A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat.The mtDNA that is affected maybe a single or multiple point deletion, with associated nuclear DNA deletions. One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the Twinkle gene which encodes specific mitochondrial protein; Twinkle.Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion.In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA. However, transmission from the mother to the progeny appears only in few cases. Both autosomal dominant and autosomal recessive inheritance can occur, autosomal recessive inheritance being more severe. Dominant and recessive forms of PEO can be caused by genetic mutations in the ANT1, POLG, POLG2 and PEO1 genes. Diagnosis
It is important to differentiate CPEO from other pathologies that may cause an ophthalmoplegia. There are specific therapies used for these pathologies.CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with Gömöri trichrome stain, one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name "ragged red fibers". While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy.
Facial muscles may be involved which lead to atrophy of facial muscle groups producing a thin, expressionless face with some having difficulty with chewing. Neck, shoulder and extremity weakness with atrophy may affect some patients and can be mild or severe.Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14).The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO.Additional symptoms are variable, and may include exercise intolerance, cataracts, hearing loss, sensory axonal neuropathy, ataxia, clinical depression, hypogonadism, and parkinsonism.Kearns–Sayre syndrome is characterized by onset before 15 years of age of CPEO, heart block and pigmentary retinopathy. Genetics
Mitochondrial DNA which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce adenosine triphosphate (ATP). Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation. This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue. However, extraocular muscles contain a volume of mitochondria that is several times greater than any other muscle group. As such, this results in the preferential ocular symptoms of CPEO.Multiple mtDNA abnormalities exist which cause CPEO. One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition. This mutation is associated with both CPEO and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).