BACKGROUND: Mitochondrial disorders are often fatal multisystem disorders, partially caused by heteroplasmic mitochondrial DNA (mtDNA) point mutations. Prenatal diagnosis is generally not possible for these maternally inherited mutations because of extensive variation in mutation load among embryos and the inability to accurately predict the clinical expression. The aim of this study is to investigate if PGD could be a better alternative, by investigating the existence of a minimal mutation level below which the chance of an embryo being affected is acceptably low, irrespective of the mtDNA mutation. METHODS: We performed a systematic review of muscle mutation levels, evaluating 159 different heteroplasmic mtDNA point mutations derived from 327 unrelated patients or pedigrees, and reviewed three overrepresented mtDNA mutations (m.3243A>G, m.8344A>G and m.8993T>C/G) separately. RESULTS: Mutation levels were included for familial mtDNA point mutations only, covering all affected (n = 195) and unaffected maternal relatives (n = 19) from 137 pedigrees. Mean muscle mutation levels were comparable between probands and affected maternal relatives, and between affected individuals with tRNA- versus protein-coding mutations. Using an estimated a priori prevalence of being affected in pedigrees of 0.477, we calculated that a 95% or higher chance of being unaffected was associated with a muscle mutation level of 18% or less. At a mutation level of 18%, the predicted probability of being affected is 0.00744. The chance of being unaffected was lower only for the m.3243A>G mutation (P < 0.001). Most carriers of mtDNA mutations will have oocytes with mutation levels below this threshold. CONCLUSIONS: Our data show, for the first time, that carriers of heteroplasmic mtDNA mutations will have a fair chance of having healthy offspring, by applying PGD. Nevertheless, our conclusions are partly based on estimations and, as indicated, do not provide absolute certainty. Carriers of mtDNA should be informed about these constraints.
BACKGROUND:Mitochondrial disorders are often fatal multisystem disorders, partially caused by heteroplasmic mitochondrial DNA (mtDNA) point mutations. Prenatal diagnosis is generally not possible for these maternally inherited mutations because of extensive variation in mutation load among embryos and the inability to accurately predict the clinical expression. The aim of this study is to investigate if PGD could be a better alternative, by investigating the existence of a minimal mutation level below which the chance of an embryo being affected is acceptably low, irrespective of the mtDNA mutation. METHODS: We performed a systematic review of muscle mutation levels, evaluating 159 different heteroplasmic mtDNA point mutations derived from 327 unrelated patients or pedigrees, and reviewed three overrepresented mtDNA mutations (m.3243A>G, m.8344A>G and m.8993T>C/G) separately. RESULTS: Mutation levels were included for familial mtDNA point mutations only, covering all affected (n = 195) and unaffected maternal relatives (n = 19) from 137 pedigrees. Mean muscle mutation levels were comparable between probands and affected maternal relatives, and between affected individuals with tRNA- versus protein-coding mutations. Using an estimated a priori prevalence of being affected in pedigrees of 0.477, we calculated that a 95% or higher chance of being unaffected was associated with a muscle mutation level of 18% or less. At a mutation level of 18%, the predicted probability of being affected is 0.00744. The chance of being unaffected was lower only for the m.3243A>G mutation (P < 0.001). Most carriers of mtDNA mutations will have oocytes with mutation levels below this threshold. CONCLUSIONS: Our data show, for the first time, that carriers of heteroplasmic mtDNA mutations will have a fair chance of having healthy offspring, by applying PGD. Nevertheless, our conclusions are partly based on estimations and, as indicated, do not provide absolute certainty. Carriers of mtDNA should be informed about these constraints.
Authors: Auke B C Otten; Alphons P M Stassen; Michiel Adriaens; Mike Gerards; Richard G J Dohmen; Adriana J Timmer; Sabina J V Vanherle; Rick Kamps; Iris B W Boesten; Jo M Vanoevelen; Marc Muller; Hubert J M Smeets Journal: Genetics Date: 2016-10-21 Impact factor: 4.562
Authors: Kristin Engelstad; Miriam Sklerov; Joshua Kriger; Alexandra Sanford; Johnston Grier; Daniel Ash; Dieter Egli; Salvatore DiMauro; John L P Thompson; Mark V Sauer; Michio Hirano Journal: Hum Reprod Date: 2016-03-02 Impact factor: 6.918
Authors: Gael Cagnone; Te-Sha Tsai; Kanokwan Srirattana; Fernando Rossello; David R Powell; Gary Rohrer; Lynsey Cree; Ian A Trounce; Justin C St John Journal: Genetics Date: 2016-01-27 Impact factor: 4.562
Authors: Auke B C Otten; Suzanne C E H Sallevelt; Phillippa J Carling; Joseph C F M Dreesen; Marion Drüsedau; Sabine Spierts; Aimee D C Paulussen; Christine E M de Die-Smulders; Mary Herbert; Patrick F Chinnery; David C Samuels; Patrick Lindsey; Hubert J M Smeets Journal: Hum Reprod Date: 2018-07-01 Impact factor: 6.918