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A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome (c) oxidase-negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity.

Kearns-Sayre syndrome always attacks before the age of 20, always paralyzes the eyes, and always involves the degeneration of the pigmented layer or the retina. Patients with Kearns-Sayre syndrome also have compete heart block (interruption of the electrical conduction controlling the heart's contraction), some functional abnormality of the cerebellum, or elevated amounts of protein in the cerebrospinal fluid, which surrounds the brain and spinal cord. The condition results from a genetic abnormality of the mitochondria. Mitochondria, which are organelles, or small structures, inside cells, are responsible for carrying out key steps in the biochemical processes which supply cells with energy. Unlike other structures within a cell, the mitochondrion carries its own DNA, or genetic material. Some of the key enzymes for the cellular energy processes come from this cellular DNA and not from the DNA of the 46 chromosomes, as do the overwhelming majority of enzymes. It is in this mitochondrial DNA (mtDNA) that the defect of Kearns-Sayre syndrome lies. Six different tissues from a patient with Kearns-Sayre syndrome were analyzed to evaluate the defects in the mitochondrial DNA in each. The analysis revealed the presence of mitochondria which had a long piece of missing DNA. However, while mtDNA exhibiting this deletion was present in all tissues, the proportion of mitochondria showing this deletion varied from tissue to tissue. In smooth muscle specimens, only about four percent of the mitochondria were affected by this deletion. However, about half the mitochondria in the skeletal muscle cells were affected, leaving only half with the normal set of mitochondrial genes. It was impossible to find a precise relationship between the percentage of affected mitochondria and the mitochondrial enzyme activities within the tissue. Because of the early onset of Kearns-Sayre syndrome, it is rarely passed on, and most cases have occurred sporadically. It seems likely that in the unfertilized ovum or in the early embryo, a random event resulted in the deletion of some genetic material from one mitochondrion. During the course of subsequent development, the offspring of the normal mitochondria and the offspring of the mutant mitochondrion become randomly distributed in the succeeding generations of embryonic cells, attaining the distribution observed within the cells of the adult. (Consumer Summary produced by Reliance Medical Information, Inc.)

Mitochondria are tiny structures within cells and are responsible for oxidative phosphorylation, a critical step in the energy metabolism of human cells. Unlike other structures within human cells, mitochondria carry some of their own genes, and in recent years it has become clear that some diseases are due to mutations in these genes. Since muscle and brain tissues have high demands for energy, they are often the most seriously affected by these mitochondrial abnormalities. These abnormalities are generally inherited only from the mother, since the mitochondria in the sperm cell die after fertilization and only the egg mitochondria contribute to the developing embryo. Some normal mitochondria are invariably present in addition to the mutant mitochondria; the distribution of the two within the developing embryo will largely determine the symptoms and severity of the disease. In a susceptible tissue such as muscle, symptoms may result if only 27 percent of the mitochondria actually contain mutations. Five different diseases have so far been identified that are associated with mitochondrial mutations; the differences appear to be due to the precise nature of the mutation. One such disorder is mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Researchers studying five patients with MELAS were able to identify a mutation in a mitochondrial transfer RNA (tRNA) gene, specifically, a tRNA that assists the incorporation of leucine into a growing protein chain. In a study of tissues from these patients obtained at autopsy, the researchers found that the percentage of mutant mitochondria was roughly the same throughout the body, ranging from 79 to 88 percent. Normal mitochondria were therefore in the minority. However, the function of organs such as the liver and the kidneys was not noticeably affected in theses patients. This suggests that these organs are less susceptible to impairment of mitochondrial function than are structures such as the muscles, heart, and brain. (Consumer Summary produced by Reliance Medical Information, Inc.)

Kearns-Sayre syndrome is an unusual genetic disorder in that the genetic material of the mitochondria is affected, rather than the DNA contained within the chromosomes. Kearns-Sayre syndrome is almost invariably associated with a deletion of DNA within the mitochondria. The condition is characterized by progressive external ophthalmoplegia and pigmentary retinopathy. The definition of the syndrome also requires the presence of at least one of the following: heart conduction block, elevated cerebrospinal fluid protein, and cerebellar syndrome. Kearns-Sayre syndrome generally makes its presence felt before the age of 20. The symptoms of individual cases may be highly varied; this is thought to be due to the distribution of mitochondria. Not all mitochondria are affected, and the ratio of intact mitochondria to mitochondria with deleted DNA may vary from tissue to tissue. In addition, not all tissues put the same demands upon these energy-producing organelles, so that some tissues with higher demands may be more likely to cross the threshold where mitochondrial defects produce clinical symptoms. The recent case of a 10-year-old boy illustrates that the range of presenting symptoms can be surprisingly wide. The patient developed signs of kidney disease; examination and laboratory tests suggested the diagnosis of renal tubular acidosis. He patient was treated for renal tubular acidosis. The condition recurred six months later, and progressed over the next several months to include progressive external ophthalmoplegia and pigmentary retinopathy. Muscle biopsy and DNA analysis confirmed a deletion of 7.5 kilobases of mitochondrial DNA, confirming Kearns-Sayre syndrome. The patient's condition continued to deteriorate, and at the age of 11 years he required the implantation of a heart pacemaker. It is not known why the kidneys were affected in the present case. Kidney symptoms are rare in Kearns-Sayre syndrome, but investigation revealed that the proportion of affected mitochondria in the kidneys of this patient was actually lower than the affected proportion in the muscles. Therefore, the commonly advanced ''threshold'' theory cannot account for the patient's presenting illness. (Consumer Summary produced by Reliance Medical Information, Inc.)