Autosomal recessive progressive external ophthalmoplegia

Autosomal recessive progressive external ophthalmoplegia (arPEO) is a rare mitochondrial disorder characterized by progressive weakness and paralysis of the muscles that control eye movement (ophthalmoplegia) and drooping of the eyelids (ptosis). Unlike autosomal dominant forms of PEO, the recessive form tends to present earlier and may follow a more severe clinical course. The condition is caused by biallelic mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, leading to the accumulation of multiple mtDNA deletions in affected tissues. Genes associated with arPEO include POLG (DNA polymerase gamma), TWNK (Twinkle helicase), RRM2B, and DGUOK, among others. Mutations in POLG are the most commonly identified cause. Beyond the hallmark eye findings, arPEO can affect multiple body systems. Patients may develop generalized skeletal muscle weakness (myopathy), exercise intolerance, dysphagia (difficulty swallowing), and sensory or sensorimotor peripheral neuropathy. Depending on the underlying genetic defect, additional features may include sensorineural hearing loss, ataxia (impaired coordination), parkinsonism, depression, and cardiac conduction defects. Muscle biopsy typically reveals ragged red fibers and cytochrome c oxidase (COX)-negative fibers, reflecting mitochondrial dysfunction. The severity and range of symptoms can vary considerably even among individuals with the same genetic mutation. Currently, there is no curative treatment for arPEO. Management is supportive and symptomatic, focusing on optimizing quality of life. Ptosis may be addressed with surgical correction or eyelid crutches. Physical therapy can help maintain muscle function, and cardiac monitoring is recommended when conduction abnormalities are suspected. Genetic counseling is important for affected families. Coenzyme Q10 and other mitochondrial supplements are sometimes used, though evidence for their efficacy remains limited. Avoidance of mitochondrially toxic medications, particularly valproic acid in patients with POLG mutations, is critical to prevent potentially fatal hepatotoxicity.

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