Progressive external ophthalmoplegia (PEO) …

Neuromuscular Disorders

Updated 11.03.2025
Released 09.17.1993
Expires For CME 11.03.2028

Chronic progressive external ophthalmoplegia

Authors: Michelangelo Mancuso MD PhD, Piervito Lopriore MD

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Editor: Nicholas E Johnson MD MSCI FAAN

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Chronic progressive external ophthalmoplegia

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Introduction

Overview

Progressive external ophthalmoplegia, also known as chronic progressive external ophthalmoplegia, is a clinical syndrome of diverse causes that all share the combination of progressive ptosis and impaired mobility of the eyes, bilaterality, affection of muscles innervated by more than one nerve, sparing of pupils, gradual progression over months or years, absence of remissions or exacerbations, and absence of evidence of a specific disorder. Indeed, progressive external ophthalmoplegia represents the most common mitochondrial phenotype linked to pathogenic variants of mitochondrial or nuclear DNA that are critical for mitochondrial functions. Most cases are sporadic. Progress in understanding pathogenesis is lagging and, like many genetic diseases, treatment is needed. As newly discovered mutations continue to be found, more roads to etiology and pathogenesis continue to emerge.

Key points

	• Progressive external ophthalmoplegia represents the most common mitochondrial phenotype.
	• Single large-scale deletions of mtDNA are the most frequent causes of sporadic chronic progressive external ophthalmoplegia.
	• Mitochondrial DNA and nuclear-encoded gene mutations are responsible for inherited cases.
	• Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms.
	• Progressive external ophthalmoplegia can be isolated or associated with extramuscular features or present in the context of more complex mitochondrial syndromes.
	• Progress in understanding the pathogenesis is lagging, and, like many inherited diseases, disease-modifying treatments are needed.

Historical note and terminology

In 1890 Beaumont introduced the term “progressive nuclear ophthalmoplegia.” For several decades, the distinction between neurogenic and myopathic causes remained uncertain. In 1968, Rosenberg and colleagues identified neurogenic cases among ocular myopathies, prompting Drachman to introduce "ophthalmoplegia-plus" for multisystem presentations. Kearns-Sayre syndrome emerged as a distinct entity characterized by external ophthalmoplegia, retinitis pigmentosa, and heart block (41). The discovery of "ragged-red fibers" as markers of mitochondrial proliferation (59), combined with recognition of maternal inheritance in MERRF and MELAS, established the importance of mtDNA. Holt and colleagues found mtDNA single large-scale deletions in mitochondrial diseases (33), with Zeviani, DiMauro, and Schon localizing major deletions to Kearns-Sayre syndrome and sporadic progressive external ophthalmoplegia. The phenotypic spectrum expanded when Rotig and colleagues identified these deletions in Pearson syndrome (68). Concurrently, Wallace discovered mtDNA point mutations in Leber hereditary optic neuropathy (79), and others identified mutations in MELAS and MERRF. CPEO can also result from mutations in nuclear genes required for mtDNA maintenance (45). Although these discoveries resolved earlier debates about clinical significance, pathogenesis remains uncertain due to phenotypic heterogeneity and locus heterogeneity (19). Clinical syndrome definitions remain useful, but genetic classification is increasingly preferred (77).

According to international consensus from the 280th ENMC Workshop (November 2024), primary mitochondrial myopathies are defined as genetically determined mitochondrial disorders with prominent skeletal muscle involvement, comprising two major phenotypes: mitochondrial myopathy with chronic progressive external ophthalmoplegia and mitochondrial myopathy without progressive external ophthalmoplegia (46).

Clinical manifestations

Presentation and course

Chronic progressive external ophthalmoplegia is one of the most common clinical manifestations of primary mitochondrial disease. In the Nationwide Italian Collaborative Network, 55.3% of genetically confirmed patients had ocular myopathy (60), whereas in the North American Registry, ptosis and progressive external ophthalmoplegia were present in 29.4% and 20.6%, respectively (03).

The defining feature is ptosis, usually associated with symmetrical and progressive limitation of eye movements with normal pupils. Sometimes only ptosis persists for years, leading to compensatory chin-up head position. Although traditionally considered rare, diplopia occurs frequently in patients with CPEO (51). A comprehensive ophthalmological evaluation revealed that 84% of patients with progressive external ophthalmoplegia / progressive external ophthalmoplegia-plus presented exodeviation for distance, with 48% showing severe extraocular muscle impairment, reflecting a high prevalence of ocular misalignment (72). Facultative suppression preventing diplopia is common in patients with strabismus, reflecting the long disease course (51).

