Hum. Reprod. Advance Access originally published online on July 29, 2008
Human Reproduction 2008 23(11):2392-2401; doi:10.1093/humrep/den290
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OPINION |
PGD to reduce reproductive risk: the case of mitochondrial DNA disorders
1 Maastricht University, Health, Ethics and Society and Research Institute GROW, Maastricht, The Netherlands 2 Ghent University, Bioethics Institute Ghent, Ghent, Belgium 3 University Hospital Maastricht Clinical Genetics, Maastricht, The Netherlands
4 Correspondence address. E-mail: a.bredenoord{at}zw.unimaas.nl
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Abstract |
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This paper discusses the pros and cons of introducing PGD for mitochondrial DNA (mtDNA) disorders such as NARP (Neurogenic muscle weakness, Ataxia, Retinis Pigmentosa)/Leigh, MELAS (Mitochondrial myopathy, Encephalopathy, Lactic acidosis, and Stroke-like episodes), private mtDNA mutations and LHON (Leber Hereditary Optic Neuropathy). Although there is little experience with PGD for mtDNA disorders, it is reasonable to assume that in many cases, the best one can achieve is the selection of the ‘least’ affected embryos for transfer. So instead of ‘promising’ parents a healthy child, PGD in these cases can only aim at reducing reproductive risk. From an ethical point of view, this raises challenging questions about parental and medical responsibilities. The main argument in favour of PGD is that it offers couples at risk the opportunity of reducing their chances of having a severely affected child. Potential objections are manifold, but we conclude that none of them supplies convincing moral arguments to regard risk-reducing PGD as unacceptable. Nevertheless, introducing this new application of PGD in clinical practice will raise further complex issues of determining conditions for its responsible use.
Key words: PGD/mitochondrial DNA/reproductive risk/ethics/genetic disorders
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Introduction |
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TopAbstractIntroductionBackgroundArguments in favour of...Arguments against PGD: valid...ConclusionFundingReferences |
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With the expanding unravelling of the causes of mitochondrial disorders, more women at a risk of having a child with a disorder caused by a mitochondrial DNA (mtDNA) mutation are identified. In order to prevent the birth of an(other) affected child, these ‘carrier’ women ask for prenatal diagnosis (PND). However, as the complexity of mitochondrial genetics negatively affects predictive value, PND is (at least for most mtDNA mutations) not a very satisfactory method of genetic testing (Bredenoord et al., 2008
). In view of this, PGD after IVF is proposed as an alternative. So far, PGD for mtDNA disorders has been performed twice and it has been seriously considered as an option in other cases (Bickerstaff et al., 2001; Steffann et al., 2006). Although PGD is subject to similar limitations as PND, PGD would allow testing prior to pregnancy. Because of this, difficult decisions are avoided about whether or not an unfavourable prediction would be a reason for abortion. Moreover, for those couples who already depend on IVF for fertility problems, PGD would be the logical approach to test for genetic disease. Nevertheless, PGD for mtDNA disorders is a new and controversial use of the technology. Traditional applications are targeted at Mendelian and chromosomal disorders. In those cases, it is (in principle) certain whether the relevant gene defect is present and which of the available embryos can safely be transferred. When PGD is performed for mtDNA disorders, this will probably be less clear. Although there is little experience with PGD for mtDNA disorders, it is conceivable that in many cases the best one can achieve is the selection of the ‘least’ affected embryos for transfer. Instead of ‘promising’ parents a healthy child, PGD in those cases can only aim at reducing reproductive risk. From an ethical point of view, this raises challenging questions about parental and medical responsibilities. Is it acceptable to start an IVF/PGD procedure knowing that there may only be affected embryos? Is it acceptable to knowingly bring a child into the world whose health may be (significantly) impaired?
In this article, we aim to contribute to the ethical discussion of the developing practice of PGD for mtDNA disorders. We will focus on the question of whether PGD for mtDNA disorders is acceptable. In other words, is PGD acceptable as a means of reducing rather than eliminating genetic risk?
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Background |
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TopAbstractIntroductionBackgroundArguments in favour of...Arguments against PGD: valid...ConclusionFundingReferences |
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Mitochondrial disorders are usually severe. They involve defects in energy production and affect the most energy demanding tissues such as the central nervous system, heart and skeletal muscles, liver and kidneys. The clinical phenotype of mitochondrial diseases is extremely variable, affecting patients at any age and in a wide variety of tissues. Mitochondrial diseases cause chronic morbidity and can be fatal at young age. In view of the absence of effective treatment (Taylor and Turnbull, 2005
; Chinnery et al., 2006), preventing the transmission of mitochondrial disorders is considered to be of key importance (White et al., 1999a; Graff et al., 2000; Chinnery and Turnbull, 2001; Dahl and Thorburn, 2001; Thorburn and Dahl, 2001; Thorburn, 2004; Jacobs et al., 2005; Brown et al., 2006; Schapira, 2006; Spikings et al., 2006). Mitochondrial disorders caused by a pathogenic mutation encoded in the nuclear DNA follow a Mendelian pattern of inheritance, causing (in cases where the molecular defect is known) no specific problems for prenatal or preimplantation genetic testing. However, many mitochondrial diseases are caused by a pathogenic mutation in an mtDNA-encoded gene. Some of these mutations are homoplasmic, meaning that only mutant mtDNA is present in all tissues of an affected individual. Genetic testing aimed at selective abortion or selective transfer is generally not a useful option in homoplasmic mtDNA mutations (we will shortly discuss a possible exception to this). Homoplasmy will be present in all embryos and fetuses of a woman carrying the mutation, since mtDNA is always maternally inherited.
Most mtDNA mutations, however, are heteroplasmic. This means that there is a mixture of normal and mutant mtDNA, the level of which can differ among tissues. If the mutant load, i.e. the ratio of mutant to normal mtDNA, exceeds a tissue- and individual-specific threshold, clinical features become manifest. However, exact genotype–phenotype correlations are usually lacking even within families. With regard to heteroplasmic mtDNA mutations, genetic testing aimed at selective abortion or transfer may be an option. In this article, we will discuss the possible role of PGD, even though many considerations will ‘mutatis mutandis’ also apply to PND.
Preventing the transmission of mtDNA disease is fraught with uncertainties. In view of this, the mitochondrial research community has developed criteria for ascertaining phenotype predictability. These criteria were developed in the context of PND (Poulton and Turnbull, 2000). When we would extrapolate these criteria to PGD, PGD could reliably be offered when there is:
- a close correlation between the mutation load and disease severity;
- a uniform distribution of mutant mtDNA in all blastomeres;
- no change in mutant load with time.
