Making a specific genetic diagnosis is helpful in various ways. It allows a comparison of that individual with other patients described in published reports, providing some guide to prognosis and highlighting complications that may evolve over time (table 2). It also has implications for genetic counselling (table 1).94 Nuclear defects may be autosomal recessive, autosomal dominant, or sex linked. mtDNA defects may be sporadic or maternally transmitted. There are no statistically based robust counselling guidelines for mtDNA disease,95 but data collection is underway, and they should become available over the next five years. Retrospective studies suggest that measuring the percentage level of mutated mtDNA in the mother will provide some guidance.39,58
At present the management of mitochondrial disease is largely supportive and aimed at identifying, preventing, and treating complications wherever possible. Pharmacological treatments have been used with varying degrees of success (recently reviewed by Chinnery & Turnbull96). Limited clinical trials have been carried out, but no consistent clinical improvements have been demonstrated. A multicentre trial is currently under way for dichloracetate to reduce lactic acidosis in MELAS patients.
Our understanding of the basic biology of mitochondrial disease provides a basis for developing new treatments. Several strategies have been employed to try and correct the underlying genetic defect. The overall aim is to reduce the proportion of mutated mtDNA to subthreshold levels. This could be achieved by adding more wild-type mtDNA, or by removing mutated mtDNA.
Adding wild-type mtDNA
Despite initial promise,46 attempts to deliver synthetic wild-type mtDNA into cells have not been successful. A more attractive strategy is to move wild-type mitochondrial genomes from one compartment to another—an approach called "gene shifting".97–99 Healthy skeletal muscle contains small precursors called satellite cells. Satellite cells proliferate and fuse with the juxtapositionary mature skeletal fibres in response to stress and exercise. In some patients with mtDNA myopathy, the percentage level of mutated mtDNA in satellite cells is lower that the level in affected skeletal muscle. It is possible to induce satellite cell proliferation by injecting a toxin into muscle (such as bupivacaine)97,98 or by exercising the muscle.99 Both techniques have been shown to deliver wild-type mtDNA from the satellite cell compartment into mature muscle fibres, to reduce the proportion of mutated mtDNA within affected tissues, and to correct the biochemical defect. Exercise also improves the strength and stamina of patients with mtDNA myopathy100—but there are concerns that it may also increase the amount of mutated mtDNA in the muscle, leading to short term improvements that may be detrimental in the longer term.101
Removing mutated mtDNA
Two strategies have been employed to remove mutated mtDNA. Both are at the experimental stage, and both require considerable development before they can be used on patients. One approach has been to develop synthetic molecules that bind to mutated mtDNA molecules and prevent them from replicating, but allowing wild-type mtDNA replication to continue unimpeded.102 While this strategy works in vitro, and it appears that the "antigenomic" molecules can be delivered into mitochondria,103 so far it has not been possible to influence the level of heteroplasmy in living cells. An alternative approach is to use drugs that select against mutated mtDNA in dividing cells, allowing wild-type mtDNA levels to increase.104
All of these approaches have the same drawback—even if they are effective, how can the treatments be delivered to the nervous system and alter the mtDNA levels in non-dividing cells? For this reason perhaps the best strategy is to remove all mutated mtDNA at an early stage in development, by nuclear transfer. By removing the nucleus from an affected zygote with a mtDNA mutation and inserting it into a healthy enucleated donor with normal mtDNA, it should be possible to form healthy offspring that do not harbour the mtDNA defect, thereby preventing the disease in that individual, and also preventing further transmission of the disease. This approach is currently at an experimental stage, but provides some hope for the future.