Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Genetics, amniocentesis, and abortion. 660 72

Research towards preimplantation diagnosis of genetic disease was initiated in the UK in the mid 1980s with the aim of helping those couples who would prefer selection to occur at this stage rather than during pregnancy. Following in vitro fertilisation, (IVF), biopsy and removal of 1 or 2 of the totipotent cells from the cleavage stage 3 day old embryo provides the material for molecular genetic diagnosis without interfering with development. Earliest applications were in the avoidance of X-linked disease by sexing embryos and selecting females for transfer to the mother. Initially, polymerase chain reaction (PCR) amplification of DNA from the biopsied blastomeres was performed using primers specific for sequences derived from the Y chromosome and this led to the birth of several normal girls. To reduce the risk of misdiagnosis due to amplification failure, PCR based methods for sexing the embryo now employ both X and Y specific sequences, but the preferred method is currently considered to be fluorescent in situ hybridisation (FISH) with fluorochrome labelled DNA probes to the embryonic nuclei that have been fixed and spread on slides. Dual FISH with probes from X and Y chromosomes allows unequivocal diagnosis of sex and determination of chromosome copy number, avoiding transfer of embryos with abnormal numbers of sex chromosomes, including those with only the maternal X that would be at 50% risk for the X-linked disease. The application of FISH for preimplantation diagnosis has also led to the realisation that chromosomal mosaicism is common at the cleavage stage of development, a finding that has important implications for diagnosis of both dominant single gene disorders and trisomies, as well as for our understanding of early human development. Cloning and sequencing of the relevant genes has enabled the development of methods for the diagnosis of certain recessive single gene disorders in cleavage stage embryos. PCR based methods have to be developed for each condition, sometimes for each family if there is heterogeneity. Preimplantation diagnosis has been successful so far for cystic fibrosis, Tay Sachs disease, and Lesch-Nyhan syndrome. Worldwide, 32 pregnancies have been established following all types of preimplantation diagnosis and with 29 babies born, there is no evidence for any adverse effect on development.
 ...
PMID:Preimplantation diagnosis. 761 68

Preimplantation genetic diagnosis now represents an alternative reproductive option for parents at high risk of having offspring affected with certain genetic diseases. Progress in the past year has included increasing reliability in embryo sexing by both polymerase chain reaction and fluorescent in situ hybridization techniques; delivery of babies free of specific diseases such as cystic fibrosis, Lesch-Nyhan syndrome, and Tay-Sachs disease; and successful development of molecular techniques for detecting common diseases such as fragile-X syndrome. In addition, sperm separation in combination with preimplantation genetic diagnosis appears to be an exciting advance in yielding more in vitro fertilization female embryos for transfer and subsequent pregnancy in families at risk for X-linked diseases. Accumulated world experience can now be reviewed to provide couples considering preimplantation genetic diagnosis with observed pregnancy rates and accuracy of diagnosis.
 ...
PMID:Preimplantation genetic diagnosis. 784 20

Research on diagnosis of inherited disease in human embryo before implantation was initiated to help those couples who would prefer to select embryos at this stage rather than during pregnancy. Following in vitro fertilization (IVF), one to two cells were removed from 3 day cleavage stage embryo and cells were analysed for genetic defects. Embryos diagnosed as unaffected were returned to the uterus and thus the resulting pregnancies were assured to be normal. First babies born after the preimplantation diagnosis were using DNA amplification of Y-linked sequences by PCR to avoid X-linked disease. Several pregnancies were obtained by identifying sex of embryos using dual fluorescent in situ hybridization (FISH) with fluorochrome labelled DNA sequences specific for X- and Y-chromosomes to interphase nuclei. Development of single cell PCR for single gene defects led to diagnose several genetic disorders. Preimplantation diagnosis was successfully achieved for predominant delta 508 deletion causing cystic fibrosis, and pregnancies were also diagnosed for Lesch-Nyhan syndrome, Tay-Sachs and Duchenne muscular dystrophy.
 ...
PMID:Preimplantation genetic diagnosis of inherited disease. 958 53

In his paper on the effects of Prenatal Genetic Intervention (PGI) on personal identity, Noam Zohar comes to a conclusion about genetic makeup and the uses of gene therapy quite different from the one I reach in another piece in this issue. Zohar's argument rests on the contention that personal identity changes with alteration of the genome, following what I have identified as the "constitutive" view. To see that this is the pillar supporting the weight of his argument, consider the following. Questions of identity aside, how can it be that altering the genome of children suffering from Lesch-Nyhan syndrome or Tay-Sachs disease so that they now produce the enzyme that they formerly lacked does not benefit them? Clearly, if their identities were not changed, such individuals would in fact realize great benefit from PGI, since the devastating bad effects of the genetic flaw would be avoided. Such a change would certainly make the altered individuals better off, that is, it would benefit them. On this, Zohar and I do not disagree. Persistence of identity through such genetic change is the sticking point.
 ...
PMID:Commentary on Zohar's "Prospects for 'genetic therapy' -- can a person benefit from being altered? 1165 51

In recent years, mouse models for human metabolic diseases have become commonplace because the information gained from in vivo study of biochemical pathways is invaluable, and many metabolic diseases are relatively easy to recreate in mice through gene knockout technology in embryonic stem cells. In certain cases, however, the knockout mice may reproduce only some of the human disease phenotype, may be more severely affected than human cases, or may have no clinical phenotype at all. Under these circumstances, the disease pathology can become more complex, causing the researcher to evaluate basic differences in mouse and human biology as well as questions of genetic background, alternate pathways, and possible gene interactions. This review is a brief analysis of gene knockout models for Lesch-Nyhan syndrome, Lowe syndrome, X-linked adrenoleukodystrophy, Fabry disease, galactosemia, glycogen storage disease type II, metachromatic leukodystrophy, and Tay-Sachs disease, which produce a biochemical model of disease but often do not reproduce clinical symptoms. These mice may be useful for studying the biochemical and physiological pathways in which certain metabolites function toward embryonic and fetal development, as well as specific functions in various organs, and they may provide an inexpensive and useful model system for development of new therapeutic techniques.
 ...
PMID:The mousetrap: what we can learn when the mouse model does not mimic the human disease. 1191 58

Genetic model systems allow researchers to probe and decipher aspects of human disease, and animal models of disease are frequently specifically engineered and have been identified serendipitously as well. Animal models are useful for probing the etiology and pathophysiology of disease and are critical for effective discovery and development of novel therapeutics for rare diseases. Here we review the impact of animal model organism research in three examples of congenital metabolic disorders to highlight distinct advantages of model system research. First, we discuss phenylketonuria research where a wide variety of research fields and models came together to make impressive progress and where a nearly ideal mouse model has been central to therapeutic advancements. Second, we review advancements in Lesch-Nyhan syndrome research to illustrate the role of models that do not perfectly recapitulate human disease as well as the need for multiple models of the same disease to fully investigate human disease aspects. Finally, we highlight research on the GM2 gangliosidoses Tay-Sachs and Sandhoff disease to illustrate the important role of both engineered traditional laboratory animal models and serendipitously identified atypical models in congenital metabolic disorder research. We close with perspectives for the future for animal model research in congenital metabolic disorders.
 ...
PMID:Animal Model Contributions to Congenital Metabolic Disease. 3230 75