Chronic Progressive External Ophthalmoplegia
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)
| 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) |
| Onset | Adult, typically 18–40 yrs; ptosis first sign | Congenital / present at birth |
| Course | Slowly progressive over years | Non-progressive (rare exceptions) |
| 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 | Congenital, typically bilateral; chin-up head posture |
| Diplopia | Usually absent (<30%) due to gradual symmetric onset | Absent; binocular vision typically never develops |
| 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 | 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) | Usually isolated; CFEOM3 may have developmental/CNS anomalies (e.g., Tukel syndrome) |
| 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 | EOM hypoplasia + hypoplastic ocular motor nerves |