title: Biochemistry and genetics of gangliosidoses.
abstract: The gangliosidoses comprise an-ever increasing number of biochemically and phenotypically variant diseases. In most of them an autosomal recessive inherited deficiency of a lysosomal hydrolase results in the fatal accumulation of glucolipids (predominantly in the nervous tissue) and of oligosaccharides. The structure, substrate specificity, immunological properties of and genetic studies on the relevant glycosidases, ganglioside GM1 beta-galactosidase and beta-hexosaminidase isoenzymes, are reviewed in this paper. Contrary to general expectation, only a poor correlation is observed between the severity of the disease and residual activity of the defective enzyme when measured with synthetic or natural substrates in the presence of detergents. For the understanding of variant diseases and for their pre- and postnatal diagnosis, the necessity of studying the substrate specificity of normal and mutated enzymes under conditions similar to the in vivo situation, e.g., with natural substrates in the presence of appropriate activator proteins, is stressed. The possibility that detergents may have adverse affects on the substrate specificity of the enzymes is discussed for the beta-hexosaminidases. The significance of activator proteins for the proper interaction of lipid substrates and water-soluble hydrolases is illustrated by the fatal glycolipid storage resulting from an activator protein deficiency in the AB variant of GM2-gangliosidosis. Recent somatic complementation studies have revealed the existence of a presumably post-translational modification factor necessary for the expression of ganglioside GM1 beta-galactosidase activity. This factor is deficient in a group of variants of GM1-glangliosidosis. Among the possible reasons for the variability of enzyme activity levels in heterozygotes and patients, allelic mutations, formation of hybrid enzymes, and the existence of patients as compound heterozygotes are discussed. All these may result in the production of mutant enzymes with an altered specificity for a variety of natural substrates.
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D005733:Gangliosidoses / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D006580:Genetic Carrier Screening; D006596:Hexosaminidases / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012497:Sandhoff Disease / Q000235:genetics / Q000378:metabolism; D013661:Tay-Sachs Disease / Q000235:genetics / Q000378:metabolism
chemical_list: D005732:Gangliosides; D006596:Hexosaminidases