title: Mitochondrial DNA mutations in epilepsy and neurological disease.
abstract: Recent discoveries in mitochondrial clinical genetics have revealed that a broad spectrum of clinical phenotypes are associated with mutations in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged-red fiber disease are caused by a mutation in the transfer RNA gene lysine. Although everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individuals. This variability correlates with the inherited percentage of mutations in the individual's mitochondrial DNA and the individual's age. Age-related expression of mitochondrial disease has also been demonstrated for mitochondrial DNA deletions. Although deletions that retain both origins of replication result in late-onset disease because of the progressive enrichment of the deleted mitochondrial DNA, a 10.4-kb deletion that lacks the light-strand replication origin and maintains a stable mutant percentage in both tissues and cultured cells has been discovered. This deletion is associated with adult-onset diabetes and deafness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy. Biochemically, it causes a generalized defect in mitochondrial protein synthesis and oxidative phosphorylation. The age-related decline in oxidative phosphorylation could reflect the accumulation of somatic mitochondrial DNA mutations. Inhibition of oxidative phosphorylation stimulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transport chain. This damages the mitochondrial DNA, further reducing oxidative phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms appear.
authors.affiliation: Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: D C
authors.initials: DC
authors.lastname: Wallace
authors.forename: M T
authors.initials: MT
authors.lastname: Lott
authors.forename: J M
authors.initials: JM
authors.lastname: Shoffner
authors.forename: S
authors.initials: S
authors.lastname: Ballinger
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D003638:Deafness / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D017243:MERRF Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics*; D010085:Oxidative Phosphorylation; D010375:Pedigree
chemical_list: D004272:DNA, Mitochondrial