This has proved to be a confusing group of processes characterized by slowly progressive myopathy primarily involving and often limited to the extraocular muscles. Usually, the levators of the eyelids are the first to be affected, causing ptosis, followed by progressive balanced ophthalmoparesis. This disorder usually begins in childhood, sometimes in adolescence, and rarely in adult life (as late as 50 years).
Several types have been described. The most common one arises from either deletions or point mutations in mitochondrial DNA and are discussed in Chap. 37 with other metabolic disorders. However, when the foregoing progressive external ophthalmoplegia (PEO) categories are eliminated, there remains a distinctly different category of dominantly inherited PEO. Males and females are equally affected; the pattern of inheritance is autosomal dominant in some and recessive or uncertain in others. Once started, the disease progresses relentlessly until the eyes are motionless. Simultaneous involvement of all extraocular muscles permits the eyes to remain in a central position, so that strabismus and diplopia are uncommon (in rare instances, one eye is affected before the other). The pupillary responses and accommodation are normal. As the patient attempts to raise his eyelids and to see under them, the head is thrown back and the frontalis muscle is contracted, wrinkling the forehead (hutchinsonian facies). The eyelids are abnormally thin due to atrophy of the levator muscles. The orbicularis oculi muscles are frequently involved in addition to the extraocular muscles. Thus, in PEO, as in myasthenia gravis and myotonic dystrophy, there can be a characteristic combination of weakness of eye closure and eye opening, a combination that is nearly always myopathic. Other facial muscles, masseters, sternocleidomastoids, deltoids, or peronei are variably weak and wasted in approximately 25 percent of cases. The characteristic feature of PEO is that ptosis and ocular paralysis precede involvement of other muscles by many years.
Given that there is considerable clinical overlap between the mitochondrial syndrome and dominantly inherited PEO, it is not surprising that some of the dominantly inherited gene defects causing PEO result in disturbances in mitochondrial DNA. Mutations in three nuclear genes have been implicated. (These are twinkle, a mitochondrial DNA binding protein; ANT1, an adenine nucleotide transporter in the intermembrane space in the mitochondrion; and POLG, a subunit of the mitochondrial DNA polymerase.) There are also recessively inherited instances of familial PEO, one of which involves a nuclear gene.
Oculopharyngeal Dystrophy (PABPN1 Mutation, See Table 45-2)
Oculopharyngeal dystrophy is inherited as an autosomal dominant trait and is unique in its late onset (usually after the forty-fifth year) and the restricted muscular weakness, manifest mainly as a bilateral ptosis and dysphagia.
E.W. Taylor first described the disease in 1915 and assumed that it was caused by a nuclear atrophy (oculomotor-vagal complex). However, Victor and colleagues, in 1962, showed that the descendants of Taylor’s cases had a late-life dystrophy (myopathic EMG and biopsy). One of the families described by Victor, Hayes, and Adams was subsequently traced by Barbeau through 10 generations to an early French-Canadian immigrant, who was the progenitor of 249 descendants with the disease. Other families showing a dominant (rarely recessive) pattern of inheritance and a number of sporadic cases have been observed in many parts of the world.