Only few mutations fulfil these criteria and even in those cases exceptions may occur. Owing to the existence of many different types of mtDNA mutations, we earlier proposed a further classification (Bredenoord et al., 2008). We will use this classification to illustrate the moral difficulties and opportunities of PGD.
The first group regards de novo mutations, but PGD will not often be considered an option for this category as the recurrence risks are fairly low (Chinnery et al., 2004).
The second group regards stable mutations, with a predictable outcome. The main examples are the mutations m.8993T>G and m.8993T>C, leading to the neurodegenerative diseases NARP (Neurogenic muscle weakness, Ataxia, Retinis Pigmentosa) and Leigh syndrome. Both mutations have a strong genotype–phenotype correlation and show very little tissue-dependent or age-dependent variation in mutant load (White et al., 1999b,c; Dahl et al., 2000). PGD has been reported once for the m.8993T>G mutation, which resulted in the transfer of two mutant-free embryos, leading to the birth of one thus far healthy child (Steffann et al., 2006). For these two mutations, reliable predictions can only be made if testing reveals a mutant load below 60%, meaning that the child is very likely to be healthy, or above 90%, in which case the child is very likely to be affected. There is a grey zone between 60 and 90% mutant load (Tatuch et al., 1992; Ciafaloni et al., 1993). This means that also with regard to the stable mtDNA mutations that fulfil the criteria mentioned above, PGD may lead to difficult questions. What if only embryos with a mutant load in the grey zone turn out to be available? Would it be acceptable to transfer these if that is what the couple requests? Is PGD acceptable if it may lead to such dilemmas? Or should its use be restricted to cases where grey zone outcomes are not to be expected?
The third group regards unstable mutations, with an unpredictable outcome. An example of this is the m.3243A>G mutation leading to MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), one of the most common mtDNA disorders (Poulton and Turnbull, 2000). The mutation shows a capricious development and genotype–phenotype correlations do not show a consistent pattern (Chinnery, 2002). However, according to experts in the field, a fairly low mutant load generally gives a better prognosis than a fairly high one. With respect to PGD, this implies that transfer of embryos with a low mutant load can be expected to lead to a higher chance of unaffected or mildly affected children. However, even in the more favourable cases (when embryos with a low mutant load are available) the child may still be affected.
The fourth group contains mutations with an unknown outcome: the private point mutations, which are patient or family-specific mutations. Characteristic for these mutations is that very little is known about them. Insufficient evidence exists to decide whether they follow the criteria above and thus allow reliable predictions. As with the m.3243A>G mutation leading to MELAS, PGD may nevertheless be an option: the transfer of an embryo with a low mutant load can be expected to lead to a higher chance of an unaffected or mildly affected child, but also here exceptions may occur.
As a final illustration of the difficulties surrounding PGD for mtDNA disorders, we point at the fifth group of homoplasmic mutations. Homoplasmic mutations are present in 100% of the mtDNA. The main example of this group is LHON (Leber Hereditary Optic Neuropathy). Most patients, usually males, experience visual loss in their late teens or early 20s. About 50% of men and 10% of women carrying a pathogenic mtDNA mutation actually develop Leber's disease (Huoponen et al., 2002; Man et al., 2002; Hudson et al., 2007). PGD for LHON with selective transfer of female embryos has been reported once, but this did not result in a pregnancy (Bickerstaff et al., 2001). As the penetrance of the disease is considerably higher in men than in women, PGD followed by sex selective transfer of female embryos would lower the risk of blindness in comparison with natural reproduction from 30 to 10% (Spruijt, 2007). This 10% risk is unavoidable. Here again, the issue is whether PGD is acceptable if, instead of eliminating the risks of disease transmission, it will at best lead to risk reduction.
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Arguments in favour of PGD |
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TopAbstractIntroductionBackgroundArguments in favour of...Arguments against PGD: valid...ConclusionFundingReferences |
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At least three arguments can be advanced for offering couples PGD for mtDNA mutations. Notwithstanding the limitations of genetic testing for mtDNA mutations, both PND and PGD offer couples at risk the opportunity to reduce their risk of having a severely affected child. It contributes to reproductive confidence. PGD not only has the additional advantage of testing prior to pregnancy, but also of testing several embryos in one cycle. This enlarges the chances of obtaining embryos without the relevant mutation or with a relatively low mutant load (or in case of PGD for LHON: female embryos). Ideally, one would only transfer embryos without a (detectable) mutant load. But in cases where these are not available, PGD for heteroplasmic disorders such as NARP/Leigh, MELAS and the private point mutations at least allows transfer of the embryo with the lowest mutant load. In such cases, selective transfer of the embryo with the lowest mutant load may still be beneficial with respect to (i) the risk of developing the disease and (ii) the severity of the disease. With regard to LHON, selecting the least affected embryo is no option, as all embryos will have a 100% mutant load. However, since the penetrance of the disease is sex-dependent, selecting female embryos will reduce the risk of clinical disease in comparison with spontaneous conception from 30 to 10%. The main argument for PGD would thus be that it allows couples at risk to avoid the higher risks of natural reproduction, by eliminating embryos with a very high mutant load.
This is indeed a limited advantage. For couples at risk who definitely want an unaffected child, PGD will not be an attractive option, except when mutation-free embryos are available. However, due to the limited experience with PGD for mtDNA disorders, it is not clear how often that will be the case. Studies done by Steffann et al. (2006) show that, for the m.8993T>G mutation leading to NARP, mutant load among embryos is likely to be skewed. This means that low mutant load or mutation-free embryos may well be available. However, no such information is available for other mtDNA mutations. Other couples may be inclined to accept transmitting certain health risks if—short of refraining from having a genetically related child—that is their only alternative. For those couples, PGD would be of value by allowing them at least to limit their reproductive risks. Furthermore, adding PGD seems a logical step for those already having an indication for IVF due to fertility problems.
The second argument in favour of PGD concerns reproductive autonomy. This is usually defined as the right to control one's own procreation unless there is a compelling reason for denying a person that control (Dworkin, 1993). The rationale behind this principle is that in a liberal democratic society, the presumption is that people should be free to make their own choices according to their own values (Harris, 2007). Denying couples access to PGD for mtDNA disorders is only acceptable when good and sufficient reasons exist to do so. We will discuss below whether indeed good and sufficient arguments exist for not offering PGD.
Thirdly, as ‘the proof of the pudding is in the eating’, doing PGD will generate important new scientific data to guide counselling and decision-making in future cases. Analysis of embryos not selected for transfer, and follow-up studies of the children born after PGD, can be expected to considerably contribute to our knowledge.
