• Chronic Progressive External Ophthalmoplegia (CPEO) is a frequent manifestation of mitochondrial cytopathies, a group of disorders characterized by dysfunction of the mitochondria due to mutations in mitochondrial DNA (mtDNA) or in nuclear genomes that code for mitochondrial components.
• CPEO is not a nosologic entity and is only a sign in the clinical spectrum of mitochondrial cytopathies, in which the heart, central nervous system, and endocrine disturbances can occur.
• Kearns-Sayers syndrome (KSS) is a clinical phenotype of mitochondrial cytopathy defined as CPEO and pigmentary retinopathy before the age of 20 years and at least one of the following: Complete heart block, high CSF protein (>1 mg/mL), cerebellar ataxia, and endocrine disturbances.
Cardiac conduction defects can be lethal and should be ruled out in patients with suspected CPEO, especially KSS.
CPEO typically have an onset in childhood or early adolescence but they can occur at any age.
• Most cases of CPEO are due to sporadic single mutations in the mitochondrial DNA occurring during the maternal oocyte stage, which is propagated to all future mtDNA during embryogenesis. These single large mutations cause large gene rearrangements in mitochondrial DNA (1).
• Autosomal dominant and autosomal recessive forms of inheritance (nuclear inheritance) are less frequent and some nuclear genes have been implicated including TP, ANTI, Twinkle, POLG1, POLG2, and OPA1 (2).
• Cells have multiple mitochondria, which can have different variations in mutant and wild-type mtDNA. This condition is referred to as heteroplasmy and occurs because of the non-random nature of mtDNA replication.
• When a certain tissue reaches a certain ratio of mutant versus wild-type mitochondria, a disease will present itself (threshold expression).
• Tissues high in energy demand such as the heart, central nervous system, skeletal muscles have low tissue-specific threshold of expression.
• The mitochondria is responsible for production of ATP by oxidative phosphorylation, the detoxification of reactive oxygen species, regulation of cell apoptosis, and other functions such iron metabolism, fatty acid oxidation, and amino acid biosynthesis.
• The protein complexes carrying out oxidative phosphorylation are partly encoded by mitochondrial genome (complex I, III, IV, ATP synthetase) and complex II is encoded exclusively by nuclear genome.
• The majority of mitochondrial proteins are encoded by nuclear genome and are transported into the mitochondria. Therefore, nuclear gene mutation can result in mitochondrial dysfunction.
COMMONLY ASSOCIATED CONDITIONS
• Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS)
– A phenotype characterized by the triad of 1) stroke-like episodes before the age of 40, 2) encephalopathy with seizures or dementia and, 3) lactic acidosis and/or ragged red fibers
– 79% of patients with MELAS will have homonymous hemianopsia due involvement of the retrochiasmal visual pathways in the occipital and parietal lobes.
• Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
– Autosomal recessive CPEO in association with peripheral neuropathy, leukoencephalopathy and gastrointestinal symptoms (nausea, vomiting, diarrhea)
• Myelonic epilepsy with ragged-red fibers (MERRF)
• Progressive myoclonic epilepsy, ataxia, optic atrophy, and/or dementia
• Progressive ptosis.
• Muscle weakness (limbs)
• Decreased vision and night blindness.
• Hearing loss
• Short stature/skeletal abnormalities
• Seizures or stroke-like episodes.
• Absence of family history does not exclude CPEO
• Symmetric ophthalmoplegia sparing the pupils
• Facial/limb weakness
• Pigmentary (salt-pepper) retinopathy in KSS
DIAGNOSTIC TESTS & INTERPRETATION
Initial lab tests
– Routine blood tests (CBC and electrolytes) and endocrine work up (Hb A1c, TSH, thyroxine)
– Serum creatinine kinase and resting lactate can be elevated
– Acetylcholine receptor antibodies to rule out myasthenia gravis
– High CSF protein in KSS (>1 mg/mL) and high lactate in MELAS
– Electrocardiography to rule out cardiac conduction defects and cardiac hypertrophy are essential in all cases of suspected CPEO
Follow-Up & Special Considerations
• Electroretinography (ERG)
– In pigmentary retinopathy in KSS, ERG can be normal or show rod, cone, or mixed rod-cone dysfunction.
• Neuroimaging of the orbit and brain is recommended to rule out other causes of ophthalmoplegia.
– MRI of the orbits: Thin extraocular muscles
– MRI of the brain: White matter and basal ganglia hyperintensities (KSS), cortical and cerebellar atrophy (3)
– MR spectroscopy: Large lactate peaks within the stroke-like lesions (MELAS)
• Skeletal muscle biopsy
– The gold standard test for diagnosis
– Staining with Gomori Trichrome stain will show ragged-red fibers in 50% of cases of CPEO.
– Biochemical stains for mitochondrial respiratory chain (I,II,IV) to show defects in oxidative phosphorylation enzymes
– Polymerase chain reaction (PCR) has been recently used to detect mutations in swabbed buccal cells.
• Ragged-red fibers are classic histological hallmarks of CPEO and represent large accumulation of enlarged mitochondria beneath the sarcolemma.
• Transmission electron microscopy can show paracrystalline (“parking-lot”) inclusions inside the abnormal mitochondria.
• Myogenic ptosis
– Congenital fibrosis syndrome
– Congenital myopathy (Myotonic dystrophy)
– Oculopharyngeal dystropy
• Neuromuscular disease
– Myasthenia Gravis
• There is no known effective treatment for CPEO and treatment is mainly symptomatic.
– Surgical treatment of severe ptosis can be beneficial in patients with CPEO. Lid surgery should be done with care since Bell’s phenomenon is often weak, which can result in exposure keratopathy.
– Strabismus surgery can be offered to patients suffering from diplopia.
• Treatment of endocrine disturbances such as hyperglycemia with anti-hyperglycemic agents
• Cardiac conduction defects should be treated with pacemakers.
• Seizures can be treated with anti-epileptics.
• Cochlear implant can be offered to patients with neurosensory deafness.
Issues for Referral
Cardiac and endocrinological manifestations can be serious and should be managed by specialists.
COMPLEMENTARY & ALTERNATIVE THERAPIES
Non-proven measures such as the supplementation of vitamins (vitamin C, thiamine, B12, vitamin E), cofactors (Coenzyme q10) can be provided and they are not toxic in their usual doses. (4)
• Avoidance of mitochondrial stressors (tobacco, excessive alcohol intake) is a nonspecific, yet prudent recommendation.
• Genetic counseling
– Most cases of CPEO are due to sporadic mutations with only 4% risk of transmission from mother to child.
– Men and women with nuclear DNA mutations need to be counseled about the risk of transmission depending on the mode of inheritance.
– Men with mitochondrial mutations need to be reassured that they cannot transmit the disease to their offspring.
Course: Chronic, slowly progressive.
• Cardiac conduction defects
• Endocrine disturbances
1. Cardaioli E, da Pozzo P, Malfatti E, et al. Chronic progressive external ophthalmoplegia: A new heteroplasmic tRNA Leu (CUN) mutation of mitochondrial DNA. J Neuro Sci 2008;272:106–9.
2. Ammati-Bonneau P, Valentino ML, Reynier P, et al. OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotype. Brain 2008;131:338–51.
3. Barragán-Campos HM, Vallée JN, Lô D, et al. Brain magnetic resonance imaging findings in patients with mitochondrial cytopathies. Arch Neurol 2005;62:737–42.
4. Rotig A, Appelkvist EL, Geromel V, et al. Quinine-responsive multiple respiratory chain dysfunction due to widespread coenzyme q10 deficiency. Lancet 2000;356:391–5.