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  • Updated 10.02.2023
  • Released 09.17.1993
  • Expires For CME 10.02.2026

Chronic progressive external ophthalmoplegia



Progressive external ophthalmoplegia, also known as chronic progressive external ophthalmoplegia, is a clinical syndrome of diverse causes that all share the combination of progressive ptosis and impaired mobility of the eyes, bilaterality, affection of muscles innervated by more than one nerve, sparing of pupils, gradual progression over months or years, absence of remissions or exacerbations, and absence of evidence of a specific disorder. Indeed, progressive external ophthalmoplegia represents the most common mitochondrial phenotype linked to pathogenic variants of mitochondrial or nuclear DNA that are critical for mitochondrial functions. Most cases are sporadic. Progress in understanding pathogenesis is lagging and, like many genetic diseases, treatment is needed. As newly discovered mutations continue to be found, more roads to etiology and pathogenesis continue to emerge.

Key points

• Progressive external ophthalmoplegia represents the most common mitochondrial phenotype.

• Single large-scale deletions of mtDNA are the most frequent causes of sporadic chronic progressive external ophthalmoplegia.

• Mitochondrial DNA and nuclear-encoded gene mutations are responsible for inherited cases.

• Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms.

• Progressive external ophthalmoplegia can be isolated or associated with extramuscular features or present in the context of more complex mitochondrial syndromes.

• Progress in understanding the pathogenesis is lagging, and, like many inherited diseases, disease-modifying treatments are needed.

Historical note and terminology

In 1890 Beaumont introduced the term “progressive nuclear ophthalmoplegia.” For the next half century, it was uncertain whether the cause was neurogenic or myopathic. That question was never resolved because none of the usual methods were sufficient to make the differentiation, nor EMG, ocular muscles biopsy, or even postmortem examination. In 1968, Rosenberg and colleagues found that 5 of 27 cases of ocular myopathy were associated with neurogenic syndromes, and David A Drachman introduced the term "ophthalmoplegia-plus" because the syndrome was often associated with neurologic multisystem diseases. A clinically distinct form of ophthalmoplegia-plus, known as Kearns-Sayre syndrome, was characterized by the triad of external ophthalmoplegia, retinitis pigmentosa, and heart block (43).

In 1975, Rowland suggested that Kearns-Sayre syndrome could be defined clinically and noted that it was almost never familial. In the next decade this was debated; many investigators thought it premature to separate individual syndromes because so many patients had symptoms and signs that overlapped classifications. However, with the 1972 recognition by Olson and colleagues that finding “ragged-red fibers” in a muscle biopsy stained with the Gomori method is a sign of mitochondrial proliferation, followed by the later recognition of maternal inheritance in syndromes called “myoclonus epilepsy with ragged red fibers” (ie, MERRF) and “mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes” (ie, MELAS), the importance of mtDNA was recognized (64). In 1988, Holt and colleagues found mitochondrial DNA (mtDNA) single large-scale deletions in some mitochondrial diseases; then, Zeviani, DiMauro, and Schon found major deletions only in Kearns-Sayre syndrome or sporadic cases of progressive external ophthalmoplegia itself. Subsequently, the phenotypic spectrum of mtDNA single large-scale deletions was expanded by the identification of these large rearrangements in infants with Pearson syndrome, a severe, often fatal, infantile onset sideroblastic anemia (74). Simultaneously, in 1988 Wallace found an mtDNA point mutation in Leber hereditary optic neuropathy, and others soon identified point mutations in MELAS and MERRF. Nevertheless, mtDNA point mutations may cause progressive external ophthalmoplegia (82; 07). Finally, chronic progressive external ophthalmoplegia can be associated with mutations in nuclear encoded genes required for mtDNA maintenance, as evidenced by the presence of mtDNA multiple deletions or depletion in muscle or other postmitotic tissues (49).

These discoveries might have ended the debates, and, in a way, they did. The significance of the clinical syndromes is no longer disputed. Pathogenesis is uncertain because a single mutation is often associated with more than one clinical syndrome (phenotypic heterogeneity) (21); conversely, a single clinical disorder is likely to be associated with more than one mutation in the same gene (allelic heterogeneity) or different genes (locus heterogeneity). It is still useful to define the syndromes clinically, but mutations of mtDNA or nuclear DNA, either autosomal dominant and, less commonly, autosomal recessive, are being identified more readily and more frequently (86; 88; 49). As a result, some experts prefer a genetic classification (91). Van Goethem introduced the term “mtDNA maintenance” to account for mutations that lead to depletion of mtDNA or multiple deletions (90).

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