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Arguments against PGD: valid objections? |
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TopAbstractIntroductionBackgroundArguments in favour of...Arguments against PGD: valid...ConclusionFundingReferences |
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What are the possible objections to PGD for mtDNA disorders—and are these objections valid? Do they undermine the acceptability of PGD for mtDNA disorders?
PGD for mtDNA disorders does not respect the welfare of the child
In a recent report by the Health Council of the Netherlands, PGD is defined in terms of allowing couples at high genetic risk to have a child not affected by the relevant disease (Health Council of the Netherlands, 2006). Similarly, in its ‘Guidance on Preimplantation Testing', the British Human Fertilisation and Embryology Authority states that ‘the purpose of PGD is to provide information that allows unaffected embryos to be selected for transfer’ (Human Fertilisation and Embryology Authority, 2003). Both reports define the goal of PGD as providing couples at risk to have a child not affected by the particular disease. This must of course be qualified: unaffected children can never be guaranteed with certainty, also because a small chance of misdiagnosis is an inherent part of PGD (and this was even more so in the early days of PGD; before the introduction of linked markers, there was a 4–8% chance of misdiagnosis). But, as shown by the examples given above, PGD for mtDNA mutations is a special case, in that it is not the technical limitations that causes the residual risks, but an embryo at (small) risk is knowingly transferred. Transferring unaffected embryos can not, even with qualifications, be seen as the aim of the procedure.
A first possible objection to PGD for mtDNA disorders may therefore be that it is at odds with the welfare of the future child. It is widely acknowledged that in reproductive medicine, the welfare of the child should be an important consideration. In this field, doctors have a dual responsibility: towards the couple asking for help and towards the child conceived by his/her assistance. With regard to PGD for mtDNA disorders, the question arises whether it is acceptable to knowingly conceive a child with a (significantly) higher risk of developing a disease. This is first of all a question that the future parents should ask themselves. However, the active part played by doctors in the conception of the child means that they cannot comfortably hide behind parental autonomy. After all, when offering IVF/PGD to carriers of mtDNA mutations, doctors are actively involved in bringing a child into the world whose health may be seriously compromised. Are not doctors in those cases inducing rather than reducing health risks? If so, whether this would be morally acceptable is strongly connected to one's view regarding the responsibility of the physician towards the welfare of the child.
Earlier, we described three possible accounts of what the appeal to the welfare of the child would entail (De Wert, 1999; Pennings, 1999; Bredenoord et al., 2008). These standards are developed to assess whether reproduction and as a consequence offering medical assistance to reproduction would be justifiable. According to the ‘minimum threshold standard', offering assisted reproduction technology is acceptable as long as the future child can be expected to have a life that reasonable persons would not regard as ‘worse than death’ (Harris, 2000; Cavaghan, 2007). Applied to our discussion, the standard entails that transferring embryos at risk is acceptable, provided the clinical manifestations of the disease are not so severe that an affected child would be better off dead. With regard to sex-selection in PGD for LHON, the worse case scenario is that the girl would become blind at a young age. Although a serious impairment, most would agree that this still remains a life worth living. Other things being equal, the welfare of the child does not provide a valid argument against doctors offering IVF/PGD. Also the other mtDNA mutations will probably enable the child to live a life worth living, though this may depend on the severity of the clinical symptoms. In particular, for mutations with a highly variable expression, such as the m.3243A>G mutation leading to MELAS, judgements will be complicated. The reasoning behind this first standard is that even if the child can be expected to have a life burdened by disability or disease, bringing it into existence would normally not amount to harming it. This is because ‘this' child could not possibly have had a better life (Parker, 2007). The only real alternative would have been non-existence (Parfit, 1984). According to the proponents of this standard, the child can only be harmed by a life so awful that it would be worse than not living at all. Insofar as violating the interests of the future child is concerned, this line of reasoning is generally accepted. There is, however, less consensus about whether this settles the issue with regard to justifying assisted reproduction. Many argue that even if being brought into the world does not harm the child, this does not make it a matter of moral indifference what quality-of-life the child can be expected to have (Arras, 1990; Steinbock and McClamrock, 1994; Parker, 2005). Although no harm is done in the sense of a violation of the child's interests, it is still meaningful to say in a more general sense that bringing a (seriously) handicapped or diseased child in the world is to cause avoidable harm. Since doing so may fall short both of parental and professional responsibilities, the minimum threshold standard strikes us as ‘aiming too low’ (Glover, 2006).
At the other end of the spectrum, we find the ‘standard of maximum welfare'. It says that reproduction, and as a consequence medical assistance to reproduction, is only acceptable if it leads to a child with the best possible quality-of-life. This would urge us to reject all forms of PGD for mtDNA disorders. Even in cases where unaffected embryos would be available for transfer, the (risk of) disease of the mother would remain a liability for the child's quality-of-life. However, this standard is also problematic. The difficulty here is that it would rule out far too much. If we were to take maximum welfare seriously as a criterion, should IVF still be available for couples living busy lives with both partners having demanding jobs? Or for couples of advanced age or of modest financial means? As the circumstances are always less than ideal, maximum welfare effectively denies reproductive assistance to most if not all. Moreover, it sets far stricter requirements for assisted reproduction than most people would apply to reproduction without medical help (Cavaghan, 2007).
