We have studied five children with mitochondrial myopathy manifesting within or soon after the first year of life. Muscle biopsies showed ragged-red fibers and decreased respiratory chain activity. All five patients had a severe decrease (2 to 34% of normal) in the amount of muscle mitochondrial DNA (mtDNA). The depletion of mtDNA correlated with absence of mtDNA-encoded translation products and with loss of cytochrome c oxidase enzyme activity in individual muscle fibers. This mitochondrial myopathy of childhood illustrates one phenotypic expression of a novel pathogenetic mechanism in mitochondrial diseases, the specific depletion of mtDNA in affected tissues.

The mitochondrial genome has an underdeveloped "DNA repair repertoire" compared with the nuclear genome, making the mitochondrial DNA more susceptible to mutations by endogenous factors such as defects of the mitochondrial polymerase itself, and by exogenous factors such as radiation and UV light. Increased sensitivity to mutagenic factors may account for the mitochondrial DNA polymorphism within ethnic groups and the mitochondrial diseases associated with all mitochondrial DNA mutations, including DNA depletion. The presence in highly developed organisms of a DNA repair repertoire less organized in the mitochondria than in the nuclei might be a source of biologic dysfunction relevant also to aging and cell death. Uncorrected mitochondrial DNA modifications may determine lethal and severe diseases or asymptomatic biochemical dysfunctions. Considering the long life span and the complex metabolism of highly developed cells, the tendency to produce and accumulate mitochondrial DNA mutations may assume a pathogenetic role with aging.

We studied three patients with Leigh's syndrome (LS) and cytochrome c oxidase (COX) deficiency. Biochemical studies in brain, muscle, heart, liver, kidney, and fibroblasts disclosed a generalized COX deficiency. Kinetic studies of COX activity in brain mitochondria showed a low Vmax and a normal Km for reduced cytochrome c. Immunologic studies showed decrease of all COX subunits studied, without a specific defect of any one of them. Southern blot analysis excluded large deletions of mitochondrial DNA (mtDNA) but revealed a generalized increase in mtDNA quantity. Although Northern blot analysis showed no alteration in the 12 COX subunit mRNAs studied, two of three patients showed a decreased steady state rate of COX transcription in brain. COX deficiency in LS thus appears to be related to a decreased amount of otherwise normal COX holoenzyme.