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chronic_progressive_external_ophthalmoplegia [2026/09/08 12:19] – created Scott Larsonchronic_progressive_external_ophthalmoplegia [2026/09/08 12:40] (current) – Scott Larson
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 ====== Chronic Progressive External Ophthalmoplegia ====== ====== Chronic Progressive External Ophthalmoplegia ======
 abbreviated CPEO  abbreviated CPEO 
 +
 +===== Overview =====
 +
 +**CPEO** is a **mitochondrial myopathy** that predominantly affects the extraocular muscles and the levator palpebrae, producing slowly progressive, generally **symmetric ophthalmoparesis** and **ptosis**. Because progression is gradual and symmetric, patients frequently do **not** report diplopia (<30%) and may be unaware of their motility deficit, often adopting a compensatory chin-up head posture.
 +
 +===== Onset and Course =====
 +
 +  * Typical onset in **adulthood** (commonly 18–40 years), with **ptosis** often the first sign.
 +  * **Slowly progressive** over years; forced ductions are free (myopathic, not restrictive) and **pupils are spared**.
 +  * **"CPEO-plus"**: pigmentary retinopathy, cerebellar ataxia, peripheral neuropathy, sensorineural hearing loss, cardiac conduction block, and diabetes. 
 +  * **Kearns-Sayre syndrome** defined as early-onset ophthalmoplegia and ptosis, pigmentary retinopathy, and cardiac conduction disease.
 +
 +===== Genetics =====
 +
 +  * Most commonly caused by a **single large-scale mtDNA deletion** (sporadic), but also by **mtDNA point mutations** and **nuclear mtDNA-maintenance genes** (e.g., **POLG, RRM2B, TWNK**).
 +  * **Heteroplasmy** matters: mutant load is far higher in skeletal muscle than in blood, so **negative peripheral blood testing does not exclude CPEO**.
 +
 +===== Diagnostic Evaluation =====
 +
 +  * **Clinical eye and systemic exam** — motility, lids, pupils, dilated fundus, cardiac review.
 +  * **Screening labs** — resting/post-exercise lactate and pyruvate, lactate:pyruvate ratio, creatine kinase, glucose/HbA1c; plus **ECG** given conduction-block risk.
 +  * **Exclude mimics** — myasthenia gravis (AChR/MuSK antibodies), oculopharyngeal and myotonic dystrophy.
 +  * **Muscle biopsy** (most accurate single test) — **ragged-red fibers** (Gomori trichrome) and **COX-negative / SDH-hyperintense fibers**; also enables respiratory-chain enzyme assays.
 +  * **Genetic testing** — whole mtDNA sequencing plus long-range PCR for deletions; **muscle is the optimal tissue**; nuclear gene panels when multiple deletions/depletion or a familial pattern is present.
 +
 +===== Key Points =====
 +
 +  * No blood test is confirmatory; diagnosis is **clinical + histochemical + genetic**.
 +  * A **negative blood mtDNA test does not rule out** the disease — proceed to muscle if suspicion is high.
 +  * Screen for and monitor **cardiac conduction disease**, a source of preventable morbidity/mortality.
  
 ====Compare CPEO with Congenital Fibrosis of EOM (CFEOM)==== ====Compare CPEO with Congenital Fibrosis of EOM (CFEOM)====
 ^Feature  ^CPEO ^CFEOM ^ ^Feature  ^CPEO ^CFEOM ^
 |Nature of disorder |Mitochondrial myopathy of extraocular muscle |Congenital cranial dysinnervation disorder (neurogenic; abnormal CN III/IV/VI development with secondary muscle fibrosis)| |Nature of disorder |Mitochondrial myopathy of extraocular muscle |Congenital cranial dysinnervation disorder (neurogenic; abnormal CN III/IV/VI development with secondary muscle fibrosis)|
-Onset Adult, typically 18–40 yrs; ptosis first sign [5-6] Congenital / present at birth [2, 7] +|Onset |Adult, typically 18–40 yrs; ptosis first sign |Congenital / present at birth | 
-Course Slowly progressive over years [1, 5] Non-progressive (rare exceptions) [4] +|Course |Slowly progressive over years |Non-progressive (rare exceptions)| 