Thirdly, the ‘reasonable welfare standard' involves an intermediate position between the other two. This is the view that for (assisted) reproduction to be justified, the child to be must have a reasonable chance of an acceptable quality-of-life. On this account, the contra-indication is a high risk of serious harm (in the sense of a seriously impaired quality-of-life) (Arras, 1990; Pennings, 1999; De Wert, 1999; Benatar, 2006). The standard requires that both the magnitude of the expected harm and the probability of the harm actually occurring, i.e. the harm/probability ratio, are included in the assessment. In our view, this third standard best balances both the welfare of the child and the importance people attach to having children of their own. Having a ‘reasonable chance of an acceptable quality of life’ is intentionally vague: it is a rule-of-thumb test, to be assessed case-by-case (Glover, 2006). Applied to PGD for mtDNA disorders, the standard entails that embryos not having a high risk of serious harm are eligible for transfer. With regard to the 8993 mutations leading to NARP/Leigh, this means embryos without detectable mutant load and embryos with a mutant load below 60%. Making reliable predictions regarding the health of the future child is difficult for embryos carrying a mutant load in the grey zone (60–90%). Whether embryos in the grey zone run a high risk of serious harm is therefore debatable. With regard to the m.3243A>G mutation leading to MELAS and the private point mutations, embryos without a (detectable) mutant load would in any case be eligible, whereas there may be discussion about transferring embryos with a low mutant load. Although implying a risk of serious harm, it seems reasonable to assume that this would not amount to a high risk. Nevertheless, transferring such embryos is at the margins of acceptability (Arras, 1990). We regard this as a borderline case about which reasonable people can have different opinions. Sex-selective PGD for homoplasmic LHON, finally, raises the question of how a 10% lifetime risk of serious visual impairment should be assessed. Most people will agree that becoming blind is not so serious that it would make a life not worth living. From the perspective of the reasonable welfare standard, however, this is not enough. The question is whether the future child can be expected to have an acceptable quality-of-life. The loss of sight, certainly when it occurs at a relatively young age, constitutes an important harm. This is not just a matter of living without the joy of seeing. The impossibility to see will also hamper daily activities and affect the quality-of-life. As a ‘general purpose means’, sight is valuable to nearly any plan of life (Buchanan et al., 2000). Nevertheless, blind persons do usually have happy and fulfilling lives. Moreover, the impact of blindness on the quality-of-life may also vary according to whether society has made successful efforts to remove practical impediments to social participation of the blind (Glover, 2006). As these considerations show, it is a matter of debate whether acquired blindness constitutes a ‘serious harm’ in the sense of a contra-indication under the reasonable welfare standard. If not, PGD for LHON is acceptable as a way of reducing but not avoiding chances that the future child will at some age become blind. However, if the expectation of acquired blindness is seen as a contra-indication, a further issue involves assessing the precise magnitude of the risks. The 50% for boys certainly constitutes a high risk, but what about the 10% for girls? Does this still amount to a high risk of serious harm? It is obvious that also this allows for different views and answers.
An additional question regarding PGD for LHON is whether it is acceptable to transfer a female embryo that, since mtDNA is always maternally transmitted, will be confronted with the same difficult reproductive decisions as her parents (provided she has a wish for a child). After all, even when she will not be clinically affected herself, her offspring will be at risk. Although decisions indeed may be tough, this will not result in an unacceptable quality-of-life and therefore could not be a convincing argument against replacement. Besides, ICSI is an accepted form of assisted reproduction as well, also in cases where this is known to transmit the patient's infertility to his sons (De Wert, 1998).
A final issue regarding the professional responsibility to take into account the welfare of the child is whether the medical team should take stock of parental intentions. Would it matter for their decision-making about whether or not offering PGD if a couple would try to have a child anyway? Or if the couple would only consider reproduction through the less risky route (with regard to the child's health) of IVF/PGD? What if natural reproduction is simply not possible for them because of a fertility problem? Doctors should of course not stop asking themselves whether all things considered it would be acceptable for them to offer PGD. The benefits must be proportional to any health risks involved. But the mere fact that certain applications of IVF technology may lead to a child with a less than complete health does not render these application unacceptable from the point of view of the reasonable welfare standard. For instance, assisted reproduction is also offered to human immunodeficiency virus-seropositive women (both fertile and unfertile), leaving a vertical transmission rate between 1 and 2% even when all prophylactic steps are taken (Pennings, 2003; Volmink et al., 2007).
We conclude that the reasonable welfare standard (according to us the best defendable account of how the welfare of the child should figure in decisions about (assisted) reproduction) does not dismiss risk-reducing PGD for mtDNA-disorders beforehand.
PGD for mtDNA disorders violates the ‘right’ not to know
A second objection could be that transferring embryos with a certain mutant load leads to children being born with a positive test result for being at risk of developing a mitochondrial disease for which no effective treatment or means of prevention exists. That would seem to be in violation of the widely (but not universally) endorsed presumption that children should not be tested for late onset diseases. The exception to this is when testing offers medical benefit for the child. This would be the case when treatment is available (Clarke, 1998; De Wert, 1999; Borry et al., 2006; Steinbock, 2007). The rationale behind this position is that genetic testing would burden children with information that could eventually be harmful to them. It would also effectively deprive them of making their own autonomous decisions about whether or not to be tested at some later age. In other words, the child is deprived of its ‘right’ not to know. The same reasoning would also apply to prenatal testing. For instance, it has been argued that prenatal testing for Huntington's disease is only acceptable if the woman agrees to a termination of pregnancy in case of an adverse test result (e.g. Laurie, 1999; De Wert, 1999; Pennings et al., 2003). Does the argument also apply to PGD for mtDNA disorders? Does it provide a valid argument for not transferring embryos with (some) mutant load in cases where no non-affected embryos are available after IVF?
Although international and professional guidelines take a position against predictive testing of minors for untreatable late-onset disorders, there has been debate on this topic for years. Some argue that knowledge of its genetic status may be a psycho-medical benefit for the child (Robertson and Savulescu, 2001; Rhodes, 2006). Others point to the fact that there are insufficient empirical data on the psychosocial consequences and impact of predictive testing in minors (Evers-Kieboom, 2006; Duncan and Delatycki, 2006). A recent study by Duncan et al. (2007) suggests that there may even be benefits of genetic testing of young people for Huntington's disease (although this study was restricted to those aged 15 years and older). Clearly, this second possible objection against PGD would not be endorsed by those who do not categorically oppose genetic testing of minors for untreatable late-onset disorders. But what should we think about the transfer of embryos with some mutant load if we would depart from the majority view of not testing children for late onset disease unless clear medical benefits exist? Clearly, no adequate treatment for mtDNA disease is currently available and the child is provided with knowledge it might have preferred not to know.
Two comments should be made. First, the child would not exist but with the knowledge of being at risk. Even if we, strictly speaking, regard the transfer of an embryo at risk as a violation of the ‘right’ not to know, one should ask what is in the interests of the child and what would have been the alternative. Clearly, the alternative would have been non-existence (as the embryo would have been deselected). The main question is whether knowledge of being at risk will have such an impact that the child will not have an acceptable quality-of-life. It is implausible that this will be the case. After all, contrary to carrying the causative mutation for Huntington's disease, carrying a low mutant load is likely to have little health impact. Otherwise, it would not have been reconcilable with the contra-indication that was formulated above: avoiding a high risk of serious harm. Secondly, suppose we would regard the transfer of an embryo with a residual risk as an insurmountable violation of the ‘right’ not to know. Then, it still does not follow that performing PGD is unacceptable. It only sets limitations on the transfer policy: only mutation-free embryos (thus probably leading to disease free offspring) are eligible for transfer. Another option may be to withhold information from the couple about the precise amount of mutant load of the transferred embryo. The future child then would only know that he/she carries no or at most a small amount of mutant mtDNA. However, determining what still constitutes a small amount of mutant load is related to personal values about acceptable risk. Parents probably (and appropriately) desire to be more involved in the decision-making process regarding embryo transfer.
