Therapeutic options in mitochondrial encephalomyopathies

Although great progress has been made in the understanding of the molecular basis of mitochondrial disorders, therapy is still woefully inadeqate. Therapeutic approaches include palliative measures, pharmacological intervention at the level of the respiratory chain including artificial electron acceptors, free radical scavangers, alternative metabolites, removal of toxic metabolites and new strategies for gene therapy. Palliative treatment remains often the only measure for severely affected patients with mitochondrial encephalomyopathies. A broad indiscriminate administration of vitamins, cofactors, oxygen radical scavengers is widely practiced. Nevertheless, no sufficient prospective multicenter studies in well defined patient populations have been carried out and most reports on therapy effects are anecdotal. Some evidence for a therapeutic benefit exists for CoQ₁₀, in isolated CoQ₁₀ deficiency and in Friedreich's ataxia, for idebenone in Friedreich's hypertrophic cardiomyopathy, for a ketogenic diet and thiamine in PDH (E1α) deficiency and for riboflavine in patients with mitochondrial myopathies due to complex I deficiency. In mitochondriopathies with secondary carnitine deficiency, carnitine supplementation is recommended. Aerobic endurance training has some effect, creatine only minor effects on myopathic patients. In recent years great efforts have been made to develop concepts for gene therapy. In PDH-(E1α) deficiency, infection of a recombinant adeno-associated virus 2 vector has been successfully accomplished in cell culture. For mtDNA related diseases the most promising approach is to reduce the ratio of mutated to wild type genomes (“gene shifting“). Interesting trials include selective inhibition of replication of the mutated mtDNA or the reduction of mutated mt DNA through importation of a restriction enzyme into mitochondria. Finally, genetic counselling is still a challenge. The extreme phenotypic diversity and tissue distribution of mutations make it very difficult to give a realistic prognostic guide to individuals harboring mtDNA defects.