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PubMed2006

Therapeutic evaluation of GM2 gangliosidoses by ELISA using anti-GM2 ganglioside antibodies.

BACKGROUND: GM2 gangliosidoses, including Tay-Sachs disease, Sandhoff disease and the AB variant, comprise deficiencies of beta-hexosaminidase isozymes and GM2 ganglioside activator protein associated with accumulation of GM2 ganglioside (GM2) in lysosomes and neurosomatic clinical manifestations. A simple assay system for intracellular quantification of GM2 is required to evaluate the therapeutic effects on GM2-gangliosidoses. METHODS: We newly established a cell-ELISA system involving anti-GM2 monoclonal antibodies for measuring GM2 storage in fibroblasts from Tay-Sachs and Sandhoff disease patients. RESULTS: We succeeded in detecting the corrective effect of enzyme replacement on elimination of GM2 in the cells with this ELISA system. CONCLUSIONS: This simple and sensitive system should be useful as additional diagnosis tool as well as therapeutic evaluation of GM2 gangliosidoses.

Antibodies, Monoclonal↗

PubMed1975

The gangliosidoses.

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.

Axons↗

PubMed1998

Biology and potential strategies for the treatment of GM2 gangliosidoses.

The GM2 gangliosidoses are a group of heritable neurodegenerative disorders caused by excessive accumulation of the ganglioside GM2 owing to deficiency in beta-hexosaminidase activity. Tay-Sachs and Sandhoff diseases have similar clinical phenotypes resulting from a deficiency in human hexosaminidase alpha and beta subunits, respectively. The lack of treatment for GM2 gangliosidoses stimulated interest in developing animal models to understand the molecular mechanisms underlying the various forms of this disease and to test new potential therapies. In this review, we discuss the molecular biology of GM2 gangliosidoses and the different strategies that have been tested in animal models for the treatment of this genetic disorder, including gene transfer and cell engraftment of neural stem cells engineered to express the hexosaminidase isoenzymes.

1-Deoxynojirimycin↗

PubMed1977

N-Acetyl-beta-hexosaminidase isoenzymes of amniotic fluid and maternal serum. Their relevance to prenatal diagnosis of the GM2 gangliosidoses.

The isoenzymes of N-acetyl-beta-hexosaminidase were quantitated in 30 amniotic fluid and 13 maternal serum samples collected between 11 and 40 weeks of gestation using DEAE-Sephadex A-25 chromatography. Isoenzymes A and B consitituted the major components of most amniotic fluids but seven samples characterized by high N-acetyl-beta-hexosaminidase activities contained high proportion of an isoenzyme apparently identical to isoenzyme P of maternal serum. This passage of maternal serum N-acetyl-beta-hexosaminidase into the amniotic cavity could lead to false negative diagnosis of type B and type O GM2 gangliosidoses if the diagnosis rely solely upon isoenzyme analysis in amniotic fluid. However, the release of maternal enzyme into amniotic fluid seems to be restricted to the third trimester of gestation and should not interfere with prenatal diagnosis of the GM2 gangliosidoses ususally performed at an earlier stage of gestation.

Amniotic Fluid↗

PubMed1984

Synopsis: gangliosidoses.

Gangliosidoses are very rare neurological diseases based on specific enzyme defects. They constitute models for the disruption of specific metabolic pathways and cellular functions with the ultimate consequence of manifest clinical symptoms. The investigation of the various steps involved in the generation of a given syndrome can therefore lead to a more profound understanding of the cell biology of the nervous system. In the present synopsis we try to briefly summarize some aspects of the present knowledge of pathophysiological mechanisms in GM1- and GM2-gangliosidoses.

Brain↗

PubMedDate not supplied

The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A gene loci.

The GM2 gangliosidoses are a group of recessive disorders characterized by accumulation of GM2 ganglioside in neuronal cells. The genes responsible for these disorders are HEXA (Tay-Sachs disease and variants), HEXB (Sandhoff disease and variants), and GM2A (AB variant of GM2 gangliosidosis). We report the establishment of three relational locus-specific databases recording allelic variation at the HEXA, HEXB, and GM2A genes and accessed at the GM2 gangliosidoses home page (http://data.mch.mcgill.ca/gm2-gangliosidoses). Submission forms are available for the addition of new mutations to the databases. The databases are available online for users to search and retrieve information about specific alleles by a number of fields describing mutations, phenotypes, or author(s).

Alleles↗

PubMed1979

The gangliosidoses: comparative features and research applications.

Ganglioside storage diseases are inherited defects of lysosomal hydrolases that result in intralysosomal accumulation of gangliosides and other complex metabolites. Gangliosidoses occur in man, cats, cattle, dogs and swine. In all species, these diseases are characterized clinically by relentlessly progressive neurological deterioration. Lysosomal hypertrophy with characteristic ultrastructural inclusions occur in neurons, endothelial and other cells. Definitive diagnosis requires biochemical identification of the storage product and enzyme deficiency. Gangliosidoses in animals are important models of human lysosomal diseases and may be a significant complication in the maintenance of certain purebred stocks of domestic animals.

