PGD for Mitochondrial Disease

Mitochondrial Diseases affect the way that the body uses the energy (food) it consumes to power itself.

Our pre-implantation genetic disease (PGD) service can help to identify Mitochondrial Diseases that could be passed onto children.

Generating power

The human body requires a lot of energy to work properly and gains this energy from the proteins, carbohydrates and fats in food. The body is unable to access this energy directly and needs to change it into a form that it can use as a power source called adenosine triphosphate (ATP for short). This process is performed by tiny batteries, found in every cell, called mitochondria.

There are millions of mitochondria throughout the body, but some extremely active organs such as brain and muscle, require huge amounts of energy and have a large number of mitochondria. If mitochondria are not working properly then the body cannot make enough ATP to provide sufficient power, and this leads to disease. 

Five protein structures known as ‘complexes’ allow mitochondria to convert energy into ATP. These complexes are found inside mitochondria and are made up of lots of smaller units. The information needed to make these units is stored in DNA. Mitochondria contain their own DNA, which stores the blueprint for some of these units, while information for making others is found in the cell control centre called the nucleus. This means that problems in mitochondria can be caused by mutations (changes) in either mitochondrial or nuclear DNA and can be passed on through families in different ways. 

Inheritance of Mitochondrial Diseases

Some patients have a form of mitochondrial disease caused by point mutations in mitochondrial DNA. How severely they are affected depends partly on how much of their mitochondrial DNA is mutated. Female patients with this type of disease risk passing the mutation on to all of their children (‘maternal inheritance’). The severity of any disease in the child then depends on how much abnormal mitochondrial DNA was present in the mother’s egg. Male patients cannot pass on the mutation because although their sperm may contain mutated mitochondrial DNA, this does not survive in the fertilized egg.

All of the machinery necessary for maintaining and repairing mitochondrial DNA and most of the units used to make the complexes are coded in nuclear DNA. Unlike mitochondrial DNA there are only two copies of nuclear DNA. Mutations in one copy can sometimes cause disease, but in other circumstances both copies need to be affected before disease occurs.

If inheriting one abnormal gene from either parent is enough to cause disease then there is a fifty-fifty chance of passing on the disease. This is called autosomal dominant inheritance. If on the other hand both copies of the gene must be mutated to cause disease then this will only happen on the rare occasion that two carriers (each with one affected copy) meet and have children. The risk that the child will be affected is one in four, with half becoming carriers and one in four escaping completely. This is called autosomal recessive inheritance. Only some of the nuclear genes that cause problems with mitochondria are known, but it is important to try and identify them as we can then better predict the risk to other family members.

Specific advice for women with mitochondrial disease

Mitochondrial DNA mutations are present in many patients with mitochondrial disease, but create a particularly difficult dilemma for women, as only they can pass on the mutation to their children. A range of reproductive advice and possibilities is available for women with mitochondrial DNA disorders including:

Genetic counselling 

Since mitochondrial DNA is transmitted from mother to child, the offspring of mothers with mitochondrial DNA mutations are at risk of developing the same disease. However, it is very important to realise that the risk to offspring varies from one mutation to another.  Furthermore, it has to be stressed that even though a mitochondrial DNA mutation may be transmitted to the child this does not necessarily mean that the child will develop mitochondrial disease. It is recommended that mothers with mitochondrial DNA mutations who want to have children should seek specialist advice if they are at all concerned about the possibility. The specialist advice should come from doctors who have experience of counselling specifically about mitochondrial genetic disorders.  

Oocyte donations

Women with mitochondrial DNA mutations may wish to consider oocyte donation. Oocyte donation is when an egg from an unrelated female is fertilised by the husband or partner’s sperm and this fertilised egg is then placed into the womb. This means that the baby will not have any mitochondria from the mother, only from the donor female. This is certainly a way to prevent the transmission of mitochondrial disease. At present in most countries there is a shortage of donor eggs. This means there can be quite a long waiting list for a technique like oocyte donation. This technique involves undergoing in-vitro fertilisation (IVF) with intracytoplasmic sperm injection (ICSI). 

Chorionic villus sampling (CVS) or Amniocentesis

These are two procedures in which cells, originating from the developing baby, are tested to see whether or not the baby carries the mitochondrial DNA mutation. These methods are often used for nuclear genetic disorders or abnormalities of the chromosomes such as Down’s syndrome. These two techniques are done at different stages during a pregnancy and while both are considered safe, there is a small risk of miscarriage associated with each procedure. Also, there is no point in undergoing one of these tests with the (small) risk involved if terminating the pregnancy would not be a consideration.

At present there have been only a few studies where CVS has been done for mothers with mitochondrial DNA mutations and it is our belief that this testing should remain in very specialised centres where appropriate, experience-based genetic advice can be provided.

Pre-implantation Genetic Diagnosis (PGD)

This technique, which can also be used for nuclear genetic disorders, involves the patient undergoing IVF with ICSI and a single cell from the developing embryo is removed and undergoes genetic analysis before placing the embryo back into the womb.

The ideal would be that if several embryos were generated during the IVF procedure, only embryos in which there was no mitochondrial DNA mutation, or very low amounts of the mitochondrial DNA mutation, would be placed back into the womb. This could either prevent or greatly reduce the chance of the child developing mitochondrial DNA disease.

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