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Genetics Home Reference: your guide to understanding genetic conditions
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Progressive external ophthalmoplegia

Reviewed June 2011

What is progressive external ophthalmoplegia?

Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40. The most common signs and symptoms of progressive external ophthalmoplegia are drooping eyelids (ptosis), which can affect one or both eyelids, and weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals may also have general weakness of the skeletal muscles (myopathy), particularly in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).

When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of structures called mitochondria and are known as ragged-red fibers. Additionally, a close study of muscle cells may reveal abnormalities in a type of DNA found in mitochondria called mitochondrial DNA (mtDNA). Affected individuals often have large deletions of genetic material from mtDNA in muscle tissue.

Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, or depression.

Progressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include other conditions caused by POLG gene mutations, such as ataxia neuropathy spectrum, as well as other mtDNA deletion disorders, such as Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.

How common is progressive external ophthalmoplegia?

The prevalence of progressive external ophthalmoplegia is unknown.

What are the genetic changes related to progressive external ophthalmoplegia?

Progressive external ophthalmoplegia is a condition caused by defects in mitochondria, which are structures within cells that use oxygen to convert the energy from food into a form cells can use. This process is called oxidative phosphorylation. Although most DNA is packaged in chromosomes within the nucleus (nuclear DNA), mitochondria also have a small amount of their own DNA, called mitochondrial DNA (mtDNA).

Progressive external ophthalmoplegia can result from mutations in several different genes. In some cases, mutations in the MT-TL1 gene, which is located in mtDNA, cause progressive external ophthalmoplegia. In other cases, mutations in nuclear DNA are responsible for the condition, particularly mutations in the POLG, SLC25A4, and C10orf2 genes. These genes are critical for mtDNA maintenance. Although the mechanism is unclear, mutations in any of these three genes lead to large deletions of mtDNA, ranging from 2,000 to 10,000 DNA building blocks (nucleotides).

Researchers have not determined how deletions of mtDNA lead to the specific signs and symptoms of progressive external ophthalmoplegia, although the features of the condition are probably related to impaired oxidative phosphorylation. It has been suggested that eye muscles are commonly affected by mitochondrial defects because they are especially dependent on oxidative phosphorylation for energy.

Related Gene(s)

Changes in these genes are associated with progressive external ophthalmoplegia.

  • C10orf2
  • MT-TL1
  • POLG
  • SLC25A4

How do people inherit progressive external ophthalmoplegia?

Progressive external ophthalmoplegia can have different inheritance patterns depending on the gene involved.

When this condition is caused by mutations in the MT-TL1 gene, it is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only mothers pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.

When the nuclear genes POLG, SLC25A4, or C10orf2 are involved, progressive external ophthalmoplegia is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Certain mutations in the POLG gene can also cause a form of the condition that is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Some mutations in the POLG gene that cause progressive external ophthalmoplegia occur during a person's lifetime and are not inherited. These genetic changes are called somatic mutations.

Where can I find information about diagnosis or management of progressive external ophthalmoplegia?

These resources address the diagnosis or management of progressive external ophthalmoplegia and may include treatment providers.

  • Gene Review: Mitochondrial DNA Deletion Syndromes (http://www.ncbi.nlm.nih.gov/books/NBK1203/)
  • Gene Review: POLG-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK26471/)
  • Genetic Testing Registry: Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1834846)
  • Genetic Testing Registry: Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1836460)
  • Genetic Testing Registry: Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1836439)
  • Genetic Testing Registry: Progressive external ophthalmoplegia (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0162674)
  • United Mitochondrial Disease Foundation: Diagnosis of Mitochondrial Disease (http://www.umdf.org/site/c.otJVJ7MMIqE/b.5692885/k.E71C/Getting_a_Diagnosis.htm)

You might also find information on the diagnosis or management of progressive external ophthalmoplegia in Educational resources (http://ghr.nlm.nih.gov/condition/progressive-external-ophthalmoplegia/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/progressive-external-ophthalmoplegia/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about progressive external ophthalmoplegia?

