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Query: UMLS:C0002895 (sickle cell disease)
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Advances in understanding genetic disorders have been rapid in the last few years and with them the need and desire for genetic counselling have grown. Almost simultaneously, particularly in the USA, several large screening programmes have been initiated to screen large numbers of people who may be carriers of such deleterious genes as those of Tay-Sachs disease and sickle cell anaemia. The authors of this paper, clinical medical students at University College Hospital, London, spent some time studying the ethical issues raised. The first part of their study, which is not published here, relates to the biochemistry of certain genetic disorders, so leading up to the aspect of the subject which must concern readers of this journal, genetic counselling. At present genetic counselling is generally the province of the medical practitioner working with clinical biochemists, and in this paper their function is described and how programmes of screening for carriers are designed. Whether the subjects of the screening tests are found to be 'innocent' or 'guilty' psychological problems confront them, and of these the genetic counsellor must be aware. In fact the range of ethical problems raised by such counselling is wide and can only be sketched in this article.
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PMID:Ethical issues arising from human genetics. 95 67

The accuracy of biochemical and molecular prenatal diagnoses using chorionic villi as the fetal source was assessed by seven centres participating in the NICHD collaborative study on the safety and accuracy of chorionic villus sampling (CVS) and amniocentesis. Of 601 pregnancies studied, biochemical methods were used to determine the diagnosis in 283 fetuses at risk for 35 different metabolic disorders. Fifteen different lysosomal storage diseases accounted for 81 per cent of the biochemical prenatal diagnoses performed, with 57 per cent of these pregnancies at risk for Tay-Sachs disease. No errors were made in the biochemical diagnoses that predicted affected or unaffected fetuses. However, the diagnoses of certain disorders (e.g., mucopolysacchariodosis type IH, metachromatic leukodystrophy, and Krabbe disease) occasionally required confirmatory studies in cultured amniocytes because the enzyme results were inconclusive in direct and/or cultured villi or due to the presence of a pseudodeficiency allele. Of these, only the diagnosis of a fetus at risk for Krabbe disease remained inconclusive after special studies to discriminate between mutant and pseudo-deficiency alleles. Recombinant DNA techniques were used to predict the diagnosis of 318 fetuses at risk for 16 different disorders in which the defective disease gene could be detected either directly or by linkage analysis to a nearby polymorphic marker. Of these, 32 per cent were for haemoglobinopathies, 25 per cent for cystic fibrosis, 24 per cent for Duchenne or Becker muscular dystrophy, and 7 per cent for haemophilias. Pregnancies at risk for known disorders with specific molecular lesions (e.g., sickle cell disease) were accurately diagnosed in direct and/or cultured villi. Diagnoses requiring analyses with closely linked polymorphic markers were occasionally uniformative or inconclusive. Maternal contamination was not reported in any biochemical or molecular-based diagnosis. These studies document the high accuracy and rapidity of both biochemical and mutation-specific prenatal diagnoses with direct and cultured chorionic villi.
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PMID:First-trimester biochemical and molecular diagnoses using chorionic villi: high accuracy in the U.S. collaborative study. 152 3

The challenges in the control of genetic disorders will be to provide pediatric surgery, continuous medical or social support, and research. The focus of this report is on the factors influencing the relevance of genetics programs for public health: genetic epidemiology, genetic structure, demographic factors, and the level of development of the country. Approaches for control of genetic diseases must accept that prevention and treatment are usually impossible. The only remaining alternative is avoidance through genetic counseling and genetic counseling and genetic screening neonatally, or before and during pregnancy with ultrasound or alpha fetoprotein serum screening. Some pregnancies at risk may be identified by advanced maternal age distribution and country. There is also the possibility of premarital carrier detection, which has been successful in the identification of thalassemia in Cyprus. Carrier detection can occur both before and during pregnancy for groups at risk for Tay-Sachs disease, sickle cell disease, and thalassemia. In the future, there may be carrier tests available for certain common inherited diseases such as cystic fibrosis. Fetal diagnosis ensures the delivery of a healthy child for some conditions. Thus far amniocentesis, fetal blood sampling, and chorionic villus sampling do not indicate an excessive rate of fetal loss, but laboratory diagnosis is dependent on accuracy of readings. Cytogenetic, biochemical, and DNA methods need improvement. The limitation of fetal diagnosis is that the only avoidance option is abortion. Problems also exist in the delivery of genetic services. Based on existing services in Europe, no more than 20% of the genetic burden is avoided, unless there is good public education an counseling at the community level. Obstetricians and practicing physicians need training in genetic counseling. Professional codes of practice need to be instituted. The effectiveness of control measures is dependent on the strategy adopted and must pertain to the country-specific needs. A monitoring body may be required to ensure fairness, effectiveness, and improvement in service delivery. Appropriate nutritional and public health strategies need to be formed to account for the genetically determined population differences, i.e., lactose intolerance, G6PD deficiencies, or hemoglobin E/Beta thalassemia, for all diseases have a genetic determinant.
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PMID:Problems in the control of genetic disorders. 213 Sep 14