Animals↗

PubMed1998

Glycosphingolipid degradation and animal models of GM2-gangliosidoses.

Glycosphingolipids form cell type-specific patterns on the surface of eukaryotic cells. Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane-derived glycosphingolipids into the lysosomes as the digesting organelles. The inherited deficiencies of lysosomal hydrolases and of sphingolipid activator proteins both give rise to sphingolipid storage diseases. Recent research has focused on the mechanisms leading to selective membrane degradation in the lysosomes and on the mechanism and physiological function of sphingolipid activator proteins. The GM2-degrading system is a paradigm for activator protein-dependent lysosomal degradation. Three polypeptide chains contribute to the in vivo degradation of ganglioside GM2: the alpha- and beta-chains of the beta-hexosaminidases and the GM2 activator. Mouse models of Tay-Sachs disease (alpha-chain deficiency), Sandhoff disease (beta-chain deficiency) and GM2 activator deficiency have been described. While the phenotypes of these variants of GM2-gangliosidoses are only slightly different in humans, the animal models show drastic differences in severity and course of the diseases. The reason for this is the specificity of sialidase, which is different between mouse and human. A double-knockout mouse lacking beta-hexosaminidases A, B and S shows a phenotype of mucopolysaccharidosis and gangliosidosis. A substrate deprivation approach to therapy is discussed with respect to animal models of the GM2-gangliosidoses.

Animals↗

PubMed1984

Clinical course of GM2 gangliosidoses. A correlative attempt.

The clinical course of the early onset gangliosidoses can be explained on the basis of the developmental time course of different brain structures and functional systems. In particular, the maturation of the four basic motor control systems--spinal cord, brain stem and cerebellum, basal ganglia, cerebral cortex--determines the appearance of certain motor deficits. In late onset GM2 gangliosidoses, however, regional preference of the storage process has to be assumed in order to explain certain characteristic features of the disorder. An attempt is made to explain cellular dysfunction in GM2 storage disorders on the basis of developmental defects and/or destruction of the endoplasmatic reticulum and Golgi apparatus distortion of the neuronal geometry. Hyperirritability and epilepsy are possibly due to a dysequilibrium between excitatory and inhibitory postsynaptic influences caused by the distortion of the synaptic geometry on the nerve cell surface. Again, the clinical appearance of hyperirritability and the type of epilepsy are dependent upon the developmental age of the affected nervous system.

Axons↗

PubMed1985

Epstein-Barr virus transformed lymphoid cell lines as a new model system in culture for the study of GM2-gangliosidoses: Tay-Sachs and Sandhoff diseases.

Epstein-Barr Virus transformed cell lines (LCL) were established from blood B-lymphocytes of patients affected with GM2-gangliosidoses variant O (Sandhoff disease, SD) and variant B (Tay-Sachs disease, TSD). LCL from SD showed a severe deficiency of activity of the major lysosomal beta-N-acetylhexosaminidase isoenzymes, Hex A and B; the residual activity was due to Hex S and Hex C. In LCL from TSD, the whole Hex activity was not deficient but isoenzyme composition was completely abnormal. Ultrastructural investigations showed the presence of pleiomorphic enlarged lysosomes appearing as clear vacuoles containing a finely fibrillo-granular material characteristic of the visceral lysosomal storage of gangliosidoses.

Adult↗

PubMedDate not supplied

Increased density of the thalamus on CT scans in patients with GM2 gangliosidoses.

In 13 patients, the GM2 gangliosidoses, Sandhoff disease and Tay-Sachs disease, were found to be constantly associated with homogeneously and symmetrically increased CT attenuation within the thalami. In the only patient examined with MR imaging, a T2-weighted sequence showed hypointense thalami. It is suggested that this finding is caused by an accumulation of calcium, associated with the intracellular storage of GM2 ganglioside. The finding of dense thalami may be useful as a specific diagnostic criterion for GM2 gangliosidoses. In a few patients with blocks in adjacent steps in the sphingolipid metabolism, this finding was not present.

Female↗

PubMed1979

Biochemistry and genetics of gangliosidoses.

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.

Adolescent↗

PubMed1986

Ganglioside loading of cultured fibroblasts: a provocative method for the diagnosis of the GM2 gangliosidoses.

Confirmation of deficient beta-hexosaminidase activity in suspected cases of GM2 gangliosidosis may be difficult with available assay systems if the residual activity is high (as in many juvenile cases and genetic compounds). Hexosaminidase activity is normal in the AB-variant (activator protein deficiency), although GM2-ganglioside (GM2) catabolism is severely impaired. We therefore examined ganglioside degradation in intact fibroblasts in culture. Intracellular ganglioside levels were determined in cultured human skin fibroblasts grown in standard tissue culture medium or medium supplemented with mixed bovine brain gangliosides. Cellular uptake and catabolism of the added gangliosides were manifested by modest increases in the intracellular concentrations of gangliosides GT + GD and GM1 in all cells tested, and marked accumulation of GM2 in fibroblasts from patients with GM2 gangliosidoses. Intracellular GM2 increased five- to fifteen-fold in all of the GM2 gangliosidosis cell lines tested, including those from patients with infantile Tay-Sachs disease (TSD), Sandhoff disease, late infantile and juvenile variants of TSD with high residual enzyme activity, adult onset GM2 gangliosidosis, and the AB-variant. Significant GM2 accumulation did not occur in fibroblasts from patients with GM2 gangliosidosis grown in standard medium, or in normal fibroblasts grown in ganglioside enriched medium. Our method of ganglioside feeding employs commercially available materials and no special equipment. It should be useful for the confirmation of impaired GM2 catabolism in a variety of settings.

