MITOCHONDRIAL-DNA MUTATIONS IN EPILEPSY AND NEUROLOGICAL DISEASE

Recent discoveries in mitochondrial clinical genetics have revealed th at a broad spectrum of clinical phenotypes are associated with mutatio ns in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged-red fib er disease are caused by a mutation in the transfer RNA gene lysine. A lthough everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individual s. This variability correlates with the inherited percentage of mutati ons in the individual's mitochondrial DNA and the individual's age. Ag e-related expression of mitochondrial disease has also been demonstrat ed for mitochondrial DNA deletions. Although deletions that retain bot h origins of replication result in late-onset disease because of the p rogressive enrichment of the deleted mitochondrial DNA, a 10.4-kb dele tion that lacks the light-strand replication origin and maintains a st able mutant percentage in both tissues and cultured cells has been dis covered. This deletion is associated with adult-onset diabetes and dea fness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy . Biochemically, it causes a generalized defect in mitochondrial prote in synthesis and oxidative phosphorylation. The age-related decline in oxidative phosphorylation could reflect the accumulation of somatic m itochondrial DNA mutations. Inhibition of oxidative phosphorylation st imulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transpo rt chain. This damages the mitochondrial DNA, further reducing oxidati ve phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms a ppear.