PREIMPLANTATIONAL DIAGNOSIS OF FRAGILE CHROMOSOME X CARRIERS AND OTHER HEREDITARY DISORDERS IN ARTIFICIAL FERTILISATION TECHNIQUES
Authors:
López de Argumedo, M.; Cantero, D.; Tejada, M.I.; Aguirre, A.; Alkorta, I.; Gutiérrez, M.A.
Technology:
Preimplantational genetic diagnosis
MESH keywords:
"Preimplantational diagnosis" "Fragile X sindrome" "Genetic Processes"
Other keywords:
"effectiveness" "safety"
Date: December 2004
Pages: 145
References: 84
Language: Spanish
ISBN: 84-457-2363-4
Introduction:
The fragile X syndrome is the most common cause of hereditary mental retardation. It is an illness linked to the chromosome X dominant, with incomplete penetrance. Molecularly, it is characterised by an abnormal expansion of the CGG triplet located in the FMR1 gene (Fragile X Mental Retardation). The function of the FMR1 gene is to codify a protein (FMRP), the lack of which is responsible for the symptoms of this syndrome.
This syndrome is therefore more frequent and more serious in males. Its prevalence is approximately between 1:4000 in men and 1:8000 in women.
In spite of the fact that experiments are underway with different treatments, in the field of genetic therapy or genetic engineering, there is no cure at present for the fragile X syndrome. Recognition of the limitations of the current treatment of fragile X and other genetic diseases, together with the fact that it is likely that the genes are transmitted from one generation to the next, has focused attention on prevention as the most reliable and effective means of tackling the problem of hereditary diseases.
Within the context of the prevention of hereditarily transmitted diseases, preimplantational genetic diagnosis (PGD) is one of the assisted reproduction techniques available to carriers of hereditary diseases to prevent the transmission of these pathologies to their descendants.
Preimplantational genetic diagnosis consists of a genetic analysis of an embryo obtained by means of in vitro fertilisation and subsequent transfer of healthy and viable embryos.
Objectives:
Assess the safety, effectiveness and diagnostic accuracy of a number of different preimplantational diagnostic techniques, used in assisted reproduction, in order to prevent the transmission of the fragile X syndrome and other genetic diseases to the descendants of carriers of this kind of pathology.
Determine the level of implantation and the use of these techniques in Spain.
Carry out an economic appraisal of the implementation of PGD.
Analyse the possible ethical repercussions and the effect that this technique may have on the organisation of the health system and examine current Spanish legislation relating to these techniques.
Methods:
FOR OBJECTIVE 1: A systematic review was made of the scientific literature.
FOR OBJECTIVE 2: This work has been divided into the following stages: a. Definition of the population under study. b. Design of a questionnaire. c. Identification of the centres to be included in the survey. d. Pilot survey. e. Sending the questionnaire. f. Data gathering. g. Analysis of data.
FOR OBJECTIVE 3: This work has been divided into the following stages: a. Calculation of the potential demand for PGD for fragile syndrome X. b. Systematic search of the scientific literature. c. Analysis of the minimisation of costs.
FOR OBJECTIVE 4: The following stages have been developed: a. Consultation with experts. b. Systematic search of literature on the ethical aspects and the preparation of a bibliographical review document. c. Analysis of current regulations in Spain through an examination of state and autonomous community regulations, as well as international agreements and compulsory Community regulations.
Economic analysis: YES Expert opinion: NO
Conclusions:
On the effectiveness of the technique:
13% of transferred embryos ended in a clinical gestation. Until the time of publication of this data, a total of 6 diagnostic errors had been the detected, with an overall diagnostic error rate of 2.65%. The final objective of producing a child free of disease would only be possible for 15% of couples who initiate the PGD, for each cycle initiated.
Concerning the safety of the technique:
Complications occurred in 33 percent of the 157 gestations registered after completing a PGD. Nevertheless, these complications are associated especially with the high number of pregnancies with more than one foetus as a consequence of in vitro fertilisation techniques.
Concerning the level of implementation and use in Spain:
According to the results of the survey, 13 assisted human reproduction centres offer PGD, but only five carry out the complete process, i.e., IVF plus genetic diagnosis, which means that the large majority of centres associated with this technique send samples to an outside laboratory in order to perform the genetic diagnosis.
Concerning organisational aspects:
It is essential that couples receive all the necessary information and that the services made available to them are of the highest quality.The current situation in the Spanish State in which there is a lack of both an official academic qualification to endorse the adequate training of professionals working in the field of genetics, and a set of regulations to certify centres engaged in clinical genetics.
Concerning the economic analysis of the technique:
The total cost involved in the installation of a PGD unit (including the PND) is estimated at 6,284€ in the case of the PCR technique and 5,931€ in the case of the FISH technique.
If the final result is a full-term pregnancy ending in a birth, the total cost would increase by 23.4% with the PCR technique and by 24.7% with the FISH technique.
During the year 2004, the initial outlay plus the necessary maintenance costs for applying the PCR technique is estimated at 151,905€ and 130,264€ in the case of the FISH technique.
Concerning the ethical aspects associated with this technique:
The manipulation of the embryo which occurs during PGD, the eugenic selection of embryos to be implanted and the storage and/or elimination of surplus embryos pose important moral problems for a section of the population, problems which societies are resolving in accordance with their cultural and social heritage.
Among the newest ethical complications is the possibility of selecting embryos affected with a no-grave ailment (deafness, achondroplasy, etc.) eliminating the healthy ones, the selection of embryos on the basis of gender, or the selection of embryos genetically compatible with a relative affected by a genetic or acquired pathology, for their use as a donor.
Concerning the legal aspects:
The practice of PGD is authorised in Spain in accordance with the provisions contained in article 1.3 of Law 35/1988 on Human Assisted Reproduction Techniques (modified recently by Law 5/2003).
The authorisation system of the medical and biological activity contained in the Law on Human Assisted Reproduction Techniques and the regulations for its development, do not provide for the granting of permits for the practice of the preimplantational diagnosis. Regulations to include the practice of genetic counselling, of licences for centres and the accreditation of authorised personnel to practice PGD should be a adopted urgently.
The modification of the LTRA favoured by Law 45/2003 restricted the number fertilisable oocytes to three. This measure made the practice of PGD extremely difficult, for which reason the National Assisted Human Reproduction Committee recommended that this technique should be considered as an exception to the number of fertilisable ovules.
Thus, Royal Decree 1720 of July 23 2004 included cases with indications of preimplantational genetic diagnosis among the physiopathological typologies that allow these general limits to be exceeded in the number of fertilisable ooctyes established by previous regulations for the fertilisation of ooctyes in assisted reproduction processes.
Recommendations:
In order to guarantee the necessary information and quality of care offered to couples, an organisational protocol should be followed, which might consist of the following steps:
One Genetic Counselling consultation.
One consultation with the Assisted Reproduction Team.
I
n view of the fact that Assisted Reproduction Centres and/or teams are authorised by the Ministry of Health, in order to implement PGD it is necessary to:Authorise Genetic Counselling consultations.
Authorise the Genetic laboratories in which the genetic tests are carried out.
Regulate the qualifications of specialists in Genetics or Genetic Counselling as well as the training in Human Reproduction and the Biology of Reproduction/Human Embryology.
In those centres where PGD is performed, a system should be implemented to control quality and to regulate good practices, for which, among other things, a registry of cases should be created to ensure that these are monitored. This information would form part of the registry of Activity Indicators contained in the Decrees that develop Law 35/1988, which are still pending development.