You may find the following resources about progressive external ophthalmoplegia helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for progressive external ophthalmoplegia?

  • chronic progressive external ophthalmoplegia
  • CPEO
  • PEO

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about progressive external ophthalmoplegia?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding progressive external ophthalmoplegia?

ataxia ; autosomal ; autosomal dominant ; autosomal recessive ; cell ; chronic ; deletion ; depression ; difficulty swallowing ; DNA ; dysphagia ; egg ; embryo ; gene ; inheritance ; inherited ; maternal ; maternal inheritance ; mitochondria ; muscle cells ; neuropathy ; nucleus ; ophthalmoplegia ; oxidative phosphorylation ; oxygen ; parkinsonism ; pattern of inheritance ; phosphorylation ; prevalence ; ptosis ; recessive ; sensorineural ; sensorineural hearing loss ; spectrum ; sperm ; symptom ; syndrome ; tissue

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Chan SS, Longley MJ, Copeland WC. The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem. 2005 Sep 9;280(36):31341-6. Epub 2005 Jul 16. (http://www.ncbi.nlm.nih.gov/pubmed/16024923?dopt=Abstract)
  • Gene Review: POLG-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK26471/)
  • Goffart S, Cooper HM, Tyynismaa H, Wanrooij S, Suomalainen A, Spelbrink JN. Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet. 2009 Jan 15;18(2):328-40. doi: 10.1093/hmg/ddn359. Epub 2008 Oct 29. (http://www.ncbi.nlm.nih.gov/pubmed/18971204?dopt=Abstract)
  • Kaukonen J, Juselius JK, Tiranti V, Kyttälä A, Zeviani M, Comi GP, Keränen S, Peltonen L, Suomalainen A. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science. 2000 Aug 4;289(5480):782-5. (http://www.ncbi.nlm.nih.gov/pubmed/10926541?dopt=Abstract)
  • Koga Y, Akita Y, Takane N, Sato Y, Kato H. Heterogeneous presentation in A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene. Arch Dis Child. 2000 May;82(5):407-11. (http://www.ncbi.nlm.nih.gov/pubmed/10799437?dopt=Abstract)
  • Milone M, Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist. 2010 Mar;16(2):84-91. doi: 10.1097/NRL.0b013e3181c78a89. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20220442?dopt=Abstract)
  • Moraes CT, Ciacci F, Silvestri G, Shanske S, Sciacco M, Hirano M, Schon EA, Bonilla E, DiMauro S. Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA. Neuromuscul Disord. 1993 Jan;3(1):43-50. (http://www.ncbi.nlm.nih.gov/pubmed/8392410?dopt=Abstract)
  • Sharer JD. The adenine nucleotide translocase type 1 (ANT1): a new factor in mitochondrial disease. IUBMB Life. 2005 Sep;57(9):607-14. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16203679?dopt=Abstract)
  • Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, Wanrooij S, Garrido N, Comi G, Morandi L, Santoro L, Toscano A, Fabrizi GM, Somer H, Croxen R, Beeson D, Poulton J, Suomalainen A, Jacobs HT, Zeviani M, Larsson C. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001 Jul;28(3):223-31. Erratum in: Nat Genet 2001 Sep;29(1):100. (http://www.ncbi.nlm.nih.gov/pubmed/11431692?dopt=Abstract)
  • Stumpf JD, Copeland WC. Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations. Cell Mol Life Sci. 2011 Jan;68(2):219-33. doi: 10.1007/s00018-010-0530-4. Epub 2010 Oct 8. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20927567?dopt=Abstract)
  • Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001 Jul;28(3):211-2. (http://www.ncbi.nlm.nih.gov/pubmed/11431686?dopt=Abstract)
  • Van Goethem G, Martin JJ, Van Broeckhoven C. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med. 2003;3(3):129-46. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12835509?dopt=Abstract)
  • Yu Wai Man CY, Chinnery PF, Griffiths PG. Extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain disorders. Neuromuscul Disord. 2005 Jan;15(1):17-23. Epub 2004 Nov 26. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15639116?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: June 2011
Published: July 21, 2014