DIAGNOSTICO GENETICO PREIMPLANTACIONAL PDF

Olesen , S. Amin - - Journal of Bioethical Inquiry 13 3 However, for some, the idea that we can intervene in the mechanisms of human existence at such a fundamental level can be, at a minimum, worrying and, at most, repugnant. Religious doctrines particularly are likely to collide with the rapidly advancing capability for science to make such interventions. In-depth interviews were conducted with religious scholars from three different religious organizations in the Klang Valley, Malaysia.

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History[ edit ] In , Robert Edwards and Richard Gardner reported the successful identification of the sex of rabbit blastocysts.

The first clinical cases[ edit ] Elena Kontogianni was studying for her PhD at the Hammersmith Hospital, on single-cell PCR for sexing, which she did by amplifying a repeated region of the Y chromosome. Because the Y chromosome region Kontogianni was amplifying contained many repeats, it was more efficient than trying to amplify a unique region. A band on the PCR gel indicated that the embryo was male and the absence of a band indicated that the embryo was female.

However, amplification failure or an anucleate blastomere also resulted in absence of a band on the PCR gel. To reduce the risk of misdiagnosis, Kontogianni went on to co-amplify sequences on the X and Y Kontogianni et al. During the s, human IVF embryos were exclusively transferred on day two of development as the culture medium used was incapable of reliably growing embryos past this stage.

Since the biopsy was to be performed on day three, the first diagnoses were all performed in one day, with transfer of the embryos late on day three. A comparison of day two and day three transfers indicated that this would not adversely affect pregnancy rates. The worry of embryos arresting was so high that some transfers took place in the early hours of day four so that the embryos were removed from culture as soon as possible.

There were many evenings at the Hammersmith when a transfer was performed at 1 a. Winston helped deliver most of the first PGD babies. In some countries, such as Germany, [15] PGD is permitted for only preventing stillbirths and genetic diseases, in other countries PGD is permitted in law but its operation is controlled by the state.

PGD may also be used to increase chances of successful pregnancy, to match a sibling in HLA type in order to be a donor, to have less cancer predisposition, and for sex selection. PGD helps these couples identify embryos carrying a genetic disease or a chromosome abnormality, thus avoiding diseased offspring. The most frequently diagnosed autosomal recessive disorders are cystic fibrosis , Beta- thalassemia , sickle cell disease and spinal muscular atrophy type 1.

Though it is quite infrequent, some centers report PGD for mitochondrial disorders or two indications simultaneously. In addition, there are infertile couples who carry an inherited condition and who opt for PGD as it can be easily combined with their IVF treatment. Main article: Embryo quality Preimplantation genetic profiling PGP has been suggested as a method to determine embryo quality in in vitro fertilization , in order to select an embryo that appears to have the greatest chances for successful pregnancy.

However, as the results of PGP rely on the assessment of a single cell, PGP has inherent limitations as the tested cell may not be representative of the embryo because of mosaicism.

HLA typing has meanwhile become an important PGD indication in those countries where the law permits it. The main ethical argument against is the possible exploitation of the child, although some authors maintain that the Kantian imperative is not breached since the future donor child will not only be a donor but also a loved individual within the family.

Cancer predisposition[ edit ] A more recent application of PGD is to diagnose late-onset diseases and cancer predisposition syndromes. Since affected individuals remain healthy until the onset of the disease, frequently in the fourth decade of life, there is debate on whether or not PGD is appropriate in these cases. Considerations include the high probability of developing the disorders and the potential for cures. For example, in predisposition syndromes, such as BRCA mutations which predispose the individual to breast cancer, the outcomes are unclear.

Although PGD is often regarded as an early form of prenatal diagnosis, the nature of the requests for PGD often differs from those of prenatal diagnosis requests made when the mother is already pregnant. Some of the widely accepted indications for PGD would not be acceptable for prenatal diagnosis.

Sex discernment[ edit ] Preimplantation genetic diagnosis provides a method of prenatal sex discernment even before implantation, and may therefore be termed preimplantation sex discernment. Potential applications of preimplantation sex discernment include: A complement to specific gene testing for monogenic disorders, which can be very useful for genetic diseases whose presentation is linked to the sex , such as, for example, X-linked diseases.