PGD for mtDNA disorders is too complex for parents to decide
A fourth possible objection has to do with the aim of counselling in reproductive genetics. Counselling intends to provide couples at risk of transmitting a genetic disease with information in order to facilitate well-informed reproductive choices. Decisions concerning reproduction are pivotal for people's sense of identity and for the realization of their life plans. Enhancing opportunities for reproductive autonomy is therefore rightly seen as a driving value in this field (Robertson, 1994; Boivin and Pennings, 2005; Cavaghan, 2007). However, with regard to PGD for mtDNA mutations, one may wonder whether the decisions are too difficult for them to handle.
Although testing for mtDNA disorders may have some predictive value, interpreting the results is often full of uncertainties. Starting an IVF/PGD procedure may lead to embryos with intermediate mutant loads of which the precise implications are unclear. Starting a new IVF-cycle in the hope of obtaining embryos with no or a lower mutation load is an option, but chances exist that even after several tries only affected embryos are available. Even in cases where the transfer of an embryo at risk would not be at odds with the reasonable welfare standard, the couple still faces a challenging choice. They want a child of their own, but the unavoidable price is accepting at least a low or moderate risk that this child will have a more or less compromised health.
We do not deny that these are difficult decisions, involving the processing and balancing of different types of information. Nor do we deny that empirical studies have shown that in general people are not very good at handling statistics (Schwartz, 2004). We also agree that there are many other pitfalls surrounding the ideal of enhancing autonomous decision-making, including emotional stress or misplaced trust that whatever doctors offer must be good. However, none of this is limited to decision-making in the context we are considering. When deciding, e.g. whether to have chemotherapy and which regimen to follow, there may also be several kinds of uncertainty to be dealt with, whereas time constraints, illness and stress are complicating factors. No matter how difficult such decisions may be, this is never taken as a ground for not offering chemotherapy. We see no reason why this should be different here. Moreover, decision-making for PGD has the (relative) advantage that the choices can be made before the IVF procedure is started. This does not take away the complexity of the decisions, but at least it leaves some time and scope for reconsideration and reflection.
Depriving competent couples at risk from the option of IVF/PGD because the decisions are too complex amounts to a form of paternalism that would be hard to justify. Since decisions like these will be very much related to the personal values of the couple, there is no good reason for thinking that doctors or society would be better placed to make the decisions. Instead of curbing autonomy, we plea for enhancing autonomy as much as possible and facilitating reproductive choice, which means that good counselling becomes even more important (and this is a topic that needs continuous concern, as time is a scarce resource in daily clinics).
PGD for mtDNA disorders ignores available alternatives
A further objection might be that there are alternatives allowing the couple to have a healthy child. They could opt for IVF using donor oocytes or apply for adoption. Should this be a reason for not offering PGD, or at least for not transferring any embryos at risk? The question is whether the available options constitute real alternatives. A first problem is that their availability may in reality be very limited. Not only generally speaking, but more specifically so for the couples involved. Donor oocytes are very scarce, but even more so when maternal relatives are not suitable donors as they may also be at risk of transmitting the same mutation. Adoption procedures are not just lengthy, complicated and expensive, but often also exclude couples with a less than perfect health.
However, for many of the couples involved, there is a more fundamental reason why these options would not count as real alternatives. They do not just want a child, they want a child of which they are the genetic parents together. Of course they also want this imagined child to be completely healthy, but should that be impossible, the alternative for them would be a less healthy child of their own, rather than a child with which they would not both be genetically related. As there are limits to the risks they are willing to take, risk-reducing PGD provides them with a valuable reproductive option, for which only natural reproduction followed by PND would be an alternative. By choosing for PGD they may reassure themselves that they did all that was reasonably possible to avoid the birth of an affected child. In the future, things may change if (pro)nuclear transfer were to become available as a way of allowing couples at risk of mtDNA mutations to have non-affected children of their own (Brown et al., 2006). At present, however, that is still a remote option, mainly because of safety concerns that have to be solved first. Besides this, nuclear transfer raises several other ethical questions.
We may of course question whether the desire for a genetically related child should be taken as important enough to justify PGD for mtDNA mutations without even considering donor IVF or adoption. It has been argued that ‘if our genetically related children will suffer some disease, perhaps we should have genetically unrelated children without these diseases’ (Savulescu, 1999). This is certainly a perspective that some couples at risk of transmitting a mtDNA mutation will find convincing. Obviously, it is important that counsellors discuss this as a possible way of looking at the situation. But to suggest that couples ought to take this view is problematic. It fails to acknowledge how deeply entrenched, both biologically and culturally, the ideal of having genetically related children seems to be. One need only to look at how current practices of assisted reproduction are built around this very ideal. For instance, in cases where the male partner is at risk of transmitting a genetic disease, ‘regular’ PGD is offered without urging the couple to try donor insemination first, even though that is a simpler, cheaper and more efficient procedure to have a healthy child. It seems unfair that only couples at risk of transmitting a mtDNA mutation would have to revise their preferences. Nor would the fact that in their case genetically related children may all be affected amount to a sufficient reason for denying them the option of PGD. To suggest otherwise betrays allegiance to the ‘perfectionist’ standard of maximum welfare that would be difficult to maintain consistently. As we have argued, short of a high risk of serious harm, the health prospects of the future child are not a good reason for withholding IVF/PGD.
PGD for mtDNA disorders leads to an unacceptable wastage of human embryos
Yet another possible objection may hold that PGD for mtDNA mutations leads to an unacceptable wastage of human embryos. There are different ways of construing this argument. If it is not to be understood as a rejection of all practices where human embryos are wasted (including IVF and natural intercourse), the issue must be about proportionality rather than acceptability per se.
PGD for mtDNA mutations is likely to consume far more embryos than ‘regular’ IVF/PGD. Although this is not true for sex-selective PGD for LHON (where on average half of the embryos will be available for transfer), it is true where heteroplasmic mutations are concerned. More embryos may have to be rejected because of an unacceptably high level of mutant load than because of Mendelian-type mutations in ‘regular’ IVF/PGD. As this will more often lead to an aborted procedure, or to having a new try, the net result is a greater wastage of embryos. To put this in perspective, however, we refer to the practice of PGD for HLA-typing, where more than 80% of the embryos are not suitable for transfer (De Wert et al., 2007). Furthermore, wasting embryos can only be proportional when it is for a sufficiently valuable end. So what about the end of PGD for mtDNA mutations (here again including homoplasmic LHON)? How does mere risk reduction compare to the ends of IVF (allowing the infertile to have children) or ‘regular’ PGD (allowing couples at risk to have unaffected children)? This will of course also depend on the amount of risk reduction that is achieved. As long as this is a considerable reduction, it would seem quite beside the point to suggest that this end would somehow be less important than those of other applications of assisted reproduction. Moreover, once a couple has been fully informed about the risks and burdens of IVF/PGD and they still wish to proceed, then this can be considered as an indication of the seriousness of the disease and the importance they attach to the reduction of the health risks (Amor and Cameron, 2008).