Some clinicians consider chronic CPEO a pure extraocular myopathy, whereas others regard it as a generalized myopathy with extraocular, oropharyngeal, and skeletal involvement (48; 60; 03). Most patients show clinical evidence of skeletal weakness or mitochondrial histological alterations (ragged-red fibers or cytochrome oxidase-negative fibers). Disease typically begins in childhood or adolescence, though later onset occurs.

Progressive external ophthalmoplegia may appear as the unique sign ("simple progressive external ophthalmoplegia") or as part of multisystem manifestations: gastrointestinal dysmotility (MNGIE), sensory ataxia (SANDO), cognitive impairment and ataxia (Kearns-Sayre syndrome), myoclonus and ataxia (MERRF), or stroke-like episodes (MELAS) are some examples. The Italian Network defined "progressive external ophthalmoplegia–plus" as ocular myopathy with additional neuromuscular and multisystem involvement (60).

In the Italian Registry cohort, pure progressive external ophthalmoplegia represented one third of all patients with progressive external ophthalmoplegia. Associated CNS features included ataxia (19.8%), cognitive impairment (13.5%), seizures (7.5%), and pyramidal signs (7.3%) (60). Systemic manifestations included muscle weakness (42.9%), exercise intolerance (23.1%), hearing loss (15.3%), and swallowing impairment (14.9%), with TYMP mutations specifically associated with muscle wasting (60). Disease severity is greater with onset before the age of 9 years old and milder with onset after the age of 20 (02).

CPEO, Kearns-Sayre syndrome, and Pearson syndrome represent overlapping phenotypes caused by mtDNA single large-scale deletions and typically occur as simplex cases (33). An invariant triad defines Kearns-Sayre syndrome: progressive external ophthalmoplegia, pigmentary retinopathy, and onset before the age of 20, plus at least one of the following of heart block, cerebrospinal fluid protein of 100 mg/dl or more, or disabling cerebellar syndrome (51).

Classic Kearns-Sayre syndrome criteria present limitations: arbitrary age cutoff, exclusion of associated features (hearing loss, failure to thrive, cognitive involvement, cardiomyopathy), and inability to classify many progressive external ophthalmoplegia patients with deletions. To address this, the Italian Network proposed simplified "Kearns-Sayre syndrome spectrum" criteria as ptosis/ophthalmoparesis plus at least one of the following: retinopathy, ataxia, cardiac defects, hearing loss, failure to thrive, cognitive involvement, tremor, or cardiomyopathy (48). This classification captured 64.5% as CPEO, 31.6% as Kearns-Sayre syndrome spectrum (6.6% classic), and 2.6% as Pearson disease. Deletion length correlated with Kearns-Sayre syndrome spectrum diagnosis, whereas heteroplasmy inversely correlated with age at onset (48).

Rodríguez-López and colleagues retrospectively analyzed 89 chronic progressive external ophthalmoplegia cases, identifying pure progressive external ophthalmoplegia (42%), Kearns-Sayre syndrome (10%), and progressive external ophthalmoplegia-plus (48%), concluding that phenotype-genotype correlations are unreliable and muscle biopsy should be the first diagnostic step when mitochondrial etiology is suspected (67). Zhao and colleagues studied 155 Chinese patients with mtDNA deletion, demonstrating that deletion length and location influence onset age and phenotype, with Kearns-Sayre syndrome patients harboring longer deletions affecting more respiratory chain and tRNA genes and muscle pathology severity correlating with systemic manifestations beyond extraocular muscles (83).

Prognosis and complications

A retrospective analysis of 69 patients with CPEO harboring mtDNA single large-scale deletions revealed that patients without neurologic involvement had later onset (median 17.5 vs. 12 years) and slower progression (02). In a 12-month follow-up study, patients with CPEO demonstrated better motor performance and lower disease severity than other mitochondrial myopathy phenotypes (54). A large international multicenter cross-sectional survey of 330 deceased patients with mitochondrial disorders showed that CPEO-plus had the longest survival among mitochondrial syndromes, with a median of 26.5 years (IQR: 22.8–40.2 years), compared to SANDO, with a median of 21.0 years (IQR: 13.8–28.5 years) (36). Respiratory failure (15.7%) and pulmonary infections (13.9%) were the most common causes of death, emphasizing the importance of respiratory care and infection management.

