Background: The role of genetic testing

At present, some women with mutated mitochondria who would like to use their own eggs to have a baby can be offered ways to minimise, but not prevent, their risk of passing on passing mitochondrial disorders to their child. This may be done by using embryo testing techniques to gather more information about the risk of passing on health problems. They may be offered preimplantation genetic diagnosis (PGD) and/or prenatal diagnosis (PND).

Preimplantation genetic diagnosis (PGD)

Preimplantation genetic diagnosis (PGD) is a process used with IVF techniques, in which one or more cells are removed from an in vitro embryo for genetic testing. For women who are at risk of passing on mutated mitochondria, PGD can be used to identify which, if any, of their embryos contain the lowest level of mutated mitochondria. Using this information, women or couples may decide to go ahead with, or to avoid putting back specific embryos into the woman’s womb in the hopes of beginning a pregnancy.

However, because many of the different types of mtDNA mutation are inherited in a complex and poorly-understood way, for many families PGD will not be useful because information gathered from their embryos will not permit doctors to make an accurate prognosis for any prospective child.

This can be due to the fact that - in many types of mitochondrial mutation - normal mitochondria exist in the cells alongside mutated mitochondria. The ‘mutant load’ (a threshold proportion of mutations in the cell beyond which the person will experience health problems) can be unpredictable and differs between individuals.

Additionally, within each individual’s body, the level at which the mutant load in their cells begins to cause problems will vary for different bodily tissues. With some types of mtDNA mutations, the mutant load in cells can also change over time, making it extremely difficult to predict how severely symptoms may be experienced in future.

PGD is also not suitable for the couples who are at the greatest risk of passing on unhealthy mitochondria, where the intending mother has a particularly high proportion of mutated mitochondria (‘heteroplasmy’), or where all of her mitochondria are mutated (‘homoplasmy’). If all of a couple’s embryos will be affected to the extent that the resulting children will have the symptoms of mitochondrial disorders, using donor eggs is currently the only way in which couples can guarantee that their children will be born unaffected.

There are currently only a minority of MtDNA mutations for which PGD can inform a reliable diagnosis¹.  These relatively few instances have specific characteristics: for example, that the severity of the disease experienced is closely linked to the level of mutant load in the cells; that the mutated mitochondria are uniformly distributed throughout the cells of the body; and that the mutant load is likely to remain at a stable level over the person’s lifetime.

Prenatal diagnosis (PND)

Prenatal diagnosis (PND) is another technique which samples cells for testing in order to gather genetic information. In this case, fetal cells are taken for analysis when a woman is pregnant. As with many other prenatal tests, depending on the information that is received, some women and their partners may face a difficult decision about whether to continue the pregnancy or to request a termination.

As with PGD, because the predictive power of the information varies greatly between different types of mitochondrial mutation, only some patients are suitable for PND.

In addition to the difficulties experienced by any couple faced with a decision of whether or not to end a wanted pregnancy because of a fetal health problem, decision-making can be especially difficult in the case of mitochondrial mutations as the degree of certainty of information gained via PND may only be improved if a woman undergoes sequential testing into the third trimester (weeks 28-30)^2,3, by which time her pregnancy is well advanced.

PGD and PND techniques are not of use to couples who are already aware that they may be very likely to pass on a high level of mitochondrial mutations, or will pass on 100 per cent mutated mitochondria. These couples currently have no options open to them if they wish to use the woman’s egg to have an unaffected baby.

Only the emerging techniques such as maternal spindle and pronuclear transfer would in theory offer women wanting to use their own gametes to have children the opportunity to prevent the transmission of mitochondrial disorders, regardless of the type of mitochondrial disorder that they are likely to pass on.

Next: Pronuclear transfer (PNT)

Previous: Ethical questions arising

_{¹ Bredenoord AL, Pennings G, Smeets HJ, and de Wert G (2008) Dealing with uncertainties: ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders Human Reproduction Update 14: 83-94.}

_{² Faivre L, Cormier-Daire V, Chrétien D et al. (2000) Determination of enzyme activities for prenatal diagnosis of respiratory chain deficiency Prenatal diagnosis 20: 732-7}

³ _{Steffann J, Gigarel N, Corcos J et al. (2007) Stability of the m.8993T→G mtDNA mutation load during human embryo-fetal development has implications for the feasibility of prenatal diagnosis in NARP syndrome Journal of Medical Genetics 44: 664-9.}