| Summary: | The instability of the mitochondrial genome in individuals harboring pathogenic mutations in the catalytic subunit of mitochondrial DNA (mtDNA) polymerase F (POLG) is well recognized, but the underlying molecular mechanisms remain to be elucidated. In 5 pediatric patients with severe myoclonic epilepsy and valproic acid induced liver failure, we identified 1 novel and 4 previously described pathogenic mutations in the linker region of this enzyme. Although muscle biopsies in these patients showed unremarkable histologic features, postmortem liver tissue available from 1 individual exhibited large cytochrome c oxidase-negative areas. These cytochrome c oxidase-negative areas contained 4-fold less mtDNA than cytochrome c oxidase-positive areas. Decreased copy numbers of mtDNA were observed not only in the liver, skeletal muscle, and brain but also in blood samples from all patients. There were also patient-specific patterns of multiple mtDNA deletions in different tissues, and in 2 patients, there were clonally expanded mtDNA point mutations. The low amount of deleted mtDNA molecules makes it unlikely that the deletions contribute significantly to the general biochemical defect. The clonal expansion of a few individual specific deletions and point mutations indicates an accelerated segregation of early mtDNA mutations that likely are a consequence of low mtDNA copy numbers. Moreover, these results suggest a potential diagnostic approach for identifying mtDNA depletion in patients.
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