The prognosis of chronic CPEO depends on associated features, particularly severe limb weakness or cerebellar involvement. In Kearns-Sayre syndrome, cerebellar and cardiac involvement are typically the most disabling components and may shorten lifespan.

Clinical vignette

At 30 years of age, a woman noted bilateral ptosis with no diurnal variation or diplopia. Soon after, she started complaining about exercise intolerance and cramps. EMG was consistent with mild proximal myopathy. Creatine kinase serum level was 251 units (normal was 0 to 165). Cardiac evaluation showed no abnormality.

Family history was unremarkable, and no history of neuromuscular diseases was detected.

Examination. Bilateral ptosis was evident, and eye closure was weak. Eye movements were asymmetric. On lateral gaze in either direction, the adducting eye moved completely, but the abducting eye movement was incomplete. Vertical movements were normal. Speech and oropharynx were normal, as were the sternomastoids. Mild deltoid weakness was observed. There was no myotonia of grasp or percussion. Tendon reflexes were not elicited.

Diagnostic test. mtDNA next-generation sequencing in blood was negative, but analysis in urine revealed a heteroplasmic (about 30%) mtDNA single, large-scale deletion.

Biological basis

Etiology and pathogenesis

Chronic progressive external ophthalmoplegia is sporadic in approximately 50% of cases, with the remaining 50% inherited through autosomal dominant, autosomal recessive, or maternal transmission.

Sporadic chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome are the most common forms (75), typically caused by de novo mtDNA single large-scale deletions not transmitted to offspring (16), though sporadic cases may also result from tRNA gene mutations (09; 74) or other mtDNA point mutations (39).

Autosomal dominant and recessive forms are associated with multiple deletions or mtDNA depletion due to impaired nuclear-mitochondrial DNA interaction (30; 76). Numerous nuclear genes cause autosomal dominant progressive external ophthalmoplegia, including POLG1 (most common), POLG2, ANT1, TWNK, RRM2B, DNA2, GMPR, and OPA1 (51; 07; 34), with striking phenotypic variability even among related carriers. SPG7 has also been associated with progressive external ophthalmoplegia and multiple mtDNA deletions (62).

Autosomal recessive forms are less common and caused by mutations in TYMP, POLG1, DGUOK, TK2, RRM2B, RNASEH1, TOP3A, and C1QBP, leading to multiple deletions or depletion (32). Progressive external ophthalmoplegia typically appears as part of complex syndromes, such as MNGIE (TYMP mutations), characterized by ophthalmoplegia, sensorimotor neuropathy, gastroenteropathy, cachexia, and leukoencephalopathy in young adults (30; 31). RRM2B mutations affect nucleotide metabolism, producing similar MNGIE phenotypes (18). Evidence links biallelic ENDOG variants with progressive external ophthalmoplegia and segmental mitochondrial myopathy (56), whereas TOP3A variants, affecting mtDNA decatenation and segregation, cause chronic progressive external ophthalmoplegia (44).

Both POLG1 and RRM2B cause dominant and recessive forms: recessive RRM2B variants are loss-of-function, whereas dominant variants have dominant-negative effects (18). POLG variants reduce polymerase gamma activity, causing replication stalling and mtDNA maintenance defects, manifesting across a phenotypic continuum from childhood to adulthood (12).

Maternally inherited progressive external ophthalmoplegia associates with point mutations, particularly m.3243A>G (50; 70; 60) and other tRNA mutations (51). MERRF less commonly presents with progressive external ophthalmoplegia (approximately 5% in Italian cohorts), though ptosis occurs in 25% (47).

Studies using patient-derived iPSCs from Pearson syndrome (11; 61) and POLG1-related disease (52) revealed impaired mitochondrial function, reduced mtDNA copy numbers, and altered NAD+:NADH ratios, enabling detailed pathomechanism investigation and treatment validation.

