Autosomal dominant progressive external ophthalmoplegia

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a rare mitochondrial disorder characterized by the progressive weakening and paralysis of the muscles that control eye movement (ophthalmoplegia) and drooping of the eyelids (ptosis). Unlike maternally inherited mitochondrial diseases, adPEO is caused by mutations in nuclear genes that are essential for mitochondrial DNA (mtDNA) maintenance, leading to the accumulation of multiple mtDNA deletions in affected tissues, particularly skeletal muscle. Several genes have been implicated, including POLG (DNA polymerase gamma), TWNK (formerly C10orf2, encoding the Twinkle helicase), ANT1 (SLC25A4), RRM2B, and POLG2. The condition is inherited in an autosomal dominant pattern, meaning a single copy of the mutated gene from one parent is sufficient to cause the disease. Symptoms typically begin in adulthood, usually between the second and fourth decades of life. The hallmark features are bilateral ptosis and progressive limitation of eye movements, which develop slowly over years. Importantly, patients rarely experience double vision (diplopia) because the ophthalmoplegia affects both eyes symmetrically. Beyond the eyes, many patients develop generalized skeletal muscle weakness (myopathy), exercise intolerance, and fatigue. Depending on the specific gene involved, additional features may include sensorineural hearing loss, peripheral neuropathy, ataxia, depression, parkinsonism, cataracts, and cardiac conduction defects. Muscle biopsy typically reveals ragged red fibers and cytochrome c oxidase-negative fibers, reflecting underlying mitochondrial dysfunction. There is currently no cure for adPEO, and treatment is primarily supportive and symptomatic. Management may include surgical correction of ptosis (frontalis sling or blepharoplasty) to improve vision when eyelid drooping becomes functionally significant. Physical therapy and exercise programs can help maintain muscle strength and function. Coenzyme Q10 supplementation is sometimes used, though evidence for its efficacy remains limited. Regular monitoring by a multidisciplinary team including ophthalmologists, neurologists, and cardiologists is recommended to address the various systemic manifestations that may arise over the course of the disease.

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