PGD for mtDNA disorders sets us on a slippery slope
Finally, it can be objected that we are stepping on a slippery slope when we apply PGD for mtDNA disorders. According to this argument (‘slippery slope’ or ‘thin end of the wedge’), introducing or accepting a technology or application (A) that in itself may not be morally problematic or unacceptable, would still be problematic or unacceptable if doing so would make it impossible (logically or empirically) to avoid the subsequent introduction or acceptance of another technology or application (B) that would be morally unacceptable (van der Burg, 1992; Burgess, 1993; McGleenan, 1995). In the logical version of the slippery slope, accepting A deprives one of valid arguments for rejecting B. The empirical version consists of the prediction that accepting A will lead to a climate of acceptance towards B as well. In both versions, the message is that anyone who regards B as undesirable should reject A (Lamb, 1988; de Wert, 2005). With regard to the acceptability of PGD for mtDNA disorders, at least three different slippery slopes are imaginable.
Sliding to increasingly higher risks
Will accepting embryos with a low mutant load (thus with small risks) as eligible for transfer unavoidably lead towards accepting the transfer of embryos with much higher risks? As in all slippery slope arguments, the first question is whether the imagined position at the bottom end of the slope is indeed to be avoided. The answer has already been given: IVF/PGD is unacceptable if there is a high risk that the resulting child will suffer serious harm. The second question is about the inevitability of sliding down. Does allowing the transfer of embryos at a low level of risk leave us without valid arguments against allowing high-risk transfer? As we have indicated, ‘high risk of serious harm’ is not a clear-cut criterion. There will be borderline cases that allow for different views and interpretations. However, that does not amount to saying that a material distinction between high and low risks cannot be made. Nor is it plausible to think that the transfer of embryos at low risk will create a climate in which gradually larger and larger risks are accepted, until ‘high risk of serious harm’ is no longer seen as a limiting criterion.
By the way, the transfer of an embryo with some mutant load would not be the first departure from the ‘norm’ of not transferring embryos at risk. Ever since the introduction of PGD, sex-selective transfer of female embryos has been standard practice for several X-linked diseases (such as Duchenne muscular dystrophy) where mutation analysis was or is not (yet) available (or is considered to be disproportionally time-consuming). Half of these female embryos will be carriers. Though generally healthy, carriers are to some extent at risk of showing relatively mild symptoms of the disease. So if there is a slippery slope here, a first step on that slope has already been set long ago. There is no indication that the long-standing practice of selecting low-risk carrier embryos in PGD for X-linked diseases has led to a greater acceptance of transferring embryos at a higher risk. It is, however, conceivable that in clinical practice the absence of embryos with a low mutant load may lead couples to ask for transfer of embryos with higher mutant loads. But this can be countered by making clear agreements with the couples when considering clinical application.
Sliding to increasingly smaller reductions of risk
IVF/PGD for mtDNA disorders aims at least to achieve a (considerable) reduction of reproductive risk. It is thought that by discarding embryos with a high or intermediate mutant load, the risk of a severely affected child can be considerably reduced. In homoplasmic LHON, sex-selective PGD in comparison to natural reproduction reduces the lifetime risk of blindness from 30 to 10% (Spruijt, 2007). Will accepting risk reduction as an alternative end of PGD set us on a slippery slope towards eventually accepting much lower percentages of risk reduction? Here again, the first question is whether the dreaded position at the foot of the slope would indeed be morally unacceptable. In this case, the question is what magnitude in risk reduction is sufficient for IVF/PGD to be offered (Amor and Cameron, 2008). This leads us back to the issue of proportionality. As the benefits of any medical procedure must be balanced against the material and immaterial costs, increasingly more marginal benefits will end up rendering risk-reducing PGD disproportional. The cost side of this equation would also have to include the risks and burdens of IVF, potential long-term risks of embryo biopsy for the health of the child, and the use of human embryos. There will of course be debate and different opinions about this, leading to various accounts of where the limit of proportionality must be drawn. But does this put us on a slippery slope? The logical version of the argument does at least not seem to apply, as the very concept of proportionality gives us a tool (albeit a rough one) for distinguishing between acceptable and non-acceptable applications. Neither is the empirical version convincing. In view of the costs and burdens of IVF and PGD, not many couples will request IVF/PGD for increasingly more marginal reductions of risk. The medical team should decide on a case-by-case basis what they still regard an acceptable amount of risk-reduction, also depending on the specific mutation and the wishes and circumstances of a specific couple.
Sliding to increasingly milder conditions
Most mtDNA mutations show an incomplete penetrance and a variable expression. This means that not all persons carrying the mutation will develop clinical symptoms and that in those who do, the severity of symptoms varies even if having the same mutant load. Will accepting PGD for such conditions set us on a slippery slope towards also accepting PGD for conditions with very low burdens of disease?
If there is a slippery slope here, PGD for mtDNA disorders is not the first step. At least not in countries, such as the UK, where—on a case-by-case basis—PGD for hereditary cancers such as BRCA I/II is now accepted (http://www.hfea.gov.uk/docs/The_Authority_decision_-_Choices_and_boundaries.pdf). Far from being low risk or mild conditions, these disorders also show an incomplete penetrance and a variable expression, in addition to a late time of onset and (limited) therapeutic options.
To the extent that slippery slope concerns are about PGD for increasingly more marginal benefits, we are again dealing with the proportionality issue. In this connection, however, there may be a further concern. PGD for disorders with a lower penetrance and a variable expression may set us on a slippery slope towards regarding smaller and smaller health problems as a reason for genetic testing and prevention. Those living with these conditions may feel compromised. Or couples at risk may experience (social) pressure to make use of genetic technology. If this is where we are heading, this is morally problematic. Nevertheless, it does not provide sufficient reasons to prohibit PGD for mtDNA mutations (or hereditary cancers). After all, accepting or not accepting these new applications of PGD will be at most a relatively minor factor in a much wider configuration of social and cultural causes affecting such a change of climate.
