Transmission & Recurrence Risks
The risk of transmitting a mtDNA disorder is difficult to assess because the offspring of a heteroplasmic woman may vary widely both in their phenotype and in their mutant load. This is because of the so-called bottleneck in transmission of mtDNA. We and others have shown that a single woman carrying pathogenic mtDNA mutants may transmit markedly different levels of variant mtDNA to different oocytes. Ours was the first study of the mitochondrial bottleneck in normal human oocytes. These and other data suggest that there may be a much smaller number of founder mtDNAs for each child than the 100,000 mtDNAs found in each normal oocyte. This mitochondrial bottleneck complicates prenatal diagnosis of mtDNA disorders, because small samples may be unrepresentative of the whole conceptus.
We have pioneered genetic counseling based on oocyte sampling. This has enabled us to estimate a patient specific recurrence risk and a good outcome. In control placentas we have demonstrated that the level of polymorphic heteroplasmic mtDNA variants is very similar in mother, baby and placenta. We are now developing criteria for prenatal diagnosis using pre-implantation genetic diagnosis and chorionic villous sampling (CVS). Now that our department has been joined by Dr Dagan Wells, a leading expert in genetic analysis of early embryos, we are able to offer preimplantation genetic diagnosis for some mtDNA disease.
We developed the current international consensus for reproductive options in mitochondrial disease, based on an workshop funded by the European Neuromuscular Centre Poulton J. et al, (2019), Neuromuscular Disorders, 29, 725 - 733