Progressive external ophthalmoplegia

Lewis P Rowland MD (Dr. Rowland of Columbia University has no relevant financial relationships to disclose.)
Michio Hirano MD, editor. (Dr. Hirano of Columbia University has no relevant financial relationships to disclose.)
Originally released September 17, 1993; last updated October 17, 2014; expires October 17, 2017

This article includes discussion of progressive external ophthalmoplegia, descending ocular myopathy, MEPOP, ocular myopathy, ocular myopathy with extraocular extension, oculopharyngeal muscular dystrophy, oculopharyngodistal muscular dystrophy, OPDMD, OPMD, and PEO. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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 mutations of mitochondrial DNA (mtDNA). Among the advances described in this article is the potential use of hematopoietic stem cell therapy to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Additionally, mutations in the gene for polymerase gamma (POLG) in mtDNA are found in syndromes other than progressive external ophthalmoplegia; in adults, this may lead to parkinsonism, ataxia, and seizures. In infants, POLG mutations may cause a lethal hepatocerebral syndrome. 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.

Key points

 

• 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 mutations of mitochondrial DNA (mtDNA).

 

• Among the important recent advances is the potential use of hematopoietic stem cell therapy to treat MNGIE.

 

• Mutations in the gene for polymerase gamma (POLG) in mtDNA are found in syndromes other than progressive external ophthalmoplegia; in adults, this may lead to parkinsonism, ataxia, and seizures. In infants, POLG mutations may cause a lethal hepatocerebral syndrome.

 

• Progress in understanding pathogenesis is lagging and, like many inherited diseases, treatment is needed.

 

• The field matured with publication of a book on Mitochondrial Medicine (DiMauro et al 2006), formation of the Mitochondrial Medicine Society, and appearance of a new journal, Mitochondrion.

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 (Yu Wai Man et al 2005).

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 (Olson et al 1972). 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 (Sotiriou et al 2009; Berardo et al 2010).

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 (Puri et al 2012).

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 1 clinical syndrome (phenotypic heterogeneity) (Emmanuele et al 2011); 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 (Van Goethem et al 2003b). Van Goethem introduced the term “mtDNA maintenance” to account for mutations that lead to depletion of mtDNA or multiple deletions (Van Goethem 2006).

Sleep disorders may be encountered more often in PEO than in the general population (Smits et al 2012), and most mitochondrial myopathies have been autosomal dominant, but autosomal recessive forms are being reported (Takata et al 2011; Tyynismaa et al 2012). Similarly, esophageal disorders may be uncovered by physiological tests, but frank dysphagia is uncommon (Domenis et al 2011). Fatigue, pain, and depression may be more common in patients with PEO than in a comparable group with myotonic muscular dystrophy (Smits et al 2011a). Respiration may be impeded (Smits et al 2011b).

Major deletions are 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 (Shanske et al 2002).

In a parallel path of progress, the clinical features of “oculopharyngeal muscular dystrophy” were first described by Taylor in 1915 (Taylor 1915) and popularized by Barbeau and by Victor and colleagues in the 1960s (Barbeau 1966). Tome and Fardeau described the characteristic inclusions in muscle (Tome and Fardeau 1986). Brais and colleagues mapped the disorder to 14q11 in 1995 and cloned the gene (Brais et al 1998).

Oculopharyngodistal myopathy was described by Schotland and Rowland (Schotland and Rowland 1964), recognized as a specific syndrome in Japan by Satoyoshi and colleagues (Satoyoshi et al 1965), and named by Fukuhara and colleagues (Fukuhara et al 1982).

Table 1. Tentative Clinical-Genetic Classification of Progressive External Ophthalmoplegia

I. Childhood-onset

 

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.

E. Others.

II. Juvenile or adult-onset

 

A. Mitochondrial diseases.

 

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 or recessive, linked to chromosome 14.

C. Oculopharyngeal muscular dystrophy, autosomal dominant, unlinked.

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 disease: abetalipoproteinemia, spinocerebellar ataxias, amyotrophic lateral sclerosis, paraproteinemic sensorimotor neuropathy, others.

Modified from (Rowland et al 1988)

Table 2. POLG-related Disorders

(Mutations in Nuclear Gene Polymerase γ)

 

• Alpers-Huttenlocher syndrome (AHS); Alpers-like infantile encephalopathy

 

• Autosomal dominant progressive external ophthalmoplegia

 

• Autosomal recessive progressive external ophthalmoplegia

 

• Childhood myocerebrohepatopathy spectrum disorders (MCHS)

 

• Myoclonic epilepsy, myopathy, sensory ataxia (MEMSA), includes spinocerebellar ataxia with epilepsy (SCAE), with or without progressive external ophthalmoplegia

 

POLG-related ataxia neuropathy spectrum disorders (ANS), includes mitochondrial recessive ataxia syndrome (MIRAS)

Modified from (Cohen et al 2010)

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