Leber's Hereditary Optic Neuropathy, Infantile Bilateral Striatal Necrosis, Early Onset-Huntington's Disease, Myoclonic Epilepsy and Mitochondrial Myopathy are all hereditary neuro-degenerative diseases associated to varying degrees with blindness, deafness, dementia, epilepsy and loss of motor control. All of these disease can be linked to defects in respiratory metabolism and the inheritance of each is influenced by a maternally transmitted genetic element. The mitochondrial DNA (mtDNA) codes for 13 key proteins of oxidative phosphorylation (OXPHOS) and is maternally inherited. I hypothesize that mutations in the mtDNA are in part responsible for these disorders. To test this, I propose to analyze mitochondrial OXPHOS enzymes, mtDNA sequences, mtDNA in vitro genetics, and mitochondrial metabolic therapy of patients with these disorders. I anticipate that the results will reveal the molecular and biochemical basis of these disease and lead to powerful new diagnostic treatment regimes. To better understand the genetics and pathophysiology of mtDNA diseases, I also propose to use transgenic technology to implant mutant mtDNAs into the mouse germ line. Such a system would permit exploration of the spectrum of mutant mtDNA symptoms, the role of mixed mtDNA populations in mutant expression, and the potential for gene therapy of this unique set of extranuclear genetic diseases of the central nervous system.
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