Ability to prepare for any sex-dependent aspects of parenting. Sex selection. A survey [25] found that 42 per cent of clinics that offer PGD have provided it for sex selection for non-medical reasons.

Nearly half of these clinics perform it only for "family balancing", which is where a couple with two or more children of one sex desire a child of the other, but half do not restrict sex selection to family balancing. In India, this practice has been used to select only male embryos although this practice is illegal. In the case of families at risk for X-linked diseases , patients are provided with a single PGD assay of gender identification. Gender selection offers a solution to individuals with X-linked diseases who are in the process of getting pregnant.

The selection of a female embryo offspring is used in order to prevent the transmission of X-linked Mendelian recessive diseases. Such X-linked Mendelian diseases include Duchenne muscular dystrophy DMD , and hemophilia A and B, which are rarely seen in females because the offspring is unlikely to inherit two copies of the recessive allele.

Since two copies of the mutant X allele are required for the disease to be passed on to the female offspring, females will at worst be carriers for the disease but may not necessarily have a dominant gene for the disease. Reasons may include the rarity of the condition or because affected males are reproductively disadvantaged.

Therefore, medical uses of PGD for selection of a female offspring to prevent the transmission of X-linked Mendelian recessive disorders are often applied. Preimplantation genetic diagnosis applied for gender selection can be used for non-Mendelian disorders that are significantly more prevalent in one sex. Three assessments are made prior to the initiation of the PGD process for the prevention of these inherited disorders. In order to validate the use of PGD, gender selection is based on the seriousness of the inherited condition, the risk ratio in either sex, or the options for disease treatment.

It is also necessary to perform a biopsy on these embryos in order to obtain material on which to perform the diagnosis. The diagnosis itself can be carried out using several techniques, depending on the nature of the studied condition. These techniques need to be adapted to be performed on blastomeres and need to be thoroughly tested on single-cell models prior to clinical use.

Finally, after embryo replacement, surplus good quality unaffected embryos can be cryopreserved, to be thawed and transferred back in a next cycle. Obtaining embryos[ edit ] Currently, all PGD embryos are obtained by assisted reproductive technology , although the use of natural cycles and in vivo fertilization followed by uterine lavage was attempted in the past and is now largely abandoned.

In order to obtain a large group of oocytes, the patients undergo controlled ovarian stimulation COH. Transvaginal ultrasound-guided oocyte retrieval is scheduled 36 hours after hCG administration. Oocytes are carefully denudated from the cumulus cells, as these cells can be a source of contamination during the PGD if PCR-based technology is used.

The main reasons are to prevent contamination with residual sperm adhered to the zona pellucida and to avoid unexpected fertilization failure. During the cleavage stage, embryo evaluation is performed daily on the basis of the number, size, cell-shape and fragmentation rate of the blastomeres. On day 4, embryos were scored in function of their degree of compaction and blastocysts were evaluated according to the quality of the throphectoderm and inner cell mass, and their degree of expansion.

Biopsy procedures[ edit ] As PGD can be performed on cells from different developmental stages, the biopsy procedures vary accordingly. Theoretically, the biopsy can be performed at all preimplantation stages, but only three have been suggested: on unfertilised and fertilised oocytes for polar bodies, PBs , on day three cleavage-stage embryos for blastomeres and on blastocysts for trophectoderm cells.

The biopsy procedure always involves two steps: the opening of the zona pellucida and the removal of the cell s. Polar body biopsy[ edit ] Main article: Polar body biopsy A polar body biopsy is the sampling of a polar body , which is a small haploid cell that is formed concomitantly as an egg cell during oogenesis , but which generally does not have the ability to be fertilized.

Compared to a blastocyst biopsy , a polar body biopsy can potentially be of lower costs, less harmful side-effects, and more sensitive in detecting abnormalities. One of the disadvantages of PB biopsy is that it only provides information about the maternal contribution to the embryo, which is why cases of maternally inherited autosomal dominant and X-linked disorders that are exclusively maternally transmitted can be diagnosed, and autosomal recessive disorders can only partially be diagnosed.

Another drawback is the increased risk of diagnostic error, for instance due to the degradation of the genetic material or events of recombination that lead to heterozygous first polar bodies. Cleavage-stage biopsy blastomere biopsy [ edit ] Cleavage-stage biopsy is generally performed the morning of day three post-fertilization, when normally developing embryos reach the eight-cell stage.

