establish genotype-specific efficacy or standard-of-care use in adPEO.

Gene replacement/editing is conceptually more tractable for nuclear adPEO than for primary mtDNA mutations, but no approved TWNK-, POLG-, POLG2-, SLC25A4-, DNA2-, or RRM2B-directed gene therapy exists. LHON ND4 gene-therapy results and mitochondrial augmentation studies concern other disorders and should not be extrapolated to adPEO. (ali2024mitochondrialchronicprogressive pages 18-19)

13. Prevention

Primary prevention by lifestyle or medication is not currently possible. The principal preventive intervention is genetic counseling: molecular confirmation, cascade testing of adult relatives, and discussion of the 50% transmission risk. If a familial pathogenic variant is known, prenatal diagnosis and PGT-M are technically possible; reproductive decisions require nondirective counseling because penetrance and severity can be variable.

Secondary prevention consists of identifying presymptomatic carriers and detecting cardiac, respiratory, hearing, swallowing, visual, or neurologic complications early. Tertiary prevention includes fall and aspiration prevention, corneal protection, paced exercise, hearing support, and timely cardiac/respiratory care. Population newborn screening, vaccination, antimicrobial prophylaxis, and public-health environmental control are not disease-specific interventions.

14. Other species and natural disease

No well-established naturally occurring veterinary disorder directly equivalent to human adPEO was identified. Thus, breed prevalence, VBO identifiers, animal incidence, and veterinary management cannot currently be populated reliably. The disease is noninfectious and has no zoonotic or cross-species transmission potential.

The implicated genes are evolutionarily conserved across mammals and many eukaryotes, particularly POLG, TWNK, OPA1, and adenine nucleotide translocators. Conservation permits functional modeling, but orthologous-gene presence does not imply naturally occurring clinical adPEO.

15. Model organisms

Experimental systems include engineered mouse models affecting Twinkle, Polg, Slc25a4/Ant1, or Opa1; patient fibroblasts/myoblasts; transmitochondrial or cybrid systems; and Saccharomyces cerevisiae models of conserved mitochondrial maintenance genes. Twinkle mutants can reproduce replication stalling and progressive multiple-deletion/respiratory-chain pathology; polymerase-γ models interrogate replication fidelity and age-related mtDNA mutation accumulation.

Yeast is useful for rapid functional validation and phenotype-based drug screening because its mitochondrial biogenesis and metabolism are experimentally tractable. A 2023 review emphasizes that yeast has been used both “to validate alleged pathogenic variants” and to identify potentially beneficial molecules, although yeast lacks extraocular muscles and cannot reproduce the complete human phenotype.

Model limitations include species-specific eye-muscle physiology, differences in mtDNA replication and lifespan, severe phenotypes in some knockouts that do not match heterozygous adult disease, and failure of cultured cells to reproduce age-dependent clonal deletion expansion. Relevant resources include MGI, IMPC, IMSR, SGD, Cellosaurus, and the Alliance of Genome Resources.

Key recent and primary sources

• Ali A, Esmaeil A, Behbehani R. “Mitochondrial Chronic Progressive External Ophthalmoplegia.” Brain Sciences. Published January 2024. DOI: https://doi.org/10.3390/brainsci14020135. Abstract: “Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies…” (ali2024mitochondrialchronicprogressive pages 1-3)
• Chen BS et al. “Mitochondria and the eye—manifestations of mitochondrial diseases and their management.” Eye. Published April 2023. DOI: https://doi.org/10.1038/s41433-023-02523-x. The abstract notes that genotype–phenotype correlations “can be imprecise.” (chen2023mitochondriaandthe pages 1-2)
• Bermejo-Guerrero L et al. “Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)/PEO-Plus Due to TWNK Mutations.” Journal of Clinical Medicine. Published December 2021. DOI: https://doi.org/10.3390/jcm11010022. The abstract reports mean onset at 43 years, diagnosis at 63 years, ptosis in 92%, PEO in 80%, and prior misdiagnosis in 56%. (bermejoguerrero2021clinicalhistologicaland pages 1-2)
• Rodríguez-López C et al. “Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia.” Journal of Medical Genetics. Published March 2020. DOI: https://doi.org/10.1136/jmedgenet-2019-106649. The abstract reports “pure PEO” in 42%, mitochondrial biopsy changes in 95%, and genetic diagnosis in 96%; this was a mixed-etiology PEO cohort. (ali2024mitochondrialchronicprogressive pages 1-3)
• Viscomi C, Zeviani M. “MtDNA-maintenance defects: syndromes and genes.” Journal of Inherited Metabolic Disease. Published March 2017. DOI: https://doi.org/10.1007/s10545-017-0027-5. Its abstract states that these disorders can cause “mtDNA depletion, accumulation of mtDNA multiple deletions, or both.” (viscomi2017mtdnamaintenancedefectssyndromes pages 2-4)

Principal knowledge gaps

The most important unresolved fields are adPEO-specific prevalence and incidence, gene- and variant-specific penetrance, longitudinal progression rates, standardized patient-reported outcomes, validated prognostic biomarkers, environmental modifiers, cell-resolved multi-omics, and controlled genotype-specific treatment trials. Broader CPEO or mitochondrial-disease findings should remain separately annotated until directly validated in autosomal-dominant mtDNA-maintenance PEO.

