Next generation mitochondrial disease: change in diagnostics with eyes on therapy

Excerpt

Is the paradigm of “mitochondrial disease” in 2015 different from how it was previously defined? Next generation sequencing (NGS) in patients with mitochondrial disease has revealed many novel gene defects with unexpected biochemical associations and clinical consequences whose metabolic basis remains unclear. These genes and their products are teaching us about novel metabolic concepts which are not primarily related to mitochondrial enzymes or the mitochondrial transcription, translation, or transport machineries (Honzik et al. 2015; Wortmann et al. 2015; Rahman et al. 2015; Horvath et al. 2015). Some are hypothesized to alter mitochondrial membrane integrity, affect signaling pathways, or change reactive oxygen species (ROS) production, but do not lead to severe mitochondrial oxidative phosphorylation (OXPHOS) complex deficiencies. In most of the recently discovered mitochondrial disorders, classical enzyme histochemistry in biopsied muscle would probably not support a diagnosis of primary mitochondrial dysfunction (Wortmann et al. 2015). Other markers of global mitochondrial dysfunction, such as oxygen consumption, ATP production, and ROS production, are frequently abnormal in these novel mitochondrial disorders. However, these changes are relatively non-specific, and including them as part of routine diagnostic work-up may not improve the success in identifying particular conditions. …