August 20, 2001
Here GNN posts abstracts to six articles on screening for Tay-Sachs disease. See The Success Story of Gene Tests
A unique screening program for the identification of Tay-Sachs Disease (TSD) heterozygotes has been performed in the traditional Orthodox Ashkenazi Jewish (AJ) community since 1983. In recent years the program has utilized the biochemical assay for the determination of hexosaminidase A levels by the heat inactivation technique as well as by direct DNA analysis. The three mutations which were analyzed were those that have been shown to be prevalent among AJ TSD patients and carriers, namely the four nucleotide insertion mutation in exon 11 (1278+TATC), the splice mutation at the 5' end of intron 12 (1421+1g-->c), and the adult mutation, a Gly(269)-->Ser substitution in exon 5 (G269S). A total of 103,133 individuals were tested by biochemical analysis, and 38,197 of them were also assayed by DNA testing. Furthermore, 151 chromosomes from TSD patients or obligate heterozygotes were subjected to DNA analysis for one of the three mutations. DNA testing of the latter identified one of the three AJ mutations in every case, predicting a very high detection rate of heterozygotes in this community by this method. By contrast, the sensitivity of the enzyme assay ranged from 93.1% to 99.1% depending on the exclusion (inclusion) of inconclusive results as positive, while the specificity ranged from 88.1% to 98.8% depending on the inclusion (exclusion) of inconclusive results as positive. Our results strongly support the use of DNA testing alone as the most cost-effective and efficient approach to carrier screening for TSD in individuals of confirmed Ashkenazi Jewish ancestry.
Am J Med Genet 2001 Feb 15;99(1):70-5.
Since 1970, more than 1.4 million individuals worldwide have been screened voluntarily to determine if they are carriers of the mutant gene for Tay-Sachs Disease (TSD). Employing both enzymatic and molecular methods (for optimal sensitivity and specificity) more than 1400 couples have been identified to be at-risk for TSD in their offspring, i.e., both parents heterozygotes. Through prenatal testing of more than 3200 pregnancies, births of over 600 infants with this uniformly fatal neurodegenerative disease have been prevented. In the United States and Canada, the incidence of TSD in the Jewish population has been reduced by more than 90%. More that 100 mutations in the hexosaminidase A gene (the TSD locus) have been identified to date. Some are associated with later onset or more chronic forms of neuronal storage disease. Two mutations cause a carrier-like "pseudo-deficiency" when enzymatic testing is used (false positives). A number of practical, social, and ethical complexities have been identified in this prototypic population-based effort. Educational and counseling components must be provided both before and after screening. Issues of privacy and confidentiality of test results must be addressed. In certain cultures insurability and employment may be involved. The public perception of the biomedical community as advocates for wide-scale testing and screening may be interpreted, in some systems, as conflicts of interest on the part of entrepreneurial scientists, clinicians, and institutions. CONCLUSION: Many new opportunities for population-based screening will be evident in this era of genome-related discovery. Accordingly, some of the experiences with Tay-Sachs disease prevention may be instructive.
Eur J Pediatr 2000 Dec;159 Suppl 3:S192-5.
The screening program in Israel for Tay-Sachs disease has proven very successful, giving Jewish couples a choice not to have affected children. The technology of carrier detection is now possible in several other severe genetic diseases that are relatively frequent among Jews. Due to the current confusion, a policy is needed to determine how the TSD screening program should be continued in the Israeli Jewish population. We propose that such a screening program include only mutations agreed by consensus as causing a disease severe enough to warrant the possibility of therapeutic abortion. We also propose that general screening include only mutations that are relatively frequent, taking into account the carrier frequencies in the Israeli Jewish population.
Isr Med Assoc J 2000 Sep;2(9):665-7.
This paper presents the findings of a community-based carrier screening program for Tay-Sachs disease, initiated on the University of Wisconsin-Madison campus in 1978. The Madison Community Tay-Sachs Screening Program (MCTSSP) is a collaborative, interdisciplinary program that organizes and conducts periodic screening for Tay-Sachs disease (TSD) for the purpose of identifying Tay-Sachs carriers. We present and analyze data on carrier detection with regard to various demographics, including family history of TSD, ancestry, gender, medication exposure, and illness. Individuals participating in the MCTSSP between 1978 and 1999 were primarily of the target population, and the carrier rate was within the expected range (1/25). Despite aggressive publicity efforts and a well-established program, attendance at the screens has declined. A recent survey of Jewish undergraduate students at the University of Wisconsin-Madison showed poor recall of family screen history and carrier status and reinforced the perception that utilization of the Madison screening program has been low. Ways to increase awareness of and interest in carrier screening for TSD are explored.
Genet Test 2000;4(3):257-63.
Tay-Sachs disease (TSD) is an autosomal-recessive, progressive, and ultimately fatal neurodegenerative disorder. Within the last 30 years, the discovery of the enzymatic basis of the disease, namely deficiency of the enzyme hexosaminidase A, made possible both enzymatic diagnosis of TSD and heterozygote identification. In the last decade, the cloning of the HEXA gene and the identification of more than 80 associated TSD-causing mutations has permitted molecular diagnosis in many instances. TSD was the first genetic condition for which community-based screening for carrier detection was implemented. As such, the TSD experience can be viewed as a prototypic effort for public education, carrier testing, and reproductive counseling for avoiding fatal childhood disease. More importantly, the outcome of TSD screening over the last 28 years offers convincing evidence that such an effort can dramatically reduce incidence of the disease.
Genet Test 1998;2(4):271-92.
CONTEXT: Rapid progress in gene discovery has dramatically increased diagnostic capabilities for carrier screening and prenatal testing for genetic diseases. However, simultaneous prenatal carrier screening for prevalent genetic disease has not been evaluated, and patient acceptance and attitudes toward this testing strategy remain undefined. OBJECTIVE: To evaluate an educational, counseling, and carrier testing program for 3 genetic disorders: Tay-Sachs disease (TSD), type 1 Gaucher disease (GD), and cystic fibrosis (CF) that differ in detectability, severity, and availability of therapy. DESIGN: Potential participants received education and genetic counseling, gave informed consent, chose screening tests, and completed pre-education and posteducation questionnaires that assessed knowledge, attitudes toward genetic testing, and disease testing preferences. SETTING: Medical genetics referral center. PATIENTS: Volunteer sample of 2824 Ashkenazi Jewish individuals enrolled as couples who were referred for TSD testing. INTERVENTION: Genetic counseling, education, and if chosen, genetic testing for any or all 3 disorders. MAIN OUTCOME MEASURE: Acceptance of screening for each of the 3 disorders. Secondary outcomes include attitudes toward genetic testing and reproductive considerations. RESULTS: Of the 2824 individuals tested for TSD, 97% and 95% also chose testing for CF and GD, respectively. The frequency of detected carriers was 1:21 for TSD, 1 :25 for CF, and 1:18 for GD. Twenty-one carrier couples were identified, counseled, and all postconception couples opted for prenatal diagnosis. Pre-education and posteducation questionnaires revealed that patients initially knew little about the diseases, but acquired disease information and increased knowledge of genetic concepts. Education and genetic counseling increased understanding and retention of genetic concepts and disease-related information, and minimized test-related anxiety. Although individuals sought screening for all 3 diseases, reproductive attitudes and decisions varied directly with disease severity and treatability. CONCLUSIONS: These findings emphasize the importance of genetic counseling for prenatal carrier testing and may improve understanding, acceptance, and informed decision making for prenatal carrier screening for multiple genetic diseases.
JAMA 1997 Oct 15;278(15):1268-72.
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