References

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2. (bermejoguerrero2021clinicalhistologicaland pages 1-2): Laura Bermejo-Guerrero, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Pablo Serrano-Lorenzo, Alberto Blázquez-Encinar, Gerardo Gutiérrez-Gutiérrez, Laura Martínez-Vicente, Lucía Galán-Dávila, Jorge García-García, Joaquín Arenas, Nuria Muelas, Aurelio Hernández-Laín, Cristina Domínguez-González, and Miguel A. Martín. Clinical, histological, and genetic features of 25 patients with autosomal dominant progressive external ophthalmoplegia (ad-peo)/peo-plus due to twnk mutations. Journal of Clinical Medicine, 11:22, Dec 2021. URL: https://doi.org/10.3390/jcm11010022, doi:10.3390/jcm11010022. This article has 12 citations.

3. (ali2024mitochondrialchronicprogressive pages 1-3): Ali Ali, Ali Esmaeil, and Raed Behbehani. Mitochondrial chronic progressive external ophthalmoplegia. Brain Sciences, 14:135, Jan 2024. URL: https://doi.org/10.3390/brainsci14020135, doi:10.3390/brainsci14020135. This article has 25 citations.

4. (chen2023mitochondriaandthe pages 1-2): Benson S. Chen, Joshua P. Harvey, Michael J. Gilhooley, Neringa Jurkute, and Patrick Yu-Wai-Man. Mitochondria and the eye—manifestations of mitochondrial diseases and their management. Eye, 37:2416-2425, Apr 2023. URL: https://doi.org/10.1038/s41433-023-02523-x, doi:10.1038/s41433-023-02523-x. This article has 44 citations and is from a peer-reviewed journal.

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6. (bermejoguerrero2021clinicalhistologicaland pages 2-4): Laura Bermejo-Guerrero, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Pablo Serrano-Lorenzo, Alberto Blázquez-Encinar, Gerardo Gutiérrez-Gutiérrez, Laura Martínez-Vicente, Lucía Galán-Dávila, Jorge García-García, Joaquín Arenas, Nuria Muelas, Aurelio Hernández-Laín, Cristina Domínguez-González, and Miguel A. Martín. Clinical, histological, and genetic features of 25 patients with autosomal dominant progressive external ophthalmoplegia (ad-peo)/peo-plus due to twnk mutations. Journal of Clinical Medicine, 11:22, Dec 2021. URL: https://doi.org/10.3390/jcm11010022, doi:10.3390/jcm11010022. This article has 12 citations.

7. (bermejoguerrero2021clinicalhistologicaland pages 7-9): Laura Bermejo-Guerrero, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Pablo Serrano-Lorenzo, Alberto Blázquez-Encinar, Gerardo Gutiérrez-Gutiérrez, Laura Martínez-Vicente, Lucía Galán-Dávila, Jorge García-García, Joaquín Arenas, Nuria Muelas, Aurelio Hernández-Laín, Cristina Domínguez-González, and Miguel A. Martín. Clinical, histological, and genetic features of 25 patients with autosomal dominant progressive external ophthalmoplegia (ad-peo)/peo-plus due to twnk mutations. Journal of Clinical Medicine, 11:22, Dec 2021. URL: https://doi.org/10.3390/jcm11010022, doi:10.3390/jcm11010022. This article has 12 citations.

8. (ali2024mitochondrialchronicprogressive pages 13-14): Ali Ali, Ali Esmaeil, and Raed Behbehani. Mitochondrial chronic progressive external ophthalmoplegia. Brain Sciences, 14:135, Jan 2024. URL: https://doi.org/10.3390/brainsci14020135, doi:10.3390/brainsci14020135. This article has 25 citations.

9. (bermejoguerrero2021clinicalhistologicaland pages 5-6): Laura Bermejo-Guerrero, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Pablo Serrano-Lorenzo, Alberto Blázquez-Encinar, Gerardo Gutiérrez-Gutiérrez, Laura Martínez-Vicente, Lucía Galán-Dávila, Jorge García-García, Joaquín Arenas, Nuria Muelas, Aurelio Hernández-Laín, Cristina Domínguez-González, and Miguel A. Martín. Clinical, histological, and genetic features of 25 patients with autosomal dominant progressive external ophthalmoplegia (ad-peo)/peo-plus due to twnk mutations. Journal of Clinical Medicine, 11:22, Dec 2021. URL: https://doi.org/10.3390/jcm11010022, doi:10.3390/jcm11010022. This article has 12 citations.

10. (bermejoguerrero2021clinicalhistologicaland pages 6-7): Laura Bermejo-Guerrero, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Pablo Serrano-Lorenzo, Alberto Blázquez-Encinar, Gerardo Gutiérrez-Gutiérrez, Laura Martínez-Vicente, Lucía Galán-Dávila, Jorge García-García, Joaquín Arenas, Nuria Muelas, Aurelio Hernández-Laín, Cristina Domínguez-González, and Miguel A. Martín. Clinical, histological, and genetic features of 25 patients with autosomal dominant progressive external ophthalmoplegia (ad-peo)/peo-plus due to twnk mutations. Journal of Clinical Medicine, 11:22, Dec 2021. URL: https://doi.org/10.3390/jcm11010022, doi:10.3390/jcm11010022. This article has 12 citations.

11. (ali2024mitochondrialchronicprogressive pages 18-19): Ali Ali, Ali Esmaeil, and Raed Behbehani. Mitochondrial chronic progressive external ophthalmoplegia. Brain Sciences, 14:135, Jan 2024. URL: https://doi.org/10.3390/brainsci14020135, doi:10.3390/brainsci14020135. This article has 25 citations.

Artifacts

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