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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.

Reye's syndrome is a rare but potentially fatal disorder which occurs primarily in children. The disorder is characterized by abnormalities in brain and liver function. Reye's syndrome develops after a viral infection and is often associated with the use of aspirin. Reye's syndrome is decreasing in incidence in the US; in 1988, there were only 20 cases reported to the Centers for Disease Control. In a recent case, the victim of a fatal case of Reye's syndrome was not a child but a 42-year-old woman. Prior to this case, only 14 cases of Reye's syndrome have been observed in patients over 25. The patient had developed a flu-like illness while on vacation; she had taken aspirin, but it is not known how much. On the third day of her illness, the patient became delirious, was breathing rapidly, and had pain and vomiting. As her condition worsened, she became comatose, and her blood pressure had dropped abnormally low. Her fever, which was as high as 105 degrees, disappeared, and she became hypothermic. By day five, she was in a deep coma, and on day eight, she died. Biochemical analyses were performed on the woman's tissues after her death and revealed a defect in the enzyme activities of some mitochondria. The activities of key mitochondrial enzymes were reduced in the liver and the brain, but not in mitochondria obtained from the patient's skeletal muscle. The decrease in activity affected the enzymes cytochrome c oxidase, citrate synthase, pyruvate carboxylase, and other key enzymes required by the mitochondria to provide cells with the chemical energy required for life. These enzyme profiles are similar to those observed in children with Reye's syndrome. The authors review the various explanations proposed to account for the potentially deadly effects of Reye's syndrome. (Consumer Summary produced by Reliance Medical Information, Inc.)

Many inherited disorders have been traced to a defect in or lack of a particular enzyme. The attenuated or absent enzymatic activity leads to a constellation of disease symptoms. Generally, such diseases are inherited as Mendelian recessive traits, since even the presence of a single normal gene for the enzyme is usually sufficient to supply the needed enzyme and prevent the development of symptoms. (Both parents must provide the recessive trait for the defect to appear in the offspring.) Investigators are searching for the genetic basis for Leigh's syndrome, the subacute necrosis of the brain and spinal cord which is characterized by psychomotor retardation and brainstem abnormalities. This condition, which generally starts in infancy or childhood, is essentially sporadic, although cases exist in which a (Mendelian) recessive mode of inheritance is suspected. Researchers examined the activity of the enzyme cytochrome c oxidase (COX) in three patients with Leigh's syndrome. This enzyme activity and pyruvate dehydrogenase are two biochemical activities known to be deficient in this syndrome. COX is remarkable among enzymes, however. It is the last step in the electron transport chain, and is a giant complex composed of 13 separate protein subunits. The three largest units are coded for by genes that are not located on the nuclear chromosomes, but rather in the mitochondrial DNA. The study of the three patients confirmed that COX activity was low. However, unlike some diseases involving reduced COX activity, the deficiency in Leigh's syndrome could not be attributed to the reduction of one of the subunit parts of the complex. Rather, all the individual components seemed to be reduced proportionately. Measurements were made of the RNA transcribed from the mitochondrial DNA, and it was found that this was proportionately reduced. The evidence, therefore, suggests that Leigh's syndrome is likely to result not from the defect of an individual enzyme subunit, but rather from a genetic defect in the mitochondria; this defect causes a deficiency in RNA transcription and reduced production of the protein subunits. (Consumer Summary produced by Reliance Medical Information, Inc.)

Cytochrome c oxidase (COX) is a complex enzyme structure that is critically important for oxidative respiration in the mitochondrion. The enzyme consists of 13 distinct subunits; the three largest, dubbed I, II, and III, constitute the actual enzymatic portion of the complex, while the other 10 participate in regulating the activity of the complex. Subunits I through III are coded for by DNA carried in the mitochondria themselves, while the remaining subunits are coded for by chromosomal DNA in the cell's nucleus. This enzyme complex is defective in a number of different syndromes of myopathy (muscle disease) and encephalomyopathy (neuromuscular disease). Two major forms of infantile myopathy involve abnormalities of cytochrome c oxidase and have completely opposite outcomes. One syndrome is invariably fatal and the other remits spontaneously during the first two or three years of life. When symptoms appear, it is difficult to distinguish between the fatal and benign forms of the deficiency. Biochemical studies do not easily make this differentiation, and more detailed biochemical studies might require more muscle biopsy material than would be appropriate to take from an infant. For this reason, an attempt was made to determine if immunohistochemical techniques could be used to distinguish between the fatal and benign forms of the disorder. Antibodies specific for different subunits of cytochrome c oxidase were used to stain histological sections of muscle biopsy material; considerably less of the precious biopsy material is required by this method. Muscle biopsies from four patients with fatal myopathy revealed a total lack of subunits VIIa and b, which are coded for by the nuclear DNA. This absence was observed in all muscle fibers. In contrast, the infants with benign myopathy lacked not only the subunits VIIa and b, but also subunit II as well. However, as recovery progressed for these patients, it was possible to show that the muscle fibers could be successfully stained for these subunits. These results suggest that the patients with the benign myopathy are lacking in some regulatory function, but are capable of manufacturing properly working enzyme complexes in their muscle fibers as they mature. (Consumer Summary produced by Reliance Medical Information, Inc.)

Dystrophin is a recently identified muscle protein which is affected in various muscular dystrophies. In Duchenne muscular dystrophy (DMD), the protein is undetectable by the Western blot method, while in Becker's muscular dystrophy, it is reduced in quantity or has an abnormal molecular weight. The gene for dystrophin is located on the X chromosome, which accounts for the occurrence of the disease only in boys. Since boys have only one X chromosome, they cannot have a normal second copy of the dystrophin gene to compensate for the mutant muscular dystrophy gene. Research has identified a number of women in families with affected boys who clearly have some myopathy. Some such cases have been severe. The condition has been attributed to preferential X inactivation. To regulate the gene dosage of X-chromosome genes, female cells randomly inactivate one or the other X chromosome. In many sex-linked diseases, having a smattering of cells with only the X chromosome with the mutant gene active is of little consequence, since just as many cells have the healthy chromosome active. There is some conjecture, however, that among women with the DMD gene and signs of myopathy, the presence of the active and unopposed DMD gene in some cells might be significant. In a recent case, however, a more curious genetic abnormality was observed. One of pair of 63-year-old identical twin sisters had a son who died of typical DMD. Both she and her sister may be presumed to be carriers of the DMD gene, but only her sister showed signs of myopathy. A karyotype analysis of the chromosomes indicated that the unaffected twin had a normal 46,XX chromosome complement, while about 18 percent of the lymphocytes of the affected twin had a 45,X karyotype, that is, were missing one X chromosome. It was thought that the muscles of the affected twin might be 45,X, with the X being the chromosome carrying the DMD gene. However, culture of fibroblasts, a connective tissue cell obtained by biopsy, revealed only normal 46,XX cells. The affected twin is a mosaic; that is, she is composed of a mixture of cells of different karyotype. It is not known how many muscles, if any, carry the abnormal karyotype, nor is it known whether the observed myopathy is related to the mosaicism. (Consumer Summary produced by Reliance Medical Information, Inc.)

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.)