In summary, our data provides evidence that the phenotype caused by a homozygous nuclear gene mutation, A467T in POLG, is strongly related to the downstream mtDNA effects in an individual patient, so that mtDNA depletion results in an early-onset severe phenotype, whereas deletions are associated with later onset disease, and in one case fixation of a heteroplasmic mtDNA point mutation (arguably the result of defective Pol γ proofreading activity) may have contributed to a MELAS-like phenotype. The gene discussed is POLG; the disease is MELAS.