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Report provided to the Human Fertilisation and Embryology Authority, April 2011 - page 12 / 45





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data from these two cell biopsies has been reassuring6, as has analysis of each cell within non-replaced affected embryos, which suggests that mitochondrial mosaicism is unusual. However routine removal of two cells has been shown to compromise the chances of pregnancy following PGD7. An alternative, that has more cells available for testing, is to wait until the blastocyst stage (day 5 or 6 of embryo development) where a group of cells from the outer trophectoderm layer can be removed with higher chances of pregnancy. This method is not thought to compromise embryo viability, but any delay in genotyping may require the embryo to be frozen and then thawed before transferring at another time. Although the available evidence suggests that the proportion of abnormal mtDNA in trophectoderm cells is equivalent to that in the inner cell mass, the data are based on relatively few embryos.

3.3.3 Threshold level of abnormal mtDNA: PGD for mtDNA disorders does not result in embryos free from abnormal mtDNA; it identifies embryos that have a level of heteroplasmy that is unlikely to result in mitochondrial disease, which in some instances may be as high as 40%. A critical issue is the level of abnormal mtDNA, assessed at biopsy, which should exclude an embryo from being suitable for transfer. This needs to be set based on the best estimate of mitochondrial proportions associated with health rather than disease. This may differ for different mutations and different clinical presentations. It may not always be possible to set a precise proportion of heteroplasmy that will guarantee the offspring to be disease-free into adult life, whilst at the same time finding sufficient embryos that fulfill the criteria for safe replacement. The only embryos available may exceed the proportion previously agreed for safe transfer. In addition, any female born after this procedure, even without apparent mitochondrial disease, will be at risk of having affected children. This has led some to propose the idea of combining the PGD test for abnormal mtDNA with sex selection, so that only sons are born.

6 7 Professor Hubert Smeets, Maastrict UMC, oral presentation to panel A. De Vos, C. Staessen, et al. (2009). Impact of cleavage-stage embryo biopsy in view of PGD on human blastocyst implantation: a prospective cohort of single embryo transfers.Hum. Reprod. 24(12): 2988-2996 Page 12 of 45

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