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Progressive multiorgan disease. The mitochondrial myopathies are a rare group of conditions affecting the respiratory chain and oxidative phosphorylation. A total of five proteins complexes make up the mitochondrial electron transport chain (see Complex Diseases/Deficiency (Overview)).

Mitochondria are the main source of adenosine tri-phosphate (ATP) in the cell. They depend on several metabolic pathways to supply ATP during varying cellular conditions: glycolysis is the main pathway during nutritional repletion state, and fatty acid oxidation is the main pathway during fasting. ATP is generated by five protein complexes, called the respiratory chain, contained in the inner mitochondrial membrane: NADH from the tricarboxylic cycle is a substrate for complex I, and the reduced form of flavin adenine dinucleotide (FADH2) from fatty acid oxidation is a substrate for complex II. Strictly speaking, disorders of pyruvate metabolism, fatty acid oxidation, ketogenesis, or ketolysis, and defects of the urea cycle or of the respiratory chain, are mitochondrial pathologies; however, the term mitochondrial diseases is usually a synonym for respiratory chain or oxidative phosphorylation anomaly.

Mitochondrial Cytopathy; Mitochondrial Myopathy

In the United States, it is estimated that one in 4,000 children will develop mitochondrial disease by the age of 10 years. The prevalence of the disease at birth is 1:4000 to have a type of mitochondrial disease.

Any mode of inheritance may be observed: autosomal recessive, dominant, X-linked, maternal, or sporadic. This is a consequence of the high number of genes encoding respiratory chain proteins: most are located in the cell DNA but 26 are in the mtDNA. Consequently, mutations, depletion, deletions, or duplications can occur in both genetic materials. Transmission of mitochondrial diseases is complex because mtDNA is maternally inherited, has a different structure than complementary DNA, and is more subject to spontaneous mutations. Therefore, many mtDNA mutations accumulate with age and are probably the cause of some diseases (e.g., Parkinson, diabetes). Moreover, there are many mitochondria in each cell, and they are randomly partitioned between daughter cells during mitosis. Thus, if normal and mutant mtDNA are present in the initial cell (heteroplasmy), some lineages will have only abnormal mtDNA or normal mtDNA (homoplasmy). There are also cases of acquired reversible mitochondrial dysfunction caused by mtDNA depletion in children with HIV treated with nucleoside analogues (mainly zidovudine [AZT]); AZT inhibits DNA polymerase γ, a nuclear protein essential for mtDNA replication and maintenance.

Whether cells can generate enough ATP depends on the amount of dysfunctional mtDNA present in the mitochondria. Because cells of different organs have different metabolic needs, some organs can tolerate a greater burden of mutated mtDNA, and the first symptoms usually appear in the organs with the greatest metabolic needs (e.g., brain, heart, muscle, liver, kidney). This is called the threshold effect. The concepts of heteroplasmy and threshold effect explain how the same mutation can present with many different phenotypes and how some clinical phenotypes are caused by different mutations. If the ...

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