The investigation of a suspected case of mitochondrial disease begins with an exploration of the family history for unusual childhood diseases including neonatal death, unexplained seizure disorders, and progressive neurologic deficits of the types already described. Unexplained deafness or diabetes in family members might also raise the level of suspicion of a mitochondrial disorder. The diagnosis should be suspected when a disorder with these characteristics occurs in a pattern that indicates maternal inheritance. However, one encounters families with mendelian patterns of inheritance due to nuclear gene defects as described in the introductory section of this chapter. Commercial tests are available for the more frequent mitochondrial point mutation sites (3243, 8993, and 8344) in leukocytes. Detection of deletions requires analysis of muscle tissue. They are useful for diagnosis but reveal abnormalities in only a modest number, estimated to be approximately 15 percent of cases that have the index aspect of this group of diseases, ragged red muscle fibers; the frequency is higher in cases with identifiable phenotypes such as MERRF and MELAS. Resting and postexercise lactate and pyruvate determinations are helpful, but this test of aerobic capacity has limitations. The more recent work of Taivassalo and colleagues, although showing a wide range of values, suggests that measurement of the partial pressure of oxygen in venous blood from the forearm after ischemic exercise (ischemic forearm test) may still be useful in distinguishing patients with mitochondrial disease from normal subjects. In the former there is a paradoxical rise in Po2 from an average of 27 to 38 mm Hg, whereas normals show a decline in this value.
A muscle biopsy will disclose several basic abnormalities; ragged red fibers can be recognized by use of the modified Gomori stain on frozen material, and the absence of succinate dehydrogenase and cytochrome oxidase by appropriate histochemical staining. In cases of suspected Leigh syndrome or MELAS, the CT or MRI may show some of the characteristic cerebral lesions; in the other mitochondrial disorders, there are often focal nondescript hyperintensities on T2-weighted MRI as well as atrophy, lucencies, or calcification. Sampling of chorionic villi for prenatal diagnosis may reveal mutant mitochondrial DNA, but this information is not entirely dependable.
It should be evident from the foregoing discussion that normal findings in any of these tests, including the muscle biopsy, do not exclude mitochondrial disease. In the final analysis, it is the clinical syndrome, family history, and corroborating evidence of a mitochondrial disorder or its genetic representation that is diagnostic. Jackson and coworkers suggest that isolated phenomena, such as dementia, muscle weakness, epilepsy, nerve deafness, migraine with strokes, small stature, myoclonic epilepsy, and cardiomyopathy, should prompt consideration of a mitochondrial disorder when no other explanation is evident.
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