At this time a rather large number of congenital abnormalities still occur. About 2-3% of pregnancies will result in children with major congenital abnormalities that cannot be detected prenatally. Yet, with the availability of prenatal diagnosis for an ever increasing number of genetic problems and, more recently, for developmental problems as well, a new option was offered to couples at risk when they took the risk of pregnancy: finding out whether the fetus was abnormal. An early argument regarding the ethics of this option was formulated by Dan Callahan, director of the Hastings Institute for Ethics, Society and the Life Sciences, when he indicated the need to be careful about the term "option." A need exists to be careful about societal pressures in favor of the new medical options--on, for example, a pregnant woman who is over 35 and does not get a prenatal diagnosis; or on a woman carrying a Down's syndrome child identified by prenatal diagnosis not to have an abortion. This was the 1st specter raised when prenatal diagnosis was introduced. The most common indication for amniocentesis is the risk of chromosomal abnormalities. The risk of discovering a chromosomal abnormality by amniocentesis is about double the risk at birth because a number of chromosomally abnormal fetuses are lost late in the 2nd trimester by spontaneous abortion. The age cutoff at 35 raises an immediate ethical question: since the total number of births to women over age 35 seems to be increasing, and at the same time a greater and greater percentage of children with Down's syndrome are born to women under age 35, the question arises as to whether amniocentesis should be done on all pregnancies, and whether all births with Down's syndrome should be selectively aborted or avoided. Amniocentesis in all pregnancies is impractical at this time from the technological and the cost perspective, but the ethical question should be raised. Among the X-linked disorders, 1 group cannot be specifically diagnosed in utero by prenatal diagnosis. If a woman is known to be a carrier, her daughters won't have the disease, but half of them will be carriers. Regarding sex preference as a reason for amniocentesis, all the geneticist can and should do is provide a couple with a base of knowledge and understanding of the options available to them and the outcome of each option. X-linked disorders such as hemophilia and Lesch-Nyhan syndrome and the autosomal recessive biochemical disorders or inborn errors of metabolism such as Tay-Sachs disease and over 100 others can now be diagnosed prenatally. In the vast majority of cases, amniocentesis is performed because the parents already have an abnormal child. Screening programs for Tay-Sachs disease, for sickle cell anemia, and for thalassemia also detect couples at risk. A variety of tools other than amniocentesis are now available for prenatal diagnosis. Much work is being conducted in the prenatal diagnosis of sickle cell anemia and thalassemia.
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PMID:Genetics, amniocentesis, and abortion. 660 72

Amniocentesis and fetoscopy are two of several modalities used to offer information during the prenatal period of the status of the fetus. Amniocentesis is most frequently used and with continuing research is becoming an invaluable aid to prenatal diagnosis. With the recent studies of DNA characteristics of globin chains of cells obtained at amniocentesis, the need to obtain blood directly from fetal vessels to diagnose major hemoglobinopathies prenatally is rapidly diminishing. Open neural tube defects are diagnosable with alpha feto protein analysis. All chromosomal defects are accurately quantitated and more than 100 inborn errors of metabolism are predictable. Fetoscopy is a technique which has a limited utility. It should be confined to major centers where adequate midtrimester abortions are done in order to provide training for those who aspire to pursue this method. With fetal blood sampling the following conditions are detected: beta thalassemia major, Hemophilia A, sickle cell anemia, chronic granulomatous disease, galactosemia and Tay Sachs disease, all of which may be diagnosed directly. Alpha and beta thalassemia, Hemophilia B and homozygous Von Willenbrand's disease may be excluded. With fetal biopsy one can diagnose congenital bullous ichthyosiform erythroderma ichthyosis. During the last ten years the amount of information brought to our attention has also brought the expectation that the next decade will be the most fruitful period in our history in this discipline.
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PMID:Amniocentesis and fetoscopy. 714 20

New reproductive genetics means recently developed techniques to prevent the birth of children with specific defects or genetic diseases by testing individuals for sickle cell anemia, the thalassemias, Tay-Sachs disease, cystic fibrosis, or Down syndrome. Third World health services have many deficiencies with high maternal mortality rates (30-40 fold higher than in developed countries), the low percentage of births delivered by health personnel, the high rates of low birth weight babies, and high child malnutrition and infant mortality rates. The main issues in women's reproductive health are fertility regulation, abortion, maternal mortality, sexually transmitted diseases, and infertility. As a result of expansion in contraceptive use worldwide, the total fertility rate in developing countries has declined from 6.1 in 1965 to 3.9 in 1990. It is estimated that, worldwide, 36-53 million induced abortions are performed each year, most of them in developing nations. WHO estimates that more than 500,000 women die each year because of complications of pregnancy, most in developing countries. More than 95% of the 13 million estimated deaths of children under 5 years of age have occurred in these countries. Approximately 200 million people carry a potentially pathologic hemoglobinopathy gene, and about 250,000 children are born every year with hemoglobinopathy, most of them in the developing world. Reproductive genetic testing in big cities and in private for-profit ventures cater to the socioeconomic elite. Amniocentesis is often misused for fetal sex determination to abort female fetuses in India. Currently, in Cuba virtually every pregnant woman is tested for sickle cell trait and maternal serum alpha-fetoprotein levels between 15 and 20 weeks of gestation. It is predicted that the judicious use of reproductive genetic testing will be possible when health and quality of life issues are addressed properly.
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PMID:Reproductive health and genetic testing in the Third World. 840

