In this week’s WCMR ‘Research in Progress’ meeting, we heard from Dr Sarah Pickett who talked about her recent publication in New England Journal of Medicine. Here, she tells us more about the study that will help predict which women could benefit from mitochondrial donation.
Mutations in mitochondrial DNA (mtDNA) are responsible for a group of maternally inherited mitochondrial diseases that are clinically very variable. Women who carry these mtDNA mutations risk passing them onto their children, who could then develop a severe mitochondrial disease depending on the level of faulty mtDNA they inherit from their mother. Mitochondrial donation is a novel IVF-based treatment that can reduce this risk by replacing faulty mtDNA in the mother’s eggs with healthy mtDNA. This offers women who risk passing mtDNA mutations to their children the chance of having their own healthy child.
For each couple requesting this treatment, an individual licence must be granted by the Human Fertilisation and Embryology Authority (HFEA). The licence application must show that the woman is at significant risk of transmitting serious mtDNA disease to her children. In addition, it must also show that other reproductive options, such as preimplantation genetic diagnosis (PGD), are unlikely to succeed due to high levels of faulty mtDNA within the woman’s eggs. Our study aimed to identify these women who could benefit from mitochondrial donation.
To do this, we evaluated risk of transmission from mother to child for the m.3243A>G mutation in the MT-TL1 gene, which is present in about one third of our patient cohort. We analysed the mutation levels of 183 mother-child pairs from 113 mothers and found that mutation levels in the offspring varied. We mathematically modelled this transmission and used our model to predict the proportion of children a woman would be likely to have with low levels of faulty mtDNA.
We found that only one-quarter of children born to mothers harbouring 50% m.3243A>G level are predicted to have low enough levels of faulty mtDNA for PGD to be a suitable reproductive option. For some women with higher mutation levels, the number of eggs required to find any with a sufficiently low level of faulty mtDNA may be too high for PGD. In these cases, mitochondrial donation may be more appropriate.
We have developed a web-based tool that clinicians can use to estimate the risk for women carrying the m.3243A>G mtDNA mutation who are considering their reproductive options (http://www.newcastle-mitochondria.com/m3243ag-heteroplasmy-levels-in-children/) and plan to expand this work to include other mtDNA mutations in the future.