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We have discussed the pros and cons of introducing applications of PGD that may only reduce rather than eliminate reproductive risk. Specifically, we examined the case of PGD for mtDNA disorders, such as NARP/Leigh, MELAS, private mtDNA mutations and LHON. The main arguments in favour of PGD are that it offers couples at risk the opportunity of reproducing while (considerably) reducing and in some cases eliminating their chances of having a severely affected child. Introducing PGD for these conditions is not only beneficial in the sense of contributing to positive health outcomes, but also enhances the reproductive autonomy of the couples involved. Further benefits for patient care in general can also be expected, as PGD will provide new possibilities for the scientific study of mtDNA genetics by using embryos not selected for transfer.
Potential objections are manifold but, as our discussion has shown, none of them supplies compelling reasons to regard risk-reducing PGD as unacceptable. Notwithstanding the acceptability of PGD for mtDNA disorders, our discussion has made clear that introducing this new form of PGD will raise complex issues in the context of determining conditions for its responsible use. Although the avoidance of a high risk of serious harm is the lower limit, an important point for discussion once a couple requests PGD is how much additional effort should be made to further reduce the health risks and to minimize harm. For example, how many IVF/PGD cycles could (or should) be done before an embryo at risk is transferred? And what should be the cut-off points above which embryos are not considered eligible for transfer? Clearly, these and other relevant questions require further interdisciplinary debate.
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This work was supported by a grant from the European Union sixth Research Framework Programme (the MITOCIRCLE project contract no 005260).
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Amor DJ, Cameron C. PGD gender selection for non-Mendelian disorders with unequal sex incidence. Hum Reprod (2008) 23:729–734.
Arras JD. AIDS and reproductive decisions: having children in fear and trembling. Milbank Q (1990) 68:353–382.[CrossRef][Web of Science][Medline]
Benatar D. Reproductive freedom and risk. Hum Reprod (2006) 21:2491–2493.
Bickerstaff H, Flinter F, Yeong CT, Braude P. Clinical application of preimplantation genetic diagnosis. Hum Fertil (2001) 4:24–30.[CrossRef]
Boivin J, Pennings G. Parenthood should be regarded as a right. Arch Dis Child (2005) 90:784–785.
Borry P, Stultiens L, Nys H, Cassiman JJ, Dierickx K. Presymptomatic and predictive genetic testing in minors: a systematic review of guidelines and position papers. Clin Genet (2006) 70:374–381.[CrossRef][Web of Science][Medline]
Bredenoord AL, Pennings G, Smeets HJ, de Wert G. Dealing with uncertainties: ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders. Hum Reprod Update (2008) 14:83–94.
Brown DT, Herbert M, Lamb VK, Chinnery PF, Taylor RW, Lightowlers RN, Craven L, Cree L, Gardner JL, Turnbull DM. Transmission of mitochondrial DNA disorders: possibilities for the future. Lancet (2006) 368:87–89.[CrossRef][Medline]
Buchanan A, Brock DW, Daniels N, Wikler D. From Chance to Choice. Genetics and Justice (2000) Cambridge: Cambridge University Press.
van der Burg W. The slippery-slope argument. J Clin Ethics (1992) 3:256–268.[Medline]
Burgess JA. The great slippery-slope argument. J Med Ethics (1993) 129:169–174.
Cavaghan C. Defending The Genetic Supermarket (2007) London: Routledge.
Chinnery PF. Inheritance of mitochondrial disorders. Mitochondrion (2002) 2:149–155.[CrossRef][Web of Science][Medline]
Chinnery PF, Turnbull DM. Epidemiology and Treatment of Mitochondrial Disorders. Am J Med Gen (Semin Med Gen) (2001) 106:94–101.[CrossRef]
Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C, Carrara F, Lombes A, Laforet P, Ogier H, et al. Risk of developing a mitochondrial DNA deletion disorder. Lancet (2004) 363:592–596.
Chinnery PF, Majamaa K, Turnbull D, Thorburn D. Treatment for mitochondrial disorders. Cochrane Database Systematic Review (2006) Issue 1. Art. No.: CD004426. DOI: 10.1002/14651858.CD004426.pub2.
Clarke A, ed. The Genetic Testing of Children (1998) Oxford and Washington, DC: Bios Scientific Publishers.
Ciafaloni E, Santorelli FM, Shanske S, Deonna T, Roulet E, Janzer C, Pescia G, DiMauro S. Maternally inherited Leigh syndrome. J Pediatr (1993) 122:419–422.[Web of Science][Medline]
Dahl HHM, Thorburn DR. Mitochondrial diseases: beyond the magic circle. Am J Med Gen (Semin Med Genet) (2001) 106:1–3.[CrossRef]
Dahl HHM, Thorburn DR, White SL. Towards reliable prenatal diagnosis of mtDNA point mutations: studies of nt8993 mutations in oocytes, fetal tissues, children and adults. Hum Reprod (2000) 15(Suppl 2):246–255.
de Wert G. Ethics of intracytoplasmic sperm injection: proceed with care. Hum Reprod (1998) 13(Suppl 1):219–227.
de Wert G. Met het oog op de toekomst. Voortplantingstechnologie, erfelijkheidsonderzoek en ethiek. (1999) Thela Thesis. Amsterdam [in Dutch].
de Wert G. Preimplantation genetic diagnosis: the ethics of intermediate cases. Hum Reprod (2005) 20:3261–3266.
de Wert G, Liebaers I, van de Velde H. The future (r)evolution of preimplantation genetic diagnosis/human leukocyte antigen testing: ethical reflections. Stem Cells (2007) 25:2167–2172.[CrossRef][Web of Science][Medline]
Duncan RE, Delatycki MB. Predictive genetic testing in young people for adult-onset conditions: where is the empirical evidence? Clin Genet (2006) 69:8–16.[CrossRef][Web of Science][Medline]
Duncan RE, Gillam L, Savulescu J, Williamson R, Rogers JG, Delatycki MB. "Holding your breath": interviews with young people who have undergone predictive genetic testing for Huntington disease. Am J Med Genet part A (2007) 143A:1984–1989.
Dworkin R. Life's Dominion. An Argument About Abortion, Euthanasia, and Individual Freedom (1993) New York: Random House.
Evers-Kieboom G. Predictief testen van minderjarigen voor aandoeningen die later in het leven tot uiting komen: psychologische aspecten en multidisciplinaire aanpak. Tijdschr voor Geneeskunde (2006) 62:463–471. (in Dutch).[CrossRef]
Glover J. Choosing children. Genes, Disability, and Design (2006) Oxford: Clarendon Press.