A hole is made in the zona pellucida and one or two blastomeres containing a nucleus are gently aspirated or extruded through the opening.

The main advantage of cleavage-stage biopsy over PB analysis is that the genetic input of both parents can be studied. On the other hand, cleavage-stage embryos are found to have a high rate of chromosomal mosaicism , putting into question whether the results obtained on one or two blastomeres will be representative for the rest of the embryo. It is for this reason that some programs utilize a combination of PB biopsy and blastomere biopsy. Furthermore, cleavage-stage biopsy, as in the case of PB biopsy, yields a very limited amount of tissue for diagnosis, necessitating the development of single-cell PCR and FISH techniques.

Although theoretically PB biopsy and blastocyst biopsy are less harmful than cleavage-stage biopsy, this is still the prevalent method. Of all cleavage-stages, it is generally agreed that the optimal moment for biopsy is at the eight-cell stage. It is diagnostically safer than the PB biopsy and, unlike blastocyst biopsy, it allows for the diagnosis of the embryos before day 5. In this stage, the cells are still totipotent and the embryos are not yet compacting. Although it has been shown that up to a quarter of a human embryo can be removed without disrupting its development, it still remains to be studied whether the biopsy of one or two cells correlates with the ability of the embryo to further develop, implant and grow into a full term pregnancy.

ZD uses a digestive enzyme like pronase which makes it a chemical drilling method. The chemicals used in ZD may have a damaging effect on the embryo. PZD uses a glass microneedle to cut the zona pellucida which makes it a mechanical dissection method that typically needs skilled hands to perform the procedure.

In a study that included 71 couples, ZD was performed in 26 cycles from 19 couples and PZD was performed in 59 cycles from 52 couples. In the single cell analysis, there was a success rate of The maternal age, number of oocytes retrieved, fertilization rate, and other variables did not differ between the ZD and PZD groups.

It was found that PZD led to a significantly higher rate of pregnancy This suggests that using the mechanical method of PZD in blastomere biopsies for preimplantation genetic diagnosis may be more proficient than using the chemical method of ZD. Currently, zona drilling using a laser is the predominant method of opening the zona pellucida. Using a laser is an easier technique than using mechanical or chemical means. However, laser drilling could be harmful to the embryo and it is very expensive for in vitro fertilization laboratories to use especially when PGD is not a prevalent process as of modern times.

PZD could be a viable alternative to these issues. It has been shown that if more than two cells are present in the same sample tube, the main technical problems of single-cell PCR or FISH would virtually disappear. On the other hand, as in the case of cleavage-stage biopsy, the chromosomal differences between the inner cell mass and the trophectoderm TE can reduce the accuracy of diagnosis, although this mosaicism has been reported to be lower than in cleavage-stage embryos.

TE biopsy has been shown to be successful in animal models such as rabbits, [30] mice [31] and primates. Human blastocyst-stage biopsy for PGD is performed by making a hole in the ZP on day three of in vitro culture.

This allows the developing TE to protrude after blastulation, facilitating the biopsy. On day five post-fertilization, approximately five cells are excised from the TE using a glass needle or laser energy, leaving the embryo largely intact and without loss of inner cell mass. After diagnosis, the embryos can be replaced during the same cycle, or cryopreserved and transferred in a subsequent cycle. There are two drawbacks to this approach, due to the stage at which it is performed.

First, only approximately half of the preimplantation embryos reach the blastocyst stage. This can restrict the number of blastocysts available for biopsy, limiting in some cases the success of the PGD. On the other hand, delaying the biopsy to this late stage of development limits the time to perform the genetic diagnosis, making it difficult to redo a second round of PCR or to rehybridize FISH probes before the embryos should be transferred back to the patient.

Cumulus cell sampling[ edit ] Sampling of cumulus cells can be performed in addition to a sampling of polar bodies or cells from the embryo. Because of the molecular interactions between cumulus cells and the oocyte, gene expression profiling of cumulus cells can be performed to estimate oocyte quality and the efficiency of an ovarian hyperstimulation protocol, and may indirectly predict aneuploidy , embryo development and pregnancy outcomes.

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