The instability of the mitochondrial genome in individuals harboring pathogenic mutations in the catalytic subunit of
mitochondrial DNA (
mtDNA) polymerase gamma (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.