Graff C, Wredenberg A, Silva JP, Bui TH, Borg K, Larsson NG. Complex genetic counselling and prenatal analysis in a woman with external ophthalmoplegia and deleted mtDNA. Prenat Diagn (2000) 20:426–431.[CrossRef][Web of Science][Medline]
Harris J. The welfare of the child. Health Care Anal (2000) 8:27–34.[CrossRef][Web of Science][Medline]
Harris J. Enhancing Evolution. The Ethical Case for Making Better People (2007) Princeton and Oxford: Princeton University Press.
Health Council of the Netherlands. Pre-implantation genetic diagnosis (2006) The Hague: Health Council of the Netherlands. Publication No 2006/01.
Hudson G, Carelli V, Spruijt L, Gerards M, Mowbray C, Achilli A, Pyle A, Elson J, Howell N, La Morgia C, et al. Clinical expression of leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet (2007) 81:228–233.[CrossRef][Web of Science][Medline]
Human Fertilisation and Embryology Authority. Guidance on Preimplantation Testing (2003) http://www.hfea.gov.uk/en/601.html.
Huoponen K, Puomilla A, Savontaus ML, Mustonen E, Kronqvist E, Nikoskelainen E. Genetic counseling in Leber hereditary optic neuropathy (LHON). Acta Ophthalmol Scand (2002) 80:38–43.[CrossRef][Web of Science][Medline]
Jacobs LJAM, De Coo IFM, Nijland JG, Galjaard RJH, Los FJ, Schoonderwoerd K, Niermeijer MF, Geraedts JPM, Scholte HR, Smeets HJM. Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation. Mol Hum Rep (2005) 11:223–228.
Lamb D. Down the Slippery Slope (1988) London: Croom Helm.
Laurie G. In defense of ignorance: genetic information and the right not to know. Eur J Health Law (1999) 6:119–132.[CrossRef][Medline]
Man PYW, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet (2002) 39:162–169.
McGleenan T. Human gene therapy and slippery slope arguments. J Med Ethics (1995) 21:350–355.
Parfit D. Reasons and Persons (1984) Oxford: Oxford University Press.
Parker M. The welfare of the child. Hum Fertil (2005) 8:13–17.[CrossRef]
Parker M. The best possible child. J Med Ethics (2007) 33:279–283.
Pennings G. Measuring the welfare of the child: in search of the appropriate evaluation principle. Hum Reprod (1999) 14:1146–1150.
Pennings G. The physician as an accessory in the parental project of HIV positive people. J Med Ethics (2003) 29:321–324.
Pennings G, Bonduelle M, Liebaers I. Decisional authority and moral responsibility of patients and clinicians in the context of preimplantation genetic diagnosis. Reprod Biomed Online (2003) 7:509–513.[Medline]
Poulton J, Turnbull DMA. 74th ENMC International Workshop: Mitochondrial Diseases 19–20 November 1999, Naarden, The Netherlands. Neuromuscul Disord (2000) 10:460–462.[CrossRef][Medline]
Rhodes R. Why Test Children for Adult-Onset Genetic Diseases? Mt Sinai J Med (2006) 73:609–616.[Medline]
Robertson JA. Children of Choice. Freedom and The New Reproductive Technologies (1994) Princeton: Princeton University Press.
Robertson S, Savulescu J. Is there a case in favour of predictive genetic testing in young children? Bioethics (2001) 15:26–49.[CrossRef][Web of Science][Medline]
Savulescu J. Should doctors do intentionally do less than the best? J Med Ethics (1999) 25:121–126.
Schapira AHV. Mitochondrial disease. Lancet (2006) 368:70–82.[CrossRef][Medline]
Schwartz B. The Paradox of Choice: Why More is Less (2004) New York: Harper Perennial.
Spikings EC, Alderson J, St John JC. Transmission of mitochondrial DNA following assisted reproduction and nuclear transfer. Hum Reprod Update (2006) 12:401–415.
Spruijt L. Leber's Hereditary Optic Neuropathy. In: Encyclopedia of Life Sciences (2007) Chichester: John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0005541.
Steffann J, Frydman N, Gigarel N, Burlet P, Ray PF, Fanchin R, Feyereisen E, Kerbrat V, Tachdjian G, Bonnefont JP, et al. Analysis of mtDNA variant segregation during early human embryonic development: a tool for successful NARP preimplantation diagnosis. J Med Genet (2006) 43:244–247.
Steffann J, Gigarel N, Corcos J, Bonniere M, Encha-Razavi F, Sinico M, Prevot S, Dumez Y, Yamgnane A, Frydman R, et al. Stability of the m.8993T>G mutation load during human embryo fetal development has implications for the feasibility of prenatal diagnosis in NARP syndrome. J Med Genet (2007) 44:664–669.
Steinbock B. Prenatal testing for adult-onset conditions: cui bono? Reprod Biomed Online (2007) 15(Suppl 2):38–42.[Web of Science][Medline]
Steinbock B, McClamrock R. When Is Birth Unfair to the Child? Hastings Center Report (1994) 6:15–21.[Medline]
Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JT, Wherret J, Smith C, Rudd N, Petrova-Benedict R, Robinson BH. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet (1992) 50:852–858.[Web of Science][Medline]
Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet (2005) 6:389–402.[CrossRef][Web of Science][Medline]
Thorburn DR. Mitochondrial disorders: prevalence, myths and advances. J Inherit Metab Dis (2004) 27:349–363.[CrossRef][Web of Science][Medline]
Thorburn DR, Dahl HHM. Mitochondrial Disorders: Genetics, Counseling, Prenatal Diagnosis and Reproductive Options. Am J Med Gen (Semin Med Genet) (2001) 106:101–114.
Volmink J, Siegfried NL, van der Merwe L, Brocklehurst P. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev (2007) 24. CD003510.
White SL, Shanske S, Biros I, Warwick L, Dahl HM, Thorburn DR, DiMauro S. Two Cases of Prenatal Analysis for the Pathogenic T to G Substitution at Nucleotide 8993 in Mitochondrial DNA. Prenat Diagn (1999) a 19:1165–1168.[CrossRef][Web of Science][Medline]
White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, Dahl HM, Thorburn DR. Genetic Counseling and Prenatal Diagnosis for the Mitochondrial DNA Mutations at Nucleotide 8993. Am J Hum Genet (1999) b 65:474–482.[CrossRef][Web of Science][Medline]
White SL, Shanske S, McGill JJ, Mountain H, Geraghty MT, DiMauro S, Dahl HH, Thorburn DR. Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue or age-related variation. J Inherit Metab Dis (1999) c 22:899–914.[CrossRef][Web of Science][Medline]
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