Human Reproduction Update Advance Access originally published online on September 30, 2005
Human Reproduction Update 2006 12(2):119-136; doi:10.1093/humupd/dmi042
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The transmission of OXPHOS disease and methods to prevent this
1 Department of Genetics and Cell Biology, 2 Research Institute GROW, 3 Department of Ethics and Philosophy, University of Maastricht, Maastricht and 4 Department of Child Neurology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
5 To whom correspondence should be addressed at: Department of Genetics and Cell Biology, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: bert.smeets{at}molcelb.unimaas.nl
Submitted on May 6, 2005; resubmitted on August 26, 2005; accepted on September 7, 2005
Diseases owing to defects of oxidative phosphorylation (OXPHOS) affect approximately 1 in 8000 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.
Key words: mitochondria / OXPHOS disease / PGD / PND / transmission
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