heteroplasmy may make the results unclear. In addition, finding that the mtDNA is normal will not help identify the affected nuclear gene.
Further work is required to develop reliable assays for mitochondrial disease caused by mutations in nuclear DNA, especially as PGD may be the preferred alternative for those who wish to prevent transmission of such diseases without having to consider prenatal diagnosis and possible termination of an affected pregnancy.
Effectiveness and safety of PGD for mtDNA disease
PGD can be used to select embryos with levels of abnormal mtDNA that are low enough to be unlikely to manifest a disease in the resulting child or adult. Again, the exact mutation will have had to be previously identified. However, even with this knowledge, PGD is not appropriate for all patients with abnormal mtDNA. It cannot be used where there is a high heteroplasmic or homoplasmic level of abnormal mtDNA, estimated to be present in about 20% of patients at risk. Where a mother is heteroplasmic, PGD cannot eliminate all abnormal mtDNA being passed on to the resulting child. It can only ever reduce the risk of the child having a mtDNA disorder by transferring embryos with as low a level of abnormal mtDNA as possible. Therefore the accuracy of the embryo biopsy and the level of abnormal mtDNA per embryo are important when assessing the effectiveness and safety of PGD for mtDNA disorders.
3.3.2 Embryo biopsy: The available evidence suggests that mtDNA is not replicating during early division of cells in an embryo. Mitochondria are therefore likely to be partitioned between these early cells at random and, because there are many per cell at this stage, theory would suggest that one blastomere should be representative of all others. However concern about non-uniformity (mosaicism) found between cells tested for nuclear chromosome abnormalities in embryos5 led to two cells being removed in initial clinical PGD procedures for mtDNA diseases in order to avoid misdiagnosis. So far,
5 L. Wilton, A. Thornhill, et al. (2009). “The causes of misdiagnosis and adverse outcomes in PGD.” Hum. Reprod. 24(5): 1221-1228 Page 11 of 45