Summary
Tay-Sachs disease is an autosomal recessive storage disease caused by the impaired activity of the lysosomal enzyme hexosaminidase A. In this fatal disease, the sphingolipid GM2 ganglioside accumulates in the neurons. Due to high carrier rates and the severity of the disease, population screening and prenatal diagnosis of Tay-Sachs disease are routinely carried out in Israel. Laboratory diagnosis of Tay-Sachs is carried out with biochemical and DNA-based methods in peripheral and umbilical cord blood, amniotic fluid, and chorionic villi samples. The assay of hexosaminidase A (Hex A) activity is carried out with synthetic substrates, 4-methylumbelliferyl-6-sulfo-N-acetyl-β-glucosaminide (4-MUGS) and 4-methylumbelliferil-N-acetyl-β-glucosamine (4-MUG), and the DNA-based analysis involves testing for the presence of specific known mutations in the α-subunit gene of Hex A. Prenatal diagnosis of Tay-Sachs disease is accomplished within 24–48 h from sampling. The preferred strategy is to simultaneously carry out enzymatic analysis in the amniotic fluid supernatant or in chorionic villi and molecular DNA-based testing in an amniotic fluid cell-pellet or in chorionic villi.
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References
Robinson, D. and Stirling, J. L. (1968) N-Acetyl-β-glucosaminidase in human spleen. Biochem. J. 107, 321–327.
Srivastava, S. and Beutler, E. (1973) Hexosaminidase A and hexosaminidase B: studies in Tay-Sachs disease and Sandhoff’s disease. Nature 241, 463.
Mahuran, D. J., Tsui, F., Gravel, R. A., and Lowden, J. A. (1982) Evidence for two dissimilar polypeptide chains in the beta subunits of hexosaminidase. Proc. Natl. Acad. Sci. USA 79, 1602–1605.
Okada, S. and O’Brien, J. S. (1969) Tay Sachs disease: generalized absence of a β-d- N-acetylhexosaminidase component. Science 165, 698–700.
Geiger, B. and Arnon, R. (1976) Chemical characterization and subunit structure of human N-acetylhexosaminidase A and B. Biochemistry 15, 3484–3493.
Conzelmann, E. and Sandhoff, K. (1978) AB variant of infantile GM2-gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2. Proc. Natl. Acad. Sci. USA 75, 3979–3983.
O’Brien, J., Okada, S., Fillerup, D., et al. (1971) Tay-Sachs disease–prenatal diagnosis. Science 172, 61–64.
Kaback, M. M., and Zeigler, R. S. (1972) Heterozygote detection in Tay-Sachs disease: a prototype community screening program for the prevention of recessive genetic disorders. In: Volk, B.W. and Aronson, S.M. (eds.), Sphingolipids, sphingolipidosis and allied disorders: advances in experimental medicine and biology. Plenum, New York, pp 613–632.
Kaback, M., Bailin, G., Hirsch, P., and Roy, C. (1977) Automated thermal fractionation of serum hexosaminidase: effects of alteration in reaction variables and implications for Tay-Sachs disease heterozygote screening and prevention. In: Kaback, M., Rimoin, D., and O’Brien, J. (eds.), Tay-Sachs disease: screening and Prevention. Alan R. Liss , New York, p 197.
Kresse, H., Fuchs, W., Glossl, J., Holtfrerich, D., and Gilberg, W. (1981) Liberation of N-acetylglucosamine-6-sulfate by human beta-N-acetylhexosaminidase. J. Biol. Chem. 256, 12926–12932.
Bayleran, J., Hetchman, P., and Saray, W. (1984) Synthesis of 4-methylumbelliferyl-β-d-N-acetylglucoseamine-6-sulfate and its use in classification of GM2 gangliosidosis genotypes. Clin. Chim. Acta 143, 73–89.
Gravel, R. A., Clarke, J. T. R., Kaback, M. M., Mahuran, D., Sandhoff, K., and Suzuki, K. (1995) The GM2 gangliosidoses. In: Scriver, C. R., Beaudet, A. L., Sly, W. S., et al. (eds.), The metabolic and molecular basis of inherited disease, 7th edn. McGraw-Hill, New York, pp 2839–2879.
Kytzia, H. J. and Sandhoff, K. (1985) Evidence for two different active sites on human beta-hexosaminidase A. Interaction of GM2 activator protein with beta-hexosaminidase A. J. Biol. Chem. 260, 7568–7572.
Hou, Y., Tse, R., and Mahuran, D. J. (1996) Direct determination of the substrate specificity of the α active site in heterodimeric β-hexosaminidase A. Biochemistry 35, 3963–3969,
Tse, R., Vavougios, G., Hou, Y., and Mahuran, D. J. (1996) Identification of an active acidic residue in the catalytic site of β-hexosaminidase. Biochemistry 35, 7599–7607.
Sharma, R., Deny, H., Leung, A., and Mahuran, D. (2001) Identification of 6-sulfate binding unique to α-subunit containing isozymes of human β-hexosaminidase. Biochemistry 40, 5440–5446.
Peleg, L. and Goldman, B. (1994) Detection of Tay-Sachs disease carriers among individuals with thermolabile hexosaminidase B. Eur. J. Clin. Chem. Clin. Biochem. 32, 65–69.
Myerovitz, R., Piekarz, R., Neufeld, E. F., Shows, T. B., and Suzuki, K. (1985) Human β-hexosaminidase α-chain: coding sequence and homology with the β chain. Proc. Natl. Acad. Sci. USA 82, 7830–7834.
Proia, R. L. and Soravia, E. (1987) Organization of the gene encoding the human β-hexosaminidase β-chain. J. Biol. Chem. 262, 5677–5681.
Proia, R. L. (1988) Gene encoding the human human β-hexosaminidase β-chain: extensive homology of intron placement in the α- and β-chains gene. Proc. Natl. Acad. Sci. USA 85, 1883–1887.
Takeda, K., Nakai, H., Hagiwara, H., et al. (1990) Fine assignment of beta-hexosaminidase A alpha subunit on 15q23–24 by high resolution in situ hybridization. Tohoku J. Exo. Med. 160, 203–211.
Fox, M. F., DoToit, D. K., Warnich, L., and Retief, A. E. (1984) Regional localization of alpha-galactosidase to Xpter-q22, hexosaminidase B (HEXB) to 5q13-qter and arylsulfatase B (ARSB) to 5pter-q13. Cytogenet. Cell. Genet. 38, 45–49.
Triggs-Raine, B. L., Feigenbaum, A. S., Natowitcz, M., et al. (1990) Screening for carriers of Tay Sachs disease among Ashkenazi Jews. N. Engl. J. Med. 323, 6–12.
Navon, R. and Proia, R. L. (1989) The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the adult form of Tay Sachs disease. Science 243, 1471–1474.
Triggs-Raine, B. L., Mules, E. H., et al. (1992) A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: Implication for carrier screening. Am. J. Hum. Genet. 51, 793–801.
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Guetta, E., Peleg, L. (2008). Rapid Detection of Fetal Mendalian Disorders: Tay-Sachs Disease . In: Hahn, S., Jackson, L.G. (eds) Prenatal Diagnosis. Methods in Molecular Biology™, vol 444. Humana Press. https://doi.org/10.1007/978-1-59745-066-9_11
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DOI: https://doi.org/10.1007/978-1-59745-066-9_11
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