A landmark study revealed distinct metabolic responses between extraocular and limb muscles in mitochondrial myopathy using the Deletor mouse model (63). Although large muscles upregulate glucose uptake and glycolytic metabolism with mitochondrial integrated stress response (ISRmt), extraocular muscles show opposite responses: PDK4-mediated inhibition of glucose and pyruvate oxidation, upregulation of fatty acid oxidation pathways, and lipid accumulation. This catabolic profile with low amino acid levels suggests reliance on amino acid oxidation for energy. These nonoptimal nutrient responses in extraocular muscles—particularly PDK4 activation and aberrant fuel selection—may explain their selective vulnerability and early atrophy in progressive external ophthalmoplegia (63).

Epidemiology

Childhood-onset primary mitochondrial disease is estimated to affect 5 to 15 per 100,000 individuals (23). In adults, the prevalence for mitochondrial diseases caused by mtDNA mutations is about 9.6 per 100,000, and it is 2.9 per 100,000 for nDNA mutations. Among these, the prevalence of single large-scale mtDNA deletions is 1.5 per 100,000, whereas autosomal dominant progressive external ophthalmoplegia is 0.7, m.3243A>G point mutation is 3.5, m.8344A>G is 0.2, OPA1 mutations is 0.4, POLG-related autosomal recessive disorders is 0.3, and RRM2B autosomal dominant disorders is 0.2 per 100,000 (24).

Within the Italian Collaborative Network, ptosis or ophthalmoparesis was the presenting sign in 42.8% of 1400 patients. In 722 patients with a definite genetic diagnosis, ocular myopathy was found in 55.3%, strongly associated with mtDNA single deletions (94.4%) and POLG1 mutations (82.6%), but rare in OPA1 mutations (93.1% had no ocular myopathy) and less frequent with mtDNA point mutations (62.9%) (60). Among ocular myopathy cases, 32.8% had encephalomyopathy, and 67.2% had no CNS involvement. Age at onset was higher in the progressive external ophthalmoplegia group (28.1 years) versus the encephalomyopathy group (17.6 years). Male proportion was lower in pure progressive external ophthalmoplegia than progressive external ophthalmoplegia-plus, related to higher m.3243A>G rates in males with encephalomyopathy. “Pure” progressive external ophthalmoplegia accounted for 36.6% and had similar onset and duration as other progressive external ophthalmoplegia types. The encephalomyopathy group had a higher prevalence of m.3243A>G, whereas single deletions (83.6%) and TWNK mutations (96%) were associated with the classic progressive external ophthalmoplegia phenotype. Other rare nuclear and mtDNA mutations mainly correlated with progressive external ophthalmoplegia plus encephalomyopathic features (60).

Differential diagnosis

Confusing conditions

Extraocular muscles are anatomically, biochemically, and immunologically distinct from other skeletal muscles, with features such as high fatigue resistance, rapid and precise movement, unique mitochondrial composition, and specialized innervation (82; 25). These properties explain both their functional versatility and their selective vulnerability in mitochondrial and neurogenetic disorders.

In chronic progressive external ophthalmoplegia, all extraocular muscles are progressively affected, leading to ptosis and symmetric limitation of eye movements. Initial involvement usually affects the levators, with thin eyelids and compensatory head posture developing as the disease advances. The central position of the eyes results from simultaneous involvement of all extraocular muscles, meaning strabismus and diplopia are rarely the predominant presentation; however, they can be present (51). Muscles such as orbicularis oculi may also be involved.

Mitochondrial disorders are distinguished by clues, such as maternal inheritance, coexisting retinopathy, sensorineural deafness, diabetes, short stature, lipomatosis, and histopathological “ragged-red fibers.” Red flags for syndromic mitochondrial disease include the classic constellations in MNGIE, SANDO, Kearns-Sayre syndrome, and Pearson syndrome; MNGIE neuropathy may even mimic CIDP (05).

Multiple genetic neuromuscular diseases present with ophthalmoplegia and should be included in the differential diagnosis: myotonic dystrophy types I/II, oculopharyngeal muscular dystrophy (OPMD), oculopharyngodistal myopathy (OPDM), several congenital myopathies, limb-girdle muscular dystrophy with ophthalmoplegia, and congenital cranial dysinnervation syndromes, such as congenital fibrosis of the extraocular muscles (CFEOM) (81). In CFEOM, maldevelopment of cranial nerves leads to nonprogressive ophthalmoparesis and ptosis, unlike the slow progression seen in mitochondrial disease.

