Progressive external ophthalmoplegia is a syndrome of diverse causes and is often accompanied by disorders of other tissues other than extraocular muscles. Most are inherited conditions, some are autosomal, and many are mutations of mitochondrial DNA (mtDNA); in fact, progressive external ophthalmoplegia represents the most common mitochondrial phenotype. Progress in understanding pathogenesis is lagging and, like many inherited diseases, treatment is needed. As newly discovered mutations continue to be found, more roads to etiology and pathogenesis continue to emerge.
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• Progressive external ophthalmoplegia is a syndrome of diverse causes and is often accompanied by disorders of organ systems other than extraocular muscles. Most are inherited conditions, some are autosomal, and many are caused by mutations of mitochondrial DNA (mtDNA).
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• Progressive external ophthalmoplegia represents the most common mitochondrial phenotype.
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• Progress in understanding pathogenesis is lagging and, like many inherited diseases, disease-modifying treatments are needed.
Historical note and terminology
Progressive external ophthalmoplegia (PEO) is a syndrome of diverse causes, all sharing the combination of ophthalmoparesis, ptosis of the eyelids, and normal pupils. The syndromes are separated by age at onset, distribution of extraocular weakness, patterns of inheritance, and specific mutations of mitochondrial DNA (mtDNA) or nuclear DNA (See Table 1). The differential diagnosis of these syndromes involves myasthenia gravis, Graves ophthalmopathy with thyroid disease, and ocular myopathies (104).
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 suffice to make the differentiation--not EMG or biopsy of ocular muscles, 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. 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 (62). In 1988, Holt and colleagues found 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. Simultaneously, in 1988 Wallace found a point mutation in Leber hereditary optic neuropathy, and others soon identified point mutations in MELAS and MERRF. Nevertheless, point mutations may cause PEO (85; 08).
In one atypical 10-year-old patient with Kearns-Sayre syndrome, limb weakness, short stature, impaired mental development, and pigmentary retinopathy were evident, but the diagnosis was apparently not made until 28 years of age after a year of recurrent syncope due to complete heart block (and cardiomegaly). Therapy included a pacemaker (66).
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 1 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 are being identified more readily and more frequently. As a result, some experts prefer a genetic classification (99). Van Goethem introduced the term mtDNA maintenance to account for mutations that lead to depletion of mtDNA or multiple deletions (98).
Sleep disorders may be encountered more often in PEO than in the general population (84), and most mitochondrial myopathies have been autosomal dominant, but autosomal recessive forms are being reported (90; 95). Similarly, esophageal disorders may be uncovered by physiological tests, but frank dysphagia is uncommon (19). Fatigue, pain, and depression may be more common in patients with PEO than in a comparable group with myotonic muscular dystrophy (82). Respiration may be impeded (83).
Single major deletion of the mtDNA is also found in an infantile anemia, the Pearson syndrome. In survivors of that disorder, features of Kearns-Sayre may appear later, and 1 mother with ophthalmoplegia but no other features of Kearns-Sayre had a child with Pearson anemia; both mother and child had the same major mutation (80).
In a parallel path of progress, the clinical features of oculopharyngeal muscular dystrophy were first described by Taylor in 1915 (91) and popularized by Barbeau and by Victor and colleagues in the 1960s (05). Tome and Fardeau described the characteristic inclusions in muscle (93). Brais and colleagues mapped the disorder to 14q11 in 1995 and cloned the gene (09).
Oculopharyngodistal myopathy was described by Schotland and Rowland (79), recognized as a specific syndrome in Japan by Satoyoshi and colleagues (78), and named by Fukuhara and colleagues (26).
Table 1. Tentative Clinical-Genetic Classification of Progressive External Ophthalmoplegia
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A. Congenital myopathies: Central core disease, multicore, centronuclear, myotubular, and nemaline myopathies.
B. Childhood oculopharyngeal muscular dystrophy.
C. Congenital myasthenia gravis.
D. PEO with intestinal pseudo-obstruction but not mitochondrial abnormality.
II. Juvenile or adult-onset
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A. Mitochondrial diseases.
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1. Kearns-Sayre syndrome, sporadic, with single deletion of mtDNA.
2. Sporadic PEO with single deletion of mtDNA.
3. Maternally inherited PEO with point mutation of mtDNA.
4. PEO with mitochondrial neuromyopathy, gastrointestinal pseudo-obstruction, encephalopathy, autosomal recessive, multiple deletions of mtDNA (MNGIE)
5. PEO, autosomal dominant, multiple deletions mtDNA.
6. PEO, autosomal recessive, multiple deletions mtDNA.
B. Oculopharyngeal muscular dystrophy, autosomal dominant, gene PABPN1.
C. Oculopharyngodistal myopathy (OPDM), autosomal dominant or recessive.
D. Oculopharyngodistal muscular dystrophy, autosomal dominant.
E. Oculopharyngodistal muscular dystrophy, autosomal recessive.
F. PEO with hypogonadism, multiple deletions, autosomal dominant.
G. PEO, autosomal recessive, unlinked.
H. PEO in neurogenic or various diseases: abetalipoproteinemia, spinocerebellar ataxias, amyotrophic lateral sclerosis, paraproteinemic sensorimotor neuropathy, others.
Modified from (73)