g(m2)-ganglioside and Lipidoses

Topics: G(M1) Ganglioside; G(M2) Ganglioside; G(M3) Ganglioside; Gangliosidoses; Genetic Carrier Screening; Genetic Counseling; Glycoside Hydrolases; Humans; Leukodystrophy, Metachromatic; Lipidoses; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis III; Mucopolysaccharidosis IV; Mucopolysaccharidosis VI; Phenotype; Polymorphism, Genetic

Topics: Animals; Cats; Cattle; Disease Models, Animal; Dogs; G(M2) Ganglioside; Gangliosidoses; Gaucher Disease; Glycogen; Glycogen Storage Disease Type II; Glycopeptides; Humans; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Lipidoses; Lysosomes; Mannosidases; Metabolism, Inborn Errors; Mice; Niemann-Pick Diseases; Rabbits; Sphingolipids

Topics: Brain; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Humans; Lipidoses

The gangliosidoses are hereditary diseases with a recessive mode of inheritance and are caused by a genetically induced enzymatic block, which results in the accumulation of gangliosides in various tissues of the body, mainly in the brain. Although Tay-Sachs disease, the most commonly occurring of the gangliosidoses, has been known for nearly 100 years, additional variants of ganglioside "storage" disorders have been discovered during the past 15 years. Considerable progress in the knowledge of these disorders has been made with the advent of electron microscopy and with the elaboration of new biochemical and enzyme-chemical techniques. At the present the gangliosidoses are not amenable to therapy. Therefore the foreseeable future the pragmatic approach involves identification of the high-risk pregnancy and antenatal diagnosis.

Topics: Axons; Cerebellum; Cerebral Cortex; Cerebrosides; Female; Fetal Diseases; G(M2) Ganglioside; Gangliosidoses; Humans; Inclusion Bodies; Lipidoses; Muscles; Neurons; Optic Nerve; Pregnancy; Retina; Spinal Cord

Ganglioside GM2 and its asialo-derivative, GA2 were radiolabeled in their N-acetyl-D-galactosaminyl moieties by oxidation with galactose oxidase and reduction with tritiated sodium borohydride. Specific activities of 6 X 10(4) dpm/nmol (GM2) and 1.8 X 10(6) dpm/nmol (GA2) were achieved. About 98% of the label was in N-acetyl-D-galactosamine. Using these substrates, an assay was developed for GM2-N-acetyl-beta-D-galactosaminidase (E.C.3.2.1.30) and GA2-N-acetyl-beta-D-galactosaminidase (E.C.3.2.1.30) activities in human cultured skin fibroblasts. The products of the GM2 cleaving reaction were identified as N-acetylgalactosamine and ganglioside GM3. Both GM2 and GA2 cleaving activities were stimulated about 5-fold by purified sodium taurocholate, and this stimulation was inhibited by neutral detergents, lipids and albumin at low concentrations. Addition of various salts, reducing agents and a protein activator factor from human liver of Li et al. (1973) did not stimulate GM2-N-acetyl-beta-D-galactosaminidase activity beyond that found with sodium taurocholate. Under optimal conditions, control fibroblast supernates cleaved ganglioside GM2 at a rate of 3.7 nmol/mg protein/h compared to 1100 for GA2-N-acetyl-beta-D-galactosaminidase and 4700 for 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminidase. Supernates from two patients with Tay-Sachs disease had markedly reduced activity levels for GM2-N-acetyl-beta-D-galactosaminidase but not for the other two substrates. Supernates from two patients with Sandhoff's disease had reduced activities for all three substrates. A supernate from one patient with juvenile GM2 gangliosidosis cleaved GM2 at a somewhat faster rate than those from Tay-Sachs or Sandhoff's patients. Two healthy adult women with markedly reduced hexosaminidase A activities using 4MU-N-acetyl-beta-D-glucosaminide as substrate had approximately half-normal activities using GM2 as substrate. A patient with the Tay-Sachs phenotype but with a partial deficiency of hexosaminidase A using the 4-MU substrate had a profound deficiency using GM2 as substrate. In such unusual hexosaminidase mutants, assays using GM2 as substrate are better indicators of phenotype than those using synthetic substrates.

Topics: Adult; Albumins; Borohydrides; Cells, Cultured; Chromatography, Thin Layer; Detergents; Female; Fibroblasts; G(M2) Ganglioside; Galactose Oxidase; Gangliosides; Gangliosidoses; Hexosaminidases; Humans; Hydrogen-Ion Concentration; Isotope Labeling; Lipidoses; Lipids; Skin; Taurocholic Acid

Topics: Cells, Cultured; Ceramides; Cerebellum; Fatty Acids; G(M2) Ganglioside; G(M3) Ganglioside; Gangliosides; Glycosphingolipids; Humans; Lipidoses; Lung; Neurons

Topics: Child, Preschool; G(M2) Ganglioside; Gangliosides; Gangliosidoses; Humans; Infant; Lipidoses; Male

Golgi and electron microscope studies of cortical neurons in several lysosomal storage diseases were carried out to elucidate structural features of the large neural processes (meganeurites) that develop as storage sites for accumulated undigestible substrates. Meganeurites occur preferentially in pyramidal neurons wherein they develop between the base of the perikaryon and the initial portion of the axon. They frequently give rise to secondary neurites which bear filopodium-like processes. Meganeurites may possess spines some of which are contacted by presynaptic processes containing synaptic vesicles. The extent of meganeurite development is related to the onset, severity and clinical course of neuronal storage disease. Extensive development of bizarre and pleomorphic meganeurites occurs in classical Tay-Sachs disease (infantile GM2-gangliosidosis, B variant), whereas a smaller proportion of neurons exhibits meganeurites in juvenile GM2-hangliosidosis and Hurler's disease. Meganeurites with spines and spine synapses were prominent in GM2-gangliosidosis, AB variant. It is proposed that meganeurites and meganeurite synapses contribute to the onset and progression of neuronal dysfunction in storage diseases by altering electrical properties of the neuron and modifying integrative operations of somadendritic synaptic inputs.