Cells, Cultured↗

PubMedDate not supplied

[Clinical and electrophysiological aspects of the gangliosidoses (author's transl)].

The gangliosidoses belong to the family of diseases known as the lipidoses and are due to an excess of ganglioside I (GM1) or II (GM2). The illness described by Landing belongs to Group I, whilst Tay-Sachs and Sandhoff's disease are type 2. This study was particularly concerned with the electro-clinical aspects of group 2, and 4 stages have been differentiated: --the first occurs between 4-10 months: the child is apathetic, hypotonic and has occasional audiogenic seizures; fundoscopy revealing the classical cherry red spot on the macula. The diagnosis can be confirmed by biopsy. The EEG is irregular but abnormalities are minor. --the second stage (10 months-2 years) the child spastic and amaurotic, often unresponsive is suffering from frequent seizures. The EEG is of high voltage, with slow and sharp waves. Auditory stimulation does not produce EEG changes. --in the third and 4th stages (after 2 years) the child is in a vegetative state with a progressive reduction in EEG voltage and sharp waves until death aged 3 or 4. Although there is a good correlation between clinical signs and EEG this is of no diagnostic value.

Brain↗

PubMed2000

Quantification of mRNAs encoding proteins of the glycosphingolipid catabolism in mouse models of GM2 gangliosidoses and sphingolipid activator protein precursor (prosaposin) deficiency.

We have investigated the mRNA amounts of six lysosomal proteins (beta-hexosaminidase alpha- and beta-subunit, sphingolipid activator protein precursor, GM2 activator protein, lysosomal sialidase, beta-glucocerebrosidase) involved in the degradation of glycosphingolipids. We analyzed extracts from brain tissues of mouse models for lysosomal storage diseases, i.e., the GM2 gangliosidoses and the deficiency of the sphingolipid activator protein precursor (prosaposin). The mRNA levels were quantified by real-time reverse transcription-polymerase chain reaction. Although storage of the respective lysosomal proteins has been reported in human and mice, no increase of their mRNA amounts could be detected here. Our results indicate that there is no transcriptional upregulation of lysosomal proteins in the examined neuronal storage disorders.

Age Factors↗

PubMed1984

Clinical course of GM1 gangliosidoses.

The GM1 gangliosidoses are clinically characterized by the combination of a degenerative process in the brain and of storage phenomena in extra-neural tissues, particularly in bones and visceral organs. Phenotypic variability is pronounced. "Classical" types, according to the age at onset, are infantile ("generalized"), juvenile, and adult forms. In rare variants, the degenerative process may be restricted to the basal ganglia and cause dystonia musculorum deformans, or it may cause infantile cardiomyopathy. Much of this variability may be explained by variable residual activities of the deficient beta-galactosidase towards various substrates.

Adolescent↗

PubMed1984

Neurophysiological investigations in GM1 and GM2 gangliosidoses.

Neurophysiological studies (EEG, ERG, VEP and BAEP) have been carried out on a total of fifty-four patients (fourty-five GM2 and nine GM1 gangliosidosis) at various stages of the disease process. In infantile GM2 gangliosidosis, the EEG was midly abnormal from an early age but by the age of one year there was a rapid and progressive deterioration. EEG changes in late onset GM2 gangliosidosis were very variable and unrelated to age or enzyme defect. In both Type 1 and Type 2 GM1 gangliosidosis there was a progressive deterioration of the EEG. Paroxysmal features were not prominent in any of the gangliosidoses, despite the occurrence of seizures. The ERG remained normal in both GM2 and GM1 patients. In the infantile GM2 patients there was progressive loss of the VEP between nine and fifteen months of age but the timing of VEP changes were more variable in all the other groups. Evidence of brainstem dysfunction was found in one of the two TSD patients tested. The combined neurophysiological features appear to be characteristic for each group of gangliosidosis and differ from other neurometabolic disorders of childhood.

Arousal↗

PubMed1984

Morphology of the gangliosidoses.

GM1 and GM2 gangliosidoses are progressive neurodegenerative diseases which accumulate intralysosomal gangliosides--and to a lesser extent oligosaccharides--chiefly in the central and peripheral nervous system owing to deficiencies of beta-galactosidase and hexosaminidases A or/and B, respectively. This intralysosomal "storage" in neuronal pericarya and their processes, and subsequent loss of such nerve cells provide the background for clinical symptoms of the central nervous system and the retina, while involvement of the peripheral nervous system and the visceral organs largely remains free of clinical findings. The morphological involvement of the latter organs is widespread though varying, thus allowing morphological investigations of lymphocytes, skin, or rectum for morphological diagnosis and as a screening procedure.

Astrocytes↗