Abstract
Publisher Summary This chapter discusses the search for enzymatic defect in Tay-Sachs disease (TSD) with a simple galactose tolerance test in a patient with Gaucher disease. Patients with this disorder accumulated a sphingoglycolipid called “glucocerebroside” and major sphingolipid of brain, called the “galactocerebroside”. Numerous attempts were made to assess glucocerebroside catabolism using: (1) unlabeled natural material; (2) radioactive glucocerebroside prepared biosynthetically; (3) and 3 H-glucocerebroside prepared by the Wilzbach isotope-exchange procedure, no significant progress was made until this compound was chemically synthesized with 14 C in specific portions of the molecule. Ganglioside G M2 is branched in the terminal portion of its molecule, its catabolism could theoretically begin, either through the action of a hexosaminidase-cleaving N-acetylgalactosamine or by a neuraminidase that catalyzed the cleavage of N-acetylneuraminic acid. Not only was there ample hexosaminidase activity present in the brain of Tay-Sachs patients measured by this procedure, but it was actually increased over that in control human brain specimens. The metabolic defect in Tay-Sachs disease was thereby established using authentic labeled ganglioside G M2 . Most testing for Tay-Sachs homozygotes and heterozygotes is performed with artificial substrates such as 4-methylumbelliferyl-β-D-N-acetylglucosaminide. There is an extraordinarily large discrepancy between the activities of purified hexosaminidase A with artificial substrates and the natural ganglioside G M2 , even in the presence of detergents.
Published Version
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