Autoimmune myasthenia gravis is the primary acquired differential diagnosis and is recognized by variably fatigable weakness, preserved respiratory function, lack of lid atrophy, and diurnal fluctuation in symptoms; tests such as ice-pack, rest, and antibody detection (AchR, MUSK, LRP4) aid diagnosis, although ocular forms may have lower autoantibody rates (43).

Genetic myasthenic syndromes, usually autosomal recessive, present with generalized weakness but may involve isolated ocular muscle symptoms (20). Other acquired causes include Graves orbitopathy (marked by exophthalmos and MRI evidence of muscle thickening), Miller Fisher syndrome (with ataxia, areflexia, anti-GQ1b antibodies), and Wernicke encephalopathy (due to thiamine deficiency, reversible with supplementation).

Further neurogenic causes encompass amyotrophic lateral sclerosis (late-onset survivors), spinocerebellar ataxias, and abetalipoproteinemia (characterized by childhood-onset retinopathy, fatty diarrhea, low cholesterol, and peripheral neuropathy). Oculomotor apraxia type 1 presents with gaze restriction, exaggerated blinking, and slow saccades due to APRATAXIN mutations; CoQ10 deficiency may also be associated (64; 65). Progressive supranuclear palsy is characterized by early eye movement impairment alongside parkinsonism and cognitive changes.

Drug-induced and environmental causes include long-term antiretroviral therapy (with muscle MRI showing conserved volume), statin toxicity (with improvement on drug cessation), and various toxins. If pupils do not respond to light, "complete ophthalmoplegia" is indicated, pointing toward central or peripheral involvement and distinguishing from the typical external presentation.

Associated or underlying disorders

Diabetes mellitus occurs more frequently in patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia, though the association remains incompletely understood. Mitochondrial dysfunction may contribute to diabetes pathogenesis via pancreatic beta-cell impairment (mtDNA defects leading to reduced insulin production) and, in some cases, through skeletal muscle insulin resistance (38). Both mtDNA and nuclear gene mutations can be associated with diabetes; maternally inherited forms are typically caused by the MELAS m.3243A>G mutation (66). In patients with POLG-related chronic progressive external ophthalmoplegia, diabetes prevalence is around 11%, and OPA1 mutations have also been implicated (38). Among all patients with mtDNA deletions, the prevalence of diabetes ranges from 11% to 14% (38).

Parkinsonism is another recognized feature in chronic progressive external ophthalmoplegia, initially seen with mutations in ANT1, TWNK, and POLG1 (14), and more recently in MPV17 (22). Late-onset, mild, and stable parkinsonism, responsive to L-dopa, has been documented in TWNK-related cases (42). In a broad Italian cohort, parkinsonism was evident in 30.5% of adults with childhood-onset mitochondrial disease, especially those with POLG1 mutations (54; 55).

Autosomal dominant optic atrophy “plus” syndrome includes chronic progressive external ophthalmoplegia and is associated with neurologic sequelae, such as hearing loss, ataxia, and neuropathy (01). OPA1 mutations should be considered when bilateral optic atrophy accompanies chronic progressive external ophthalmoplegia, although most affected individuals do not report visual complaints but may show subclinical retinal nerve fiber loss (10).

Other frequent comorbidities are sleep and esophageal disorders, psychiatric symptoms (major depression, anxiety, panic, psychosis), and high rates of severe fatigue, pain, and dependency in daily life (73; 49; 40). Psychiatric conditions are more prevalent in mitochondrial disease than in other neuromuscular disorders and may reflect a direct mechanistic link. Somatic mtDNA mutations have been seen with increased “common deletion” levels in the brains of bipolar patients, especially frontal lobes (40). POLG1 mutations are associated with higher functional impairment but not with increased rates of fatigue, depression, or pain (73). Respiratory compromise may also occur (73).

Diagnostic workup

The “biopsy-first” diagnostic approach in suspected mitochondrial myopathies has largely been replaced by a “genetic-first” approach using next-generation sequencing, reflecting the high clinical and genetic heterogeneity of these disorders (08; 80). Clinical phenotyping, supported by biochemical and histochemical laboratory analyses, still guides initial targeted genetic testing (mtDNA or nDNA panels), but unbiased methods like whole-exome or genome sequencing are increasingly used when phenotypes are atypical (57).

