Concise Reviews: Assisted Reproductive Technologies to Prevent Transmission of Mitochondrial DNA Disease

Abstract

While the fertilized egg inherits its nuclear DNA from both parents, the mitochondrial DNA is strictly maternally inherited. Cells contain multiple copies of mtDNA, each of which encodes 37 genes, which are essential for energy production by oxidative phosphorylation. Mutations can be present in all, or only in some copies of mtDNA. If present above a certain threshold, pathogenic mtDNA mutations can cause a range of debilitating and fatal diseases. Here, we provide an update of currently available options and new techniques under development to reduce the risk of transmitting mtDNA disease from mother to child. Preimplantation genetic diagnosis (PGD), a commonly used technique to detect mutations in nuclear DNA, is currently being offered to determine the mutation load of embryos produced by women who carry mtDNA mutations. The available evidence indicates that cells removed from an eight-cell embryo are predictive of the mutation load in the entire embryo, indicating that PGD provides an effective risk reduction strategy for women who produce embryos with low mutation loads. For those who do not, research is now focused on meiotic nuclear transplantation techniques to uncouple the inheritance of nuclear and mtDNA. These approaches include transplantation of any one of the products or female meiosis (meiosis II spindle, or either of the polar bodies) between oocytes, or the transplantation of pronuclei between fertilized eggs. In all cases, the transferred genetic material arises from a normal meiosis and should therefore, not be confused with cloning. The scientific progress and associated regulatory issues are discussed. Stem Cells 2015;33:639–645

Assisted reproductive technology in reproductive medicine — possibilities and limitations

“…12 www. journals.viamedica.pl/ginekologia_polska has been approved by the FDA in the US, it is the source of much controversy in many countries [28,29,36].…”

When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

“…Annual ophthalmologic, audiologic, cardiologic (electrocardiogram and echocardiogram), and endocrinologic ( fasting blood sugar and TSH) assessments also are recommended 25 . Children of woman with mtDNA mutation can inherit the mutation 34 . The risk to other family members depends on the genetic status of the mother 25,34 .…”

“…Children of woman with mtDNA mutation can inherit the mutation 34 . The risk to other family members depends on the genetic status of the mother 25,34 . However, it is appropriate to evaluate other family members because the phenotype manifestation results from a combination of factors, due to the different inherit percentages of mutant mtDNA, and therefore, can have a wide range of clinical symptoms from asymptomatic to full manifestation.…”

“…It is appropriate to offer genetic counseling (including discussion of potential risks to children and reproductive options) to young women in fertile age who are affected or at risk 58 . Prenatal testing and preimplantation genetic diagnosis may be an option for some families in which the disease-causing mutations have been identified but their interpretation is complex yet 25,34,58 . The transfer of nuclear DNA from fertilized oocytes or zygotes harboring a mtDNA mutation to an enucleated recipient cells could theoretically prevent transmission of mtDNA diseases and this promising therapy is under investigation 34,58 .…”

“…Prenatal testing and preimplantation genetic diagnosis may be an option for some families in which the disease-causing mutations have been identified but their interpretation is complex yet 25,34,58 . The transfer of nuclear DNA from fertilized oocytes or zygotes harboring a mtDNA mutation to an enucleated recipient cells could theoretically prevent transmission of mtDNA diseases and this promising therapy is under investigation 34,58 . In the pregnancy, MELAS women should be monitored, mainly for diabetes mellitus and respiratory failure, which may require specific therapeutic interventions 25 .…”