Current molecular diagnostic algorithm for mitochondrial disorders

Mitochondrial respiratory chain disorders (RCD) are a group of genetically and clinically heterogeneous diseases, due in part to the biochemical complexity of mitochondrial respiration and the fact that two genomes, one mitochondrial and one nuclear, encode the components of the respiratory chain. Because of the large number of genes involved, attempts to classify mitochondrial RCD incorporate clinical, biochemical, and histological criteria, in addition to DNA-based molecular diagnostic testing. While molecular testing is widely viewed as definitive, confirmation of the diagnosis by molecular methods often remains a challenge because of the large number of genes, the two genome complexity and the varying proportions of pathogenic mitochondrial DNA (mtDNA) molecules in a patient, a concept termed heteroplasmy. The selection of genes to be analyzed depends on the family history and clinical, biochemical, histopathological, and imaging results, as well as the availability of different tissues for analysis. Screening of common point mutations and large deletions in mtDNA is typically the first step. In cases where tissue-specific, recognizable clinical syndromes or characteristic RC complex deficiencies and histochemical abnormalities are observed, direct sequencing of the specific causative nuclear gene(s) can be performed on white blood cell DNA. Measurement of mtDNA content in affected tissues such as muscle and liver allows screening for mtDNA depletion syndromes. The ever-expanding list of known disease-causing genes will undoubtedly improve diagnostic accuracy and genetic counseling.