Family history should be reviewed for evidence of maternal inheritance as the same mtDNA mutation may cause differing phenotypes within families, although most pure chronic progressive external ophthalmoplegia cases are simplex; some show Mendelian inheritance. The initial blood work-up should include complete blood count, creatine phosphokinase, transaminases, albumin, lactate, and pyruvate; EMG may help confirm proximal myopathy (06).

Kearns-Sayre syndrome work-up should involve brain imaging, ECG, cerebrospinal fluid analysis, EMG, nerve studies, retinal and audiological assessment, and screening for diabetes, hypoparathyroidism, and hypoadrenalism. Nuclear gene defects can be checked in blood, but if an mtDNA mutation is suspected, analysis should favor muscle due to possible tissue restriction; urine testing for m.3243A>G and recent advances for mtDNA single deletions in urine can expand detection (78). MNGIE may be screened with blood thymidine levels (58). Muscle biopsy should still be considered when genetic tests are negative or discordant, allowing confirmation of diagnostic histopathological features. Muscle should, when available, also be sent for mtDNA analysis and enzyme assays.

In general, blood DNA sequencing is recommended as first-line for suspected primary mitochondrial myopathies; importantly, normal respiratory chain function does not exclude primary mitochondrial myopathies, especially in adults. Muscle biopsy remains indicated in unresolved cases or for diagnostic confirmation, and mtDNA deletions are better detected in muscle and urine than in blood (46).

Key differential diagnoses include myasthenia gravis (AchR/MUSK antibodies, repetitive stimulation, chest CT), Graves disease (TSH/fT4, orbital imaging), abetalipoproteinemia or MNGIE (malabsorption, serum cholesterol, GI work-up), and syndromic ataxias or motor neuron diseases (53; 28). Notably, mitochondrial disease rarely mimics classic motor neuron disease.

Table 1 sums up a clinical-molecular classification of chronic progressive external ophthalmoplegia.

Table 1. Genetic Causes of Chronic Progressive External Ophthalmoplegia and Related Syndromes

Genetic alteration	Inheritance	PEO phenotypes
Single large-scale mtDNA deletion	Sporadic	cPEO/KSS/PMPS
AFGL2	AD	cPEO plus
C1QBP	AR	cPEO
DGUOK	AR	cPEO
DNA2	AD	cPEO
ENDOG	AR	cPEO
GMPR	AD	cPEO
LIG3	AR	MNGIE-like
MGME1	AR	cPEO
OPA1	AD	cPEO plus (optic atrophy)
POLG	AD/AR	cPEO/cPEO plus/SANDO/MNGIE-like
POLG2	AD/AR	cPEO
RNASEH1	AR	cPEO/cPEO plus
RRM1	AD/AR	cPEO/MNGIE-like
RRM2B	AD/AR	cPEO/KSS/MNGIE-like
SLC25A4 (ANT1)	AD/AR	cPEO
SPG7	AR	cPEO plus
TK2	AR	cPEO/cPEO-plus
TOP3A	AR	cPEO plus
TWNK	AD/AR	cPEO
TYMP	AR	MNGIE
MT-TF	matrilinear	cPEO
MT-TL1 (m 3243A> G the most common)	matrilinear	cPEO/cPEO plus
MT-TA	matrilinear	cPEO
MT-TE	matrilinear	cPEO
MT-TI	matrilinear	cPEO/cPEO plus
MT-TN	matrilinear	cPEO
AD: autosomal dominant; AR: autosomal recessive; cPEO: chronic progressive external ophthalmoplegia; KSS: Kearns-Sayre syndrome; MNGIE: mitochondrial neurogastrointestinal encephalomyopathy; PMPS: Pearson marrow pancreas syndrome; SANDO: sensory ataxic neuropathy, dysarthria and ophthalmoplegia

Single, large-scale mtDNA deletions or nuclear gene defects associated with disordered mtDNA maintenance resulting in multiple mtDNA deletions are frequently associated with progressive external ophthalmoplegia. mtDNA point mutations are rarely detected in patients with progressive external ophthalmoplegia. For mtDNA point mutations, only the name of the mt-gene, and not the specific variants reported in the literature, are reported. Note that all these genes may be associated with other mitochondrial syndromes here not repositioned. More information can be found at https://www.mitomap.org/.

