This study reports a novel mitochondrial disease characterized by a variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy, which is maternally transmitted. The disease was not histologically confirmed as mitochondrial myopathy. Blood and muscle samples from affected individuals contained two populations of mitochondrial DNA (mtDNA): one normal and one mutant. The mutant mtDNA was associated with a previously unreported restriction site for AvaI, due to a point mutation at nucleotide 8993, resulting in an amino acid change from leucine to arginine in subunit 6 of the mitochondrial H+ATPase. The severity of clinical symptoms correlated with the amount of mutant mtDNA. This is the third reported case of mtDNA heteroplasmy associated with disease in humans, suggesting a link between persistent heteroplasmy and deleterious mtDNA mutations.This study reports a novel mitochondrial disease characterized by a variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy, which is maternally transmitted. The disease was not histologically confirmed as mitochondrial myopathy. Blood and muscle samples from affected individuals contained two populations of mitochondrial DNA (mtDNA): one normal and one mutant. The mutant mtDNA was associated with a previously unreported restriction site for AvaI, due to a point mutation at nucleotide 8993, resulting in an amino acid change from leucine to arginine in subunit 6 of the mitochondrial H+ATPase. The severity of clinical symptoms correlated with the amount of mutant mtDNA. This is the third reported case of mtDNA heteroplasmy associated with disease in humans, suggesting a link between persistent heteroplasmy and deleterious mtDNA mutations.