Recently, a new form of mitochondrial DNA (mtDNA) abnormality, mtDNA depletion, has been reported in several children. Clinically, the syndrome of mtDNA depletion is heterogeneous. Specific tissues (for example, muscle, liver) may be affected in some patients; while in others, mtDNA depletion is a multisystemic disorder. Based on age at onset, two subtypes are distinguished: congenital (or early-onset) and infantile (or later- onset). Although survival is longer in the later-onset form, the syndrome is fatal in almost all patients, and currently there is no effective treatment. In these children, no qualitative defects of mtDNA, such as point mutations or deletions, were found, and depletion of mtDNA is considered the primary etiology. In contrast, mtDNA-depleted muscle fibers have also been found to coexist with fibers harboring deleted mtDNA in diseases such as autosomal dominant progressive external ophthalmoplegia with multiple deletions and inclusion-body myositis. Although the mechanisms leading to mtDNA depletion in these disorders are unknown, this type of depletion is considered secondary. Because of the Mendelian mode of inheritance in patients with primary mtDNA depletion, a defect to nuclear DNA or in intergenomic communication may be responsible for the phenotype. However, no such defect has yet been identified. Currently, the etiology of the etiology of the secondary form of mtDNA depletion is not known. The long-term goals of this project are to identify the pathogenetic mechanisms involved in primary and secondary mtDNA depletion, and to further characterize the roles of secondary mtDNA depletion in diseases caused by qualitative mtDNA defects. A variety of techniques, including in situ hybridization, single-fiber PCR, and tissue cultures, will be employed. The data obtained will enhance our understanding of the pathogenesis of mtDNA depletion and form a basis for the therapeutic strategies. I have available patient material, tissue culture systems, and methodologies necessary for the study mtDNA depletion at the molecular level. I am eager to undertake this study under the sponsorship of Dr. DiMauro and in collaboration with other members of the H. Houston Merritt Clinical Research Center.
