Mitochondrial Enzyme Defects

Mitochondrial DNA (mtDNA) was first discovered in 1963, and in the following 20 years the basic principles of mitochondrial genetics were established. y These are maternal inheritance, replicative segregation, threshold expression, high mtDNA mutation rate (compared with nuclear DNA genes), and accumulation of somatic mutations with aging.

The mtDNA of the mother is transmitted to all of her children through the egg cytoplasm, containing 200,000 to 300,000 mtDNAs. The number of mitochondria increases hundred-fold, whereas the mtDNA copy number per mitochondrion decreases from 2 to 10 to 1 to 2 mtDNAs during oogenesis. After fertilization the early embryo goes through nuclear DNA replication and cell cleavage without significant increase in number of mitochondria or mtDNAs. The mtDNA copy number per mitochondrion varies according to cell type, with an inverse relationship between mitochondrial density and copy number. The highest mtDNA copy number is in brain mitochondria. Mutations in cellular mtDNAs result in mixed intracellular populations of mutant and normal genomes, a situation called heteroplasmy. When heteroplasmic cells divide, different mtDNAs partition randomly into daughter cells (replicative segregation), resulting in variation of cell genotypes.

What clinical phenotype a mitochondrial disease expresses depends on the severity of the mtDNA mutation, the percentage of mutant mtDNAs, and the differing energy

requirements and reserve of tissues. Each tissue requires a different minimum level of mitochondrial adenosine triphosphate (ATP) production (a threshold) to sustain normal cell function. In a family with heteroplasmic mtDNA mutations, different family members can inherit different percentages of mutant mtDNAs and therefore present with different clinical symptoms. The phenotypical effect of the mutations depends on the severity of the damage to the protein the gene encodes. Cells with the lowest potential to replicate, like neurons, appear to be the ones most susceptible to degenerative changes in proteins, lipids, nuclear DNA, and mtDNA. Which neurons accumulate mtDNA mutations is proportional to the metabolic rate. Thus, cerebral cortex, which in positron emission tomography (PET) shows a high glucose utilization rate, and basal ganglia, which also have dopaminergic neurons that generate hydrogen peroxide and oxygen radicals, are the brain areas most susceptible to accumulation of mtDNA damage.

Among the many disorders of oxidative phosphorylation, clinical classifications that focus on the most severe organ system presentations are misleading. y Because the expression of mtDNA defects of oxidative phosphorylation depends on the quantitative principles stated earlier, complete phenotypes are rarely exhibited. Biochemical classifications have the same shortcomings because the type and severity of the enzyme defect varies with the percentage of mutant mtDNA in heteroplasmic families. A molecular genetic classification is therefore the most useful. It includes four categories: class I, nuclear DNA mutations; class II, mtDNA point mutations; class III, mtDNA deletions and duplications; and class IV, genetics not yet defined. In keeping with the previous section of aminoacidopathies and organic acidopathies, these diseases are listed in Table.31-5 by order of most likely age presentation. Only the major diseases are discussed here.

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