Tay-Sachs Disease Carrier Screening: A Model for Prevention of Genetic Disease

Abstract

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.

The frequency of Tay-Sachs disease causing mutations in the Brazilian Jewish population justifies a carrier screening program

“…However, while DNA test is adequate for Ashkenazi Jews, the enzyme assay is more appropriate for the general population since different mutations may be present. 28 In addition to the continuity of this screening program for Tay-Sachs disease carriers, an ideal outcome from this research would be to bring it to the attention of physicians assisting Brazilian Jewish couples that they may be attending a Tay-Sachs disease carrier couple. It is important to note that the carrier frequency of Tay-Sachs disease among the general population is about 10 times lower than in the population at risk, significantly diminishing but not eliminating Tay-Sachs disease among non-Jews.…”

“…Recently, due to intermarriage and declining awareness of ancestry, screening has been recommended even for couples for whom only one member is thought to have ancestry in a high-risk population. 28 Screening can confirm or exclude the possibility of both members of a couple being TaySachs disease carriers, and is the best indication for prevention until an effective treatment becomes available for this disease.…”

Human Genetic Individuality

“…For example, Tay-Sachs disease, an autosomal recessive defect in lipid metabolism that is uniformly fatal in early childhood, is 100 times more common in individuals of Ashkenazi ancestry than in the general population (54). Three alleles account for ∼95% of disease-causing mutations in patients of Ashkenazi ancestry, whereas the rare cases that occur in the general population are caused by a large array of rare alleles, most cataloged examples of which have been seen only once (54).…”

“…For example, Tay-Sachs disease, an autosomal recessive defect in lipid metabolism that is uniformly fatal in early childhood, is 100 times more common in individuals of Ashkenazi ancestry than in the general population (54). Three alleles account for ∼95% of disease-causing mutations in patients of Ashkenazi ancestry, whereas the rare cases that occur in the general population are caused by a large array of rare alleles, most cataloged examples of which have been seen only once (54). The most common of the Ashkenazi alleles has been estimated, based on haplotype divergence, to have originated ∼1,200 years before present, a period during which the Ashkenazi population is known from the historical record to have expanded from a small founding population in central Europe (32).…”

Evaluation of two-year Jewish genetic disease screening program in Atlanta: insight into community genetic screening approaches

“…Carrier screening in the Jewish population began in the early 1970s with hexosaminidase A (Hex A) enzyme assay targeting identification of carriers of Tay-Sachs disease (TSD) (Kaplan 1998). Over the last 40 years, genetic screening for TSD has dramatically reduced the incidence of this disease in the worldwide Jewish population, with at least a 90 % decrease in North America (Kronn et al 1998).…”