The mildest form of muscle disorder caused by mitochondrial disease is a benign and relatively static proximal weakness that tends to be more severe in the arms. Exercise intolerance alone is reported by more than half of these patients. There are adult-onset cases, but careful questioning usually reveals lifelong symptoms (weakness, poor endurance, discomfort, exertional dyspnea, and tachycardia), which may be so slight and slowly progressive that the patient leads a relatively normal life for decades. Less-frequent patterns of muscle disease include a fascioscapulohumeral or limb-girdle pattern of weakness as well as occasional episodes of exertional myoglobinuria. Some patients develop PEO several years after the limb weakness becomes evident. Several mutations are associated with a pure or predominant myopathic syndrome, the most common one being located at position 3250 of the mitochondrial genome. Rare variants, such as combined skeletal weakness and cardiomyopathy, are referable to other loci.
At the opposite end of the spectrum is an infantile myopathy in which weakness and lactic acidosis become evident in the first week of life and are fatal by 1 year. Many of these patients and some members of their families have a history of renal dysfunction combined with weakness of early onset. The muscle tissue shows numerous ragged red fibers, and cytochrome oxidase activity is virtually absent. DiMauro (1983) and others have described a remarkable partly reversible form, which, early on, requires ventilatory support and gastric feeding but improves clinically as the child ages; the lactic acidosis disappears by age 2 or 3 years. In these severe childhood cases, the deficiencies in cytochrome oxidase suggest a defect in mitochondrial genes, but the site has not been found.
As mentioned above, the histologic feature that unites mitochondrial myopathies is the presence of ragged red fibers. This finding points to the diagnosis of a mitochondrial disorder in any case where weakness is coupled with exercise intolerance and elevated serum lactate, particularly if there is a family history of similar problems. Also, the presence of ragged red fibers differentiates the mitochondrial myopathies from the glycogenoses but it bears emphasizing that ragged red fibers are rare in infants and young children, even in those with confirmed mitochondrial disease.
Progressive External Ophthalmoplegia and Kearns-Sayre Syndrome (See Also Chap. 45)
The combination of progressive ptosis and symmetrical ophthalmoplegia is a common manifestation of mitochondrial disease. Usually there is no diplopia or strabismus or at most only transient diplopia, despite slightly dysconjugate gaze. Mitochondrial abnormalities are found in the extraocular muscles of these patients. We have been impressed at how long the illness can exist before it brings the patient to a physician. To be differentiated is myasthenia gravis, which is characterized by fatigable weakness and responsiveness to cholinergic medications, neither of which is a feature of mitochondrial disorders. In our experience, nearly all cases of PEO are because of mitochondrial disorders, but rarely the condition may be simulated by one of several genetically determined muscular dystrophies, including oculopharyngeal dystrophy and a type in which there are no other associated weaknesses but is, however, linked to facioscapulohumeral dystrophy (FSH; Chap. 45).
PEO bears a close relationship to the Kearns-Sayre syndrome of retinitis pigmentosa (onset before age 20 years), ataxia, heart block and other conduction defects, and elevated CSF protein; sensorineural deafness, seizures, or pyramidal signs may be added (see Chap. 45 for clinical description). The CNS syndromes of MELAS or MERRF (see further on) may also be combined with PEO.