Progressive external ophthalmoplegia

ALSO KNOWN AS: PEO

DEFINITION Progressive external ophthalmoplegia (PEO) is a mitochondrial myopathy disorder that is characterized by painless, slowly progressive paralysis of certain eye muscles. PEO is typically caused by a mitochondrial DNA (mtDNA) deletion in the skeletal muscle during oogenesis or embryogenesis.

Risk Factors

Males and females are affected equally by this mutation. Onset of symptoms tends to begin in young adulthood. Although the mutation occurs almost always as a sporadic point mutation, it can be inherited as a point mutation of maternal mitochondrial tRNA or as autosomal dominant and autosomal recessive deletions of mtDNA, with the autosomal recessive inheritance usually being more severe. However, the mother of a child with PEO is usually unaffected. The risk to siblings is extremely low as no cases of maternal transmission to more than one child have been reported. The offspring of males with an mtDNA mutation are not at risk.

Etiology and Genetics

Mitochondrial diseases affect the mitochondria, which are found in almost all cells and are responsible for providing the energy that cells need to survive. Since most cells rely on mitochondria for energy, a mitochondrial disease can affect many different types of cells. When a mitochondrial disease causes prominent muscular complications, it is called a mitochondrial myopathy. PEO is a mitochondrial myopathy that is characterized by slowly progressive paralysis of the six muscles that control the movement of the human eye (extraocular muscles).

PEO involves multiple mtDNA deletions in the skeletal muscles. Several types of deletions of varying lengths have been identified in PEO. Most mitochondrial DNA deletions associated with PEO typically range in size from two to ten kilobases. The same person may have variable proportions of deleted mtDNA in different tissues throughout their body which can ultimately determine how significantly the tissue is clinically affected. However, no correlation exists between the size or location of the mtDNA deletion and phenotype.

Mitochondrial DNA deletions are almost always caused by a point mutation. Specifically in PEO, deletions of mtDNA have been identified by mutations in the MT-TL1 mitochondrial gene as well as in SLC25A4, POLG, and C10orf2, which are nuclear genes involved with mtDNA maintenance. When PEO is caused by MT-TL1 mutations, it is always transmitted by ; various mtDNA point mutations have been found in people with maternally inherited PEO. When PEO is the result of mutations in nuclear genes, the inheritance pattern is usually autosomal dominant. Some mutations in the POLG nuclear gene cause PEO inherited via an autosomal recessive pattern, while somatic mutations in this gene are not inherited but happen during a person's lifetime (GHR 2014).

Symptoms

Severity and phenotypic variability of symptoms vary greatly with PEO. This often makes an early diagnosis more difficult. The most consistent symptoms usually begin to manifest in late adolescence or young adulthood. Symptoms typically progress slowly. The defect in ocular motility is usually bilateral and symmetric so most patients do not complain of double vision. Primary symptoms include reduced superior visual field, corneal dryness and ulceration due to poor blinking reflexes, droopy eyelids, loss of Bell’s reflex (eyes roll upward when lids are closed), muscle weakness and wasting, exercise intolerance, muscle cramps, and low energy.

Screening and Diagnosis

Diagnosis of PEO relies upon the presence of characteristic physical findings as well as through laboratory and imaging studies. When PEO is suspected, a complete ophthalmologic exam including a dilated retinal exam, a cranial nerve test, and a forced duction test should be performed. Thin, symmetrical extraocular muscles are often found during magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound studies. Laboratory testing is often used to differentiate between PEO and other conditions with similar physical symptoms (such as myasthenia gravis). Serum creatine is usually measured since this may be elevated in mitochondrial disease. In addition, deletions in mtDNA in PEO patients can be detected in muscle tissue by analysis of samples taken from a muscle biopsy. Genetic tests can be performed to screen for known mutations/deletions.

Treatment and Therapy

There is no cure for PEO, but treatments do exist for the alleviation of some of the associated symptoms. Mechanical devices such as placement of eyelid slings have helped to decrease severe drooping. Surgical procedures can also be performed to lift a drooping eyelid. However, since poor blink responses are often associated with PEO, the cornea of the eye can become dry or scratched following surgical intervention. The use of artificial tears and/or eye patching at night can often help to alleviate this problem. Recently, dietary supplements such as coenzyme Q10 and L-carnitine, which are involved in increasing ATP production in the cells, have shown modest results in some people. Physical and occupational therapy as well as treatments aimed at preventing/treating symptoms of depression which are often present in people suffering from a chronic disease are also frequently incorporated into the overall treatment strategy for PEO.

Prevention and Outcomes

There is no effective means of prevention of PEO. Genetic counseling enables people to make more informed medical and personal decisions and should always be encouraged and available to patients and their families especially regarding options for at-risk mothers. PEO is not a fatal disease; however, associated disabilities may affect mortality.

Bibliography

Ali, Ali, Ali Esmaeil, and Raed Behbehani. "Mitochrondrial Chronic Progressive External Opthalmoplegia." Brain Sciences, vol. 14, no. 2, 27 Jan. 2024, p. 135, doi.org/10.3390/brainsci14020135. Accessed 9 Sept. 2024.

Bau, Viktoria, and Stephan Zierz. “Update on Chronic Progressive External Ophthalmoplegia.” Strabismus13.3 (2005): 133–142. Print.

Cohen, Bruce H., Patick F. Chinnery, and William C. Copeland. "POLG-Related Disorders." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 11 Oct. 2012. Web. 19 Aug. 2014.

DiMaura, Salvatore, and Michio Hirano. "Mitochondrial DNA Deletion Syndromes." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 3 May 2011. Web. 19 Aug. 2014.

Genetics Home Reference. "Progressive External Ophthalmoplegia." Genetics Home Reference. US NLM, 18 Aug. 2014. Web. 19 Aug. 2014.

Lewin, Benjamin. Genes X. 10th ed. Sudbury: Jones, 2011. Print.

Riordan-Eva, Paul, et al. Vaughan & Asbury’s General Ophthalmology. 18th ed. New York: McGraw, 2011. Print.