As more mutations are identified in genes of known sequence, there is a crucial need in the areas of medical genetics and genome analysis for rapid, accurate and cost-effective methods of mutation detection. We have developed a multiplex allele-specific diagnostic assay (MASDA) for analysis of large numbers of samples (> 500) simultaneously for a large number of known mutations (> 100) in a single assay. MASDA utilizes oligonucleotide hybridization to interrogate DNA sequences. Multiplex DNA samples are immobilized on a solid support and a single hybridization is performed with a pool of allele-specific oligonucleotide (ASO) probes. Any probes complementary to specific mutations present in a given sample are in effect affinity purified from the pool by the target DNA. Sequence-specific band patterns (fingerprints), generated by chemical or enzymatic sequencing of the bound ASO(s), easily identify the specific mutation(s). Using this design, in a single diagnostic assay, we tested samples for 66 cystic fibrosis (CF) mutations, 14 beta-thalassemia mutations, two sickle cell anemia (SCA) mutations, three Tay-Sachs mutations, eight Gaucher mutations, four mutations in Canavan disease, four mutations in Fanconi anemia, and five mutations in BRCA1. Each mutation was correctly identified. Finally, in a blinded study of 106 of these mutations in > 500 patients, all mutations were properly identified. There were no false positives or false negatives. The MASDA assay is capable of detecting point mutations as well as small insertion or deletion mutations. This technology is amenable to automation and is suitable for immediate utilization for high-throughput genetic diagnostics in clinical and research laboratories.
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PMID:High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes. 914 36

We reviewed all referrals for prenatal diagnosis for inborn errors of metabolism and haemoglobinopathies performed at the Montreal Children's Hospital Prenatal Diagnosis Centre/McGill University during the period 1990-1995; 92 procedures were performed for these indications (less than 1 per cent of all referrals for prenatal diagnosis). All prenatal diagnoses for haemoglobinopathies (n = 55) were exclusively DNA-based. The three most frequent referrals were for beta-thalassaemia, sickle cell anaemia, and Tay-Sachs disease, accounting for 68 per cent of cases; the other indications were predominantly for untreatable inborn errors of metabolism. Our unit maintains population-based carrier screening programmes in high schools for beta-thalassaemia and Tay-Sachs diseases. Carriers detected in these programmes accounted for the majority of referrals for these two conditions. This study indicates that carrier testing and screening for sickle cell anaemia may be also welcomed by at-risk groups in Quebec.
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PMID:Prenatal diagnosis for inborn errors of metabolism and haemoglobinopathies: the Montreal Children's Hospital experience. 924 71

Reproductive technology comprises abortion, contraception, amniocentesis (more than 40 genetic disorders can be diagnosed), chorionic villus sampling, genetic screening (to reduce the risk of chromosomal defects such as Down syndrome, sickle cell anemia, Tay-Sachs disease, and cystic fibrosis), in vitro fertilization, artificial insemination by spouse or donor, the development of sperm banks, storage of frozen sperm (cryopreservation), the development of artificial wombs, techniques for predetermining the sex of a fetus, and nursery environments to maintain a fetus removed from the womb in the 1st trimester. In recent years, the demand for these services has increased because of higher infertility and the drop in the number of babies available for adoption. Surrogacy is especially controversial: it has become a symbol of the dehumanization of modern life and the exploitation of women. The feminist perspective discloses how patriarchal values about the subordinate status of women, about the nature of motherhood, infertility, and the family are both implicit and explicit in prevailing thinking about reproduction. The new technology offers women who wish to remain unmarried the opportunity to have a family, and it enables lesbian women to bear children. The research literature favors a Eurocentric nuclear family without any awareness that in Canada, and in the Western world, new forms of family life have been evolving as couples marry, divorce, and remarry. There is no awareness either that in other cultures this Eurocentric nuclear model is dysfunctional. Because of the rigid notion of the 2-parent nuclear family, the 3rd parties who are involved in either surrogate relationships or artificial insemination are deprecated. The feminist literature is more critical of the nuclear family, but it has been sometimes inconsistent on the relevant issues.
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PMID:Public policies and reproductive technology: a feminist critique. 1231 72

Genetics is an important area of focus for the preconception visit (Table 4). Folic acid should be recommended for all women. The genetic and pregnancy history should be evaluated for clues to a genetic disorder. Preconception screening and counseling are available for many diseases that are indicated in the family history. Screening may be offered for sickle cell anemia, thalassemia, Tay Sachs disease, and cystic fibrosis in the appropriate population groups. Older couples should be counseled about their increased risks for having complications during pregnancy and for having children with genetic disorders.
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PMID:Genetics issues in preconception health care. 1241 84


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