POLG and progressive external ophthalmoplegia: Pathogenic POLγA mutations are associated with the accumulation of secondary mtDNA mutations and/or progressive mtDNA depletion due to errors in DNA replication.3, –, 6 A common clinical manifestation of POLγA-related diseases is progressive external ophthalmoplegia (PEO), a disorder involving progressive weakening of the extraocular muscles that is frequently combined with symptoms from other parts of the neuromuscular and nervous system.