title: Preventing the transmission of mitochondrial DNA disorders: selecting the good guys or kicking out the bad guys.
abstract: Mitochondrial disorders represent the most common group of inborn errors of metabolism. Clinical manifestations can be extremely variable, ranging from single affected tissues to multisystemic syndromes. Maternally inherited mitochondrial DNA (mtDNA) mutations are a frequent cause, affecting about one in 5000 individuals. The expression of mtDNA mutations differs from nuclear gene defects. Mutations are either homoplasmic or heteroplasmic, and in the latter case disease becomes manifest when the mutation load exceeds a tissue-specific threshold. Mutation load can vary between tissues and in time, and often an exact correlation between mutation load and clinical manifestations is lacking. Because of the possible clinical severity, the lack of treatment and the high recurrence risk of affected offspring for female carriers, couples request prevention of transmission of mtDNA mutations. Previously, choices have been limited due to a segregational bottleneck, which makes the mtDNA mutation load in embryos highly variable and the consequences largely unpredictable. However, recently it was shown that preimplantation genetic diagnosis offers a fair chance of unaffected offspring to carriers of heteroplasmic mtDNA mutations. Technically and ethically challenging possibilities, such maternal spindle transfer and pronuclear transfer, are emerging and providing carriers additional prospects of giving birth to a healthy child.
authors.affiliation: Unit Clinical Genomics, Department of Genetics and Cell Biology, School for Growth and Development and for Cardiovascular Research, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address: bert.smeets@maastrichtuniversity.nl.
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
mesh_terms: D000818:Animals; D005111:Extrachromosomal Inheritance; D018014:Gene Transfer Techniques; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000517:prevention & control*; D011296:Prenatal Diagnosis / Q000379:methods*; D027724:Reproductive Techniques, Assisted
keywords: chromosome–spindle transfer; germ-line therapy; mtDNA disease; nuclear genome transfer; preimplantation genetic diagnosis; prenatal diagnosis