Management

Management of chronic progressive external ophthalmoplegia is largely supportive and multidisciplinary, focusing on symptom relief and monitoring for multisystem involvement. Ptosis can be managed surgically, but procedures such as levator resection, frontalis/brow suspension, or eyelid slings require careful preoperative assessment given the risk of corneal exposure and recurrence due to disease progression (37; 71; 17). Nonsurgical options include eyelid crutches, though these are often poorly tolerated. Choice of procedure depends on levator function, and brow suspension may offer greater eyelid elevation but has its own postoperative risks. Prismatic glasses and strabismus surgery may address diplopia and misalignment, but recurrence is possible due to the progressive nature of muscle dysfunction (17).

Children with Kearns-Sayre syndrome require early cardiac assessment and documentation for pacemaker implantation due to the risk of heart block. Associated diabetes, hearing loss, and hypoparathyroidism should be managed per standard guidelines (27).

For disorders with malabsorption (eg, abetalipoproteinemia), vitamin E supplementation may improve neurologic disability. For MNGIE, beyond standard symptomatic care and nutritional support, experimental approaches include enzyme replacement therapy, stem cell transplantation, and, more recently, liver transplantation, with limited supporting evidence (29; 04; 13).

Ongoing clinical trials are seeking targeted or disease-modifying therapies for various mitochondrial syndromes, but no definitive treatments for chronic progressive external ophthalmoplegia or related mitochondrial myopathies exist to date. For updates on interventional studies, see www.clinicaltrials.gov.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Michelangelo Mancuso MD PhD

Dr. Mancuso of the University Hospital of Pisa has no relevant financial relationships to disclose.
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Piervito Lopriore MD

Dr. Lopriore of the University of Pisa has no relevant financial relationships to disclose.
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Editor

Nicholas E Johnson MD MSCI FAAN

Dr. Johnson of Virginia Commonwealth University received consulting fees and/or research grants from AMO Pharma, Avidity, Dyne, Novartis, Pepgen, Sanofi Genzyme, Sarepta Therapeutics, Takeda, and Vertex, consulting fees and stock options from Juvena, and honorariums from Biogen Idec and Fulcrum Therapeutics as a drug safety monitoring board member.
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Former Authors

Lewis P Rowland MD
Elena Caldarazzo Ienco MD
Emma Ciafaloni MD FAAN

Patient Profile

Age range of presentation: 1 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor

autosomal dominant

autosomal recessive

mitochondrial DNA inheritance (matrilinear)
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Progressive external ophthalmoplegia: H49.4
ICD-11: Progressive external ophthalmoplegia: 9C82.0
OMIM: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 1: #157640

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2: #609283

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3: #609286

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 4: #610131

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive: #258450

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Chronic progressive external ophthalmoplegia

Associated Disorders

diabetes mellitus
parkinsonism
dominant optic atrophy
sleep and esophageal disorders
psychiatric symptoms
- high rates of severe fatigue, pain, and dependency in daily life
- somatic mtDNA mutations
- POLG1 mutations
- respiratory compromise

Differential Diagnosis

myotonic dystrophy types I/II
oculopharyngeal muscular dystrophy (OPMD)
oculopharyngodistal myopathy (OPDM)
several congenital myopathies
limb-girdle muscular dystrophy with ophthalmoplegia
- congenital cranial dysinnervation syndromes
- fibrosis of the extraocular muscles (CFEOM)
- autoimmune myasthenia gravis
- genetic myasthenic syndromes
- Graves orbitopathy
- Miller Fisher syndrome
- Wernicke encephalopathy
- amyotrophic lateral sclerosis (late-onset survivors)
- spinocerebellar ataxias
- abetalipoproteinemia
- oculomotor apraxia type 1
- CoQ10 deficiency
- progressive supranuclear palsy
- long-term antiretroviral therapy
- statin toxicity
- various toxins

Also Relevant

Kearns-Sayre syndrome
MELAS
Mitochondrial disorders
Myoclonus epilepsy with ragged-red fibers
POLG-related disorders

Chronic progressive external ophthalmoplegia

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 1. Genetic Causes of Chronic Progressive External Ophthalmoplegia and Related Syndromes

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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