-Symmetry / gaze Generally symmetric, diffuse limitation of all directions; superior rectus often prominently involved [8-9] Fixed characteristic pattern — CFEOM1: eyes fixed in infraduction, absent upgaze; CFEOM2: large-angle exotropia [7, 10] +|Symmetry / gaze |Generally symmetric, diffuse limitation of all directions; superior rectus often prominently involved |Fixed characteristic pattern — CFEOM1: eyes fixed in infraduction, absent upgaze; CFEOM2: large-angle exotropia| 
-Ptosis Common, may be uni- or bilateral, progressive [5] Congenital, typically bilateral; chin-up head posture [2, 7] +|Ptosis |Common, may be uni- or bilateral, progressive |Congenital, typically bilateral; chin-up head posture| 
-Diplopia Usually absent (<30%) due to gradual symmetric onset [11] Absent; binocular vision typically never develops [2] +|Diplopia |Usually absent (<30%) due to gradual symmetric onset|Absent; binocular vision typically never develops| 
-Pupils Spared Spared in CFEOM1; poorly reactive in CFEOM2 [10] +|Pupils |Spared |Spared in CFEOM1; poorly reactive in CFEOM2| 
-Inheritance / genetics Single large-scale mtDNA deletion (~50%, sporadic); also nuclear mtDNA-maintenance genes (POLG, RRM2B, TWNK) and mtDNA point mutations [6, 12] Mendelian: CFEOM1 (AD, KIF21A); CFEOM2 (AR, PHOX2A); CFEOM3 (AD, TUBB3/TUBB2B/TUBA1A/KIF21A) [10, 13] +|Inheritance / genetics |Single large-scale mtDNA deletion (~50%, sporadic); also nuclear mtDNA-maintenance genes (POLG, RRM2B, TWNK) and mtDNA point mutations |Mendelian: CFEOM1 (AD, KIF21A); CFEOM2 (AR, PHOX2A); CFEOM3 (AD, TUBB3/TUBB2B/TUBA1A/KIF21A)| 
-Systemic/associated features "CPEO-plus": retinopathy, ataxia, neuropathy, deafness, cardiac conduction block, diabetes (Kearns-Sayre) [8, 14] Usually isolated; CFEOM3 may have developmental/CNS anomalies (e.g., Tukel syndrome) [10] +|Systemic/associated features |"CPEO-plus": retinopathy, ataxia, neuropathy, deafness, cardiac conduction block, diabetes (Kearns-Sayre) |Usually isolated; CFEOM3 may have developmental/CNS anomalies (e.g., Tukel syndrome)| 
-Muscle biopsy Ragged-red / COX-negative fibers; mitochondrial abnormalities [5] Not a mitochondrial biopsy diagnosis; muscle shows fibrosis/denervation changes [7] +|Muscle biopsy |Ragged-red / COX-negative fibers; mitochondrial abnormalities| Not a mitochondrial biopsy diagnosis; muscle shows fibrosis/denervation changes| 
-Orbital MRI Mild EOM atrophy with fatty/spongiform T1 signal [4, 9] EOM hypoplasia + hypoplastic ocular motor nerves [2, 10]+|Orbital MRI |Mild EOM atrophy with fatty/spongiform T1 signal| EOM hypoplasia + hypoplastic ocular motor nerves| 
 + 
 +===== References ===== 
 + 
 +  - [[https://link.springer.com/article/10.1007/s11910-016-0652-7|McClelland C, Manousakis G, Lee MS. Progressive External Ophthalmoplegia. Curr Neurol Neurosci Rep. 2016.]] 
 +  - [[https://pubmed.ncbi.nlm.nih.gov/12849395/|McFarland R, Taylor RW, Turnbull DM. The Neurology of Mitochondrial DNA Disease. Lancet Neurol. 2002.]] 
 +  - [[https://pubmed.ncbi.nlm.nih.gov/41105897/|Li BY, Greenberg JH, Steigerwald C, et al. Pearls and Oy-Sters: Chronic Progressive External Ophthalmoplegia With Electrical Myotonia and Negative Initial Genetic Testing. Neurology. 2025.]] 
 +  - [[https://www.nature.com/articles/nrdp201680|Gorman GS, Chinnery PF, DiMauro S, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016.]] 
 +  - [[https://pubmed.ncbi.nlm.nih.gov/32161153/|Rodriguez-Lopez C, Garcia-Cardaba LM, Blazquez A, et al. Clinical, Pathological and Genetic Spectrum in 89 Cases of Mitochondrial Progressive External Ophthalmoplegia. J Med Genet. 2020.]] 
 +  - [[https://pubmed.ncbi.nlm.nih.gov/34146515/|Ng YS, Bindoff LA, Gorman GS, et al. Mitochondrial Disease in Adults: Recent Advances and Future Promise. Lancet Neurol. 2021.]] 
 +