The transmission of OXPHOS disease and methods to prevent this.

Diseases owing to defects of oxidative phosphorylation (OXPHOS) affect approximately 1 in 8,000 individuals. Clinical manifestations can be extremely variable and range from single-affected tissues to multisystemic syndromes. In general, tissues with a high energy demand, like brain, heart and muscle, are affected. The OXPHOS system is under dual genetic control, and mutations in both nuclear and mitochondrial genes can cause OXPHOS diseases. The expression and segregation of mitochondrial DNA (mtDNA) mutations is different from nuclear gene defects. The mtDNA mutations can be either homoplasmic or heteroplasmic and in the latter case disease becomes manifest when the mutation exceeds a tissue-specific threshold. This mutation load can vary between tissues and often an exact correlation between mutation load and phenotypic expression is lacking. The transmission of mtDNA mutations is exclusively maternal, but the mutation load between embryos can vary tremendously because of a segregational bottleneck. Diseases by nuclear gene mutations show a normal Mendelian inheritance pattern and often have a more constant clinical manifestation. Given the prevalence and severity of OXPHOS disorders and the lack of adequate therapy, existing and new methods for the prevention of transmission of OXPHOS disorders, like prenatal diagnosis (PND), preimplantation genetic diagnosis (PGD), cytoplasmic transfer (CT) and nuclear transfer (NT), are technically and ethically evaluated.

Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation.

A family presented with three affected children with Leigh syndrome, a progressive neurodegenerative disorder. Analysis of the OXPHOS complexes in muscle of two affected patients showed an increase in activity of pyruvate dehydrogenase and a decrease of complex V activity. Mutation analysis revealed the T9176C mutation in the mtATPase 6 gene (OMIM 516060) and the mutation load was above 90% in the patients. Unaffected maternal relatives were tested for carrier-ship and one of them, with a mutation load of 55% in blood, was pregnant with her first child. The possibility of prenatal diagnosis was evaluated. The main problem was the lack of data on genotype-phenotype associations for the T9176C mutation and on variation of the mutation percentage in tissues and in time. Therefore, multiple tissues of affected and unaffected carriers were analysed. Eventually, prenatal diagnosis was offered with understanding by the couple that there could be considerable uncertainty in the interpretation of the results. Prenatal diagnosis was carried out twice on cultured and uncultured chorion villi and amniotic fluid cells. The result was a mutation percentage just below the assumed threshold of expression (90%). The couple decided to continue the pregnancy and an apparently healthy child was born with an as yet unclear prognosis. This is the first prenatal diagnosis for a carrier of the T9176C mutation. Prenatal diagnosis for this mutation is technically reliable, but the prognostic predictions are not straightforward.

Pearson syndrome and the role of deletion dimers and duplications in the mtDNA.

Pearson syndrome is an often fatal multisystem disease associated with mitochondrial DNA rearrangements. Here we report a patient with a novel mtDNA deletion of 3.4 kb ranging from nucleotides 6097 to 9541 in combination with deletion dimers. The mutation percentage in different tissues (blood, muscle and liver) varied between 64% and 95%. After a remission period of about a year, the patient suddenly died at the age of 3 years owing to a severe lactic acidosis. A second patient with a previously reported deletion of 8 kb and a milder phenotype was found to have mitochondrial duplications and died at the age of 10 years. From these data and data from previous reports, we hypothesize that duplications might be beneficial in the clinical course of the disease and in life expectancy.