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Sandhoff disease/GM2 gangliosidosis/deficiency of Hex A and Hex B subunit deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Patients with Sandhoff disease accumulate GM2 ganglioside in the brain [1]. The amounts found are 100–300 times the normal concentrations and quite similar to those of Tay-Sachs disease. In contrast to patients with Tay-Sachs disease, these patients also accumulate globoside, the common neutral glycolipid of erythrocyte and renal membranes, which has the same amino terminal sugar as GM2 ganglioside, N-acetyl galactosamine, in extraneural tissues, especially the liver, kidney, and spleen [17–20]. In the brain, there is storage of GM2; in addition, the asialo derivative of GM2 (GA2) accumulates, and this too is a difference from Tay-Sachs disease. Globoside may be demonstrated in urinary sediments and plasma [18]. The stored compounds are all structurally related. The asialo derivative differs from GM2 in the absence of the N-acetylneuraminic side chain, whereas globoside contains an extra galactose moiety. GA2 is found in the brain in Sandhoff disease in amounts 100 times normal [17]. Oligosaccharides and glycopeptides, which have a glycosidically bound N-acetylhexosamine, accumulate in various tissues, and they are excreted in the urine [21, 22], providing a readily accessible approach to diagnosis.
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
One precursor of glucocerebrosides is globoside, N-acetyl-galactosaminyl-galactosyl-galactosyl-ceramide which occurs in great amounts in the stroma of erythrocytes. Leukoytesare other likely sources of glucocerebroside; they contain glycolipids and the precursor or intermediate ceramide lactoside and glucocerebroside occur as predominant lipid constituents. Leukocyte breakdown provides probably most glycolipids. The turnover of gangliosides is fairly rapid in infancy and slows down later in life. In the adult type of Gaucher’s disease, there is probably some glucocerebrosidase activity in the brain which metabolizes the glucocerebroside arising from leukocyte gangliosides during the neonatal period. Thus, the residual enzyme activity prevents the development of abnormalities in the central nervous system.
Composition of The Chromaffin Cell
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Ariga, Macala, Saito et al. (1988) studied the lipid composition of PC12 cells cultured in the presence and absence of nerve growth factor. The concentration of neutral glycolipids was about 1.7 μg/mg of protein for both untreated and growth factor-treated cells. The neutral glycolipid fraction contained a major component that accounted for 80% of the total and was characterized as globoside. This and other glycolipids were characterized further.
Sandhoff disease in the elderly: a case study
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Leidy García Morales, Reinaldo Gaspar Mustelier Bécquer, Laura Pérez Joglar, Tatiana Zaldívar Vaillant
Sandhoff disease is an infrequent genetically-caused disorder with a recessive inheritance pattern. It belongs to the gangliosidosis GM2 group and it is produced by mutations in gen HEXB (chromosome 5q13) leading to reduced activity of enzymes β-hexosaminidase A and B, and deposition of sphingolipids (ganglioside GM2 and globoside) in brain and other organs. Nearly, 40 specific mutations causing this disease have been reported (1). Clinical manifestations and age of onset depend on the enzymatic residual catabolic activity, associated with infantile, juvenile, and adult variants (2). The homozygous state is associated with earlier onset and greater disease severity (1). The clinical manifestations of the adult variant are heterogeneous and poorly characterized. It may appear as a combination of motor neuron disease, spinocerebellar ataxia, neuropathy, autonomic dysfunction, cognitive impairment, movement disorders, and psychiatric manifestations (2–4). At this time, there is no effective treatment for this disease (2).
The clinical use of parvovirus B19 assays: recent advances
Published in Expert Review of Molecular Diagnostics, 2018
B19V shows a selective tropism for erythroid progenitor cells in the bone marrow, due to the presence of specific receptors, such as the glycolipid globoside and a specific receptor binding the VP1 unique N-terminal domain, and to functional internalization processes [4,5]. In a permissive cellular environment, a coordinated series of macromolecular syntheses occurs [6–8]. From the parental single-stranded template, cellular DNA repair synthesis generates a double stranded DNA template, then a first phase transcription mainly produces mRNAs coding for the NS protein, followed by rolling hairpin replication of the genome and extended second phase transcription, mainly producing mRNAs coding for structural VP proteins. Accumulation of VP proteins eventually leads to the assembly of capsids, encapsidation of progeny single-stranded genomes and release of virions from infected cells. The permissive environment is restricted to cells in the erythroid lineage at differentiation stages ranging from CFU-E to erythroblasts [7], and is critically dependent on Erythropoietin stimulation and hypoxic conditions [6,8], through a signaling cascade eventually leading to formation of a functional replicative complex involving the viral NS and cellular proteins [9]. In productively infected cells, the virus exerts a complex series of effects, including arrest of the cell cycle and induction of apoptosis [10], thus causing a temporary block in erythropoiesis that can manifest as a transient or persistent erythroid aplasia. The virus can infect other different cellular types in diverse tissues, including endothelial, stromal, or synovial cells. However, cellular environments other than erythroid progenitor cells are normally non-permissive to viral replication, so in these, the presence and persistence of the viral genome may not be associated with its replication, transcription or protein synthesis. In non-erythroid tissues, although a productive viral replication that may contribute directly to pathological processes can be sporadically documented, infection is usually abortive and the virus is supposed to exert its pathological potential by indirect mechanisms, such as the induction of inflammatory or autoimmune processes (extensively reviewed in [11] and critically discussed in [12]).
Myocarditis: causes, mechanisms, and evolving therapies
Published in Expert Opinion on Therapeutic Targets, 2023
Tin Kyaw, Grant Drummond, Alex Bobik, Karlheinz Peter
Parvoviruses: Parvoviruses are very small (18 to 26 nm in diameter), non-enveloped single-stranded DNA viruses. In contrast to experimental myocarditis where several parvoviruses have been identified as contributing pathogens, only parvovirus B19 (B19V) has been associated with myocarditis [15]. It is the most frequent cause of acute myocarditis