Mitochondrial Donation
Symposium Presentations
The UK Experience
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Mitochondrial Donation in the United Kingdom
- The United Kingdom became the first country to legalize the creation of human embryos from the DNA of three people.
- A lot of work has been done to ensure the safe implementation of mitochondrial donation in the United Kingdom.
- Mitochondrial donation could help approximately 150 couples each year who are at risk of passing on certain genetic diseases.
Specialised Services for Mitochondrial Disease
- A highly specialised service was created within the NHS to provide reproductive options to women who have pathogenic mtDNA changes.
- Mitochondrial donation is not the only focus; ensuring couples are fully informed about all their options is also a priority.
- Women seeking mitochondrial donation often have mitochondrial disease themselves, and partners may lack knowledge about it. Education on mitochondria, their function, and the impact of diet is provided.
Understanding Mitochondrial Disease and Inheritance
- Mitochondrial disease is complex and personalised, with varying forms and genetic implications. The focus is on maternal inheritance, as paternal mitochondria are discarded during fertilization.
- Genetic diagnosis is confirmed through tissue samples (mouth swab, urine, blood) to assess the level of faulty mitochondria and inform reproductive options, including fitness for fertility.
Reproductive Options and Procedures
- Preimplantation genetic diagnosis (PGD) involves fertilizing multiple eggs, testing each embryo for the lowest level of faulty mutations, and transplanting the selected embryo back into the woman.
- Mitochondrial donation involves fertilizing both a donor egg and the egg of the woman with mitochondrial disease, removing the nuclear material from both, discarding the faulty mitochondria from the woman's egg, and transplanting her nuclear material into the donor egg.
Monitoring and Follow-up
- Children born from mitochondrial donation are followed up with a rigorous pathway of developmental milestones, including checking for carryover of the faulty gene and an additional assessment at 18 months.
The State of Play In Australia
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The clinical application with Professor Carolyn Sue
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Mitochondrial Disease Inheritance and Symptoms
- Mitochondrial disease can be caused by changes in either mitochondrial DNA or nuclear DNA.
- Mitochondrial DNA is inherited solely from the mother, meaning that all children of a mother with a mitochondrial DNA mutation are at risk of inheriting the mutation and developing mitochondrial disease.
- The severity of mitochondrial disease symptoms is generally correlated with the proportion of mutated mitochondrial DNA within cells, a concept referred to as heteroplasmy.
- Mitochondrial diseases can manifest in various ways depending on the affected organ, including heart troubles, seizures, strokes, and migraines.
Case Studies of Mitochondrial Disease Inheritance
- A 24-year-old female patient with a low mutational load of the m.3243A>G genetic change, which is present in 1 in 500 Australians, sought advice on the risk of transmitting mitochondrial disease to her children. Despite her low mutation load, her brother had MELAS syndrome with a 25% mutation load in his blood.
- Another case involved a female patient with a family history of Leber's hereditary optic neuropathy (LHON) caused by the m.11778G>A genetic change. Although LHON is associated with high mutation loads, males with 100% mutation load only have a 50% chance of developing the disease in their lifetime.
Family Planning Options for Individuals with Mitochondrial DNA Mutations
- People who have mitochondrial DNA changes have several options if they want to have children, including natural pregnancy, preimplantation genetic diagnosis, and mitochondrial donation.
- Mitochondrial donation replaces faulty mitochondria, reducing the amount of mutated mitochondrial DNA passed from mother to child.
- Mitochondrial donation is currently the best option for people with mitochondrial DNA mutations to have a biologically related child with a lower risk of inheriting mitochondrial disease.
The clinical application with Dr Suzanne Sallevelt
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Mitochondrial Disease Diagnosis and Testing
- Heteroplasmy is the mixture of faulty and normal mitochondrial DNA (mtDNA), which is common in mitochondrial diseases. The threshold for developing a mitochondrial disease is often unknown for a given mutation.
- Amniocentesis is preferred over chorionic villus sampling (CVS) for prenatal testing of mtDNA mutations because it more accurately reflects the baby's mutation load. However, amniocentesis cannot always determine if a baby will be healthy or sick.
Preimplantation Genetic Testing (PGT) for Mitochondrial DNA Mutations
- Preimplantation genetic testing (PGT) involves testing embryos created through IVF for mtDNA mutations. This allows parents to select embryos with mutation loads below the disease threshold, although these thresholds can be difficult to determine.
- Suzanne Sallevelt's team initially tested two cells from day-three embryos to determine mutation load but later switched to single-cell testing due to a low risk of misrepresentation (0.34%).
- Sallevelt suggests day-three preimplantation genetic testing (PGT) over day-five or -six testing for mitochondrial DNA (mtDNA) mutations, citing research demonstrating greater mutation load variation in later-stage embryos.
- Sallevelt notes that PGT data, specifically the observation of both positive and negative selection in mtDNA mutation transmission patterns, is crucial for establishing a transfer threshold for PGT and informing mitochondrial donation procedures.
Determining the Best Course of Action
- The most suitable option for a couple needs to be assessed on a case-by-case basis.
- Mutation-specific transmission patterns, including selection events, are relevant in this context.
The Patient Perspective
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- Rebecca Patterson, an Australian woman living with mitochondrial disease, was diagnosed at age 19 while working as a hairdresser.
- The Mito Foundation provided support and connected Rebecca with other people with mitochondrial disease.
- Rebecca advocates for the legalization of mitochondrial donation in Australia, believing it will allow her and others to have children without passing on the disease. mitochondrial disease, removing the nuclear material from both, discarding the faulty mitochondria from the woman's egg, and transplanting her nuclear material into the donor egg.
The IVF cycle
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- A typical IVF cycle involves ovarian stimulation, egg collection, sperm preparation, fertilization, embryo culture (for 2-6 days), and embryo transfer.
- During IVF, typically one or two embryos are transferred to the uterus, while the remaining viable embryos are frozen for potential future use.
- Mitochondrial donation, as an IVF technique, involves hyperstimulation and egg retrieval from two women, sperm collection from a male, fertilization, mitochondrial donation, embryo culture, potential embryo transfer and/or freezing, and pregnancy testing.
