Walsh & Hoyt: Point Mutations of Mitochondrial tRNAs in Maternally Inherited Ophthalmoplegia

Although most cases of CPEO are sporadic, some are hereditary. Because nearly all mtDNA is maternally transmitted, point mutations in mtDNA show a maternal pattern of inheritance. Mothers pass these mutations to offspring of both sexes, but the mutations are passed to subsequent generations only through the female line. Maternal inheritance of CPEO is associated with point mutations in highly conserved regions of mitochondrial tRNAs. The best characterized of these mutations is the ANG transition of nucleotide-3243 of tRNALeu(UUR) (i.e., the A3243G transition). This mutation is most often associated with the clinical phenotype called MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). MELAS syndrome is characterized by (a) stroke before the age of 40 years, (b) encephalopathy characterized by seizures, dementia, or both, and (c) evidence of mitochondrial dysfunction characterized by lactic acidosis, RRFs in skeletal muscle, or both. This illustrates a recurring theme in mitochondrial diseases: a given mutation of mtDNA can be associated with more than one disease phenotype, in this case CPEO and MELAS.