Topics: Adolescent; Biopsy; Brain; Ceroid; Child; G(M2) Ganglioside; Gangliosidoses; Humans; Infant; Lipid Metabolism, Inborn Errors; Lipidoses; Lipofuscin; Male; Mucopolysaccharidosis I; Neurons; Pyramidal Tracts; Synapses

With a view to the biochemical detection of homo- and heterozygous carriers of GM2-gangliosidosis, serum hexosaminidase activities were investigated in patients from Tay-Sachs and from Sandhoff disease, respectively, in their relatives, and in normal controls. Two related methods for the differential determination of hexosaminidase A and B activities were tested. Homozygous carriers (patients) were detected by both methods in a similar manner. As regards the identification of heterozygous carriers more conclusive results were attained by the "heat inactivation method" (O'Brien, J.S., Okada, S., Chen, A. and Fillerup, D.L. (1970) New Engl. J. Med 283, 15).

Topics: Diagnosis, Differential; G(M2) Ganglioside; Gangliosidoses; Genes; Heterozygote; Hexosaminidases; Homozygote; Humans; Lipidoses

Cultured cells derived from Tay-Sachs disease (TSD) fetal cerebellum were shown to accumulate GM2 ganglioside when compared with control cultures. In contrast, fibroblasts derived from TSD fetal lung do not contain GM2. GM2 was identified by thin-layer chromatography (TLC) and confirmed by gas-liquid chromatography (GLC). Unlike fetal TSD brain, the cell cultures established from fetal TSD brain have high concentrations of globoside and GD3 and little or no asialo GM2(GA2). The GM2 and related glycosphingolipids in these cultured cells contain a high percentage of C24:0 and C24:1 fatty acids. In spite of these differences, this TSD cell strain is unique in that it accumulates GM2, and can therefore serve as a useful in vitro model for the study of TSD.

Topics: Cells, Cultured; Cerebellum; Cerebrosides; Fatty Acids; Fetus; Fibroblasts; G(M2) Ganglioside; Gangliosides; Humans; Infant, Newborn; Lipidoses; Lung; Models, Biological

Clinical and neuropathological studies of a case of AB variant GM2-gangliosidosis have been presented. The patient was a 14 months old black female infant who had "black cherry spot" in the retinas. The total activities of beta-galactosidase and N-acetyl-beta-hexosaminidase, as well as the proportion of hexosaminidase A and B components in her serum and leukocytes were normal when the assays were carried out with artificial fluorogenic substrate. Diagnosis of GM2-gangliosidosis AB variant was established by an abnormal increase of GM2-ganglioside in the biopsied brain tissue, similar to classical Tay-Sachs disease. Her clinical manifestation appeared to be similar but somewhat milder than those of classical Tay-Sachs disease. Light microscopic features of the cerebral biopsy were also closely similar to Tay-Sachs disease and Sandhoff disease but gliosis and neuronal loss were less pronounced. Electron microscopic study revealed numerous membranous cytoplasmic bodies (MCB) and zebra bodies in neurons. In addition, varieties of large intracytoplasmic inclusions in astrocytes, a feature distinctly different from classical Tay-Sachs disease, were observed. Numerous cytoplasmic inclusions were also present in oligodendroglia, pericytes and microglial cells.

Topics: Acetylglucosaminidase; Acid Phosphatase; Astrocytes; Brain Chemistry; Capillaries; Cerebral Cortex; Female; G(M2) Ganglioside; Galactosidases; Gangliosidoses; Humans; Inclusion Bodies; Infant; Lipidoses; Neuroglia; Neurons

Topics: Cell Fusion; Female; G(M2) Ganglioside; Galactosidases; Genetic Complementation Test; Genetic Variation; Heterozygote; Hexosaminidases; Humans; Hybrid Cells; Isoenzymes; Lipidoses; Male; Mutation

Topics: G(M2) Ganglioside; Genetic Complementation Test; Hexosaminidases; Humans; Hybrid Cells; Hybridization, Genetic; Lipidoses; Metabolism, Inborn Errors

Topics: Animals; Cell Line; Cricetinae; G(M2) Ganglioside; Genetic Complementation Test; Hexosaminidases; Humans; Hybrid Cells; Lipidoses

Topics: Animals; Arylsulfatases; Brain; Disease Models, Animal; G(M2) Ganglioside; Gangliosides; Hexosaminidases; Isoenzymes; Leukodystrophy, Metachromatic; Lipidoses; Rats; Sulfatases; Vitamin E Deficiency

Topics: Amino Acids; Brain; Chromatography; G(M2) Ganglioside; Gangliosides; Humans; Lipid Metabolism; Lipidoses; Peptides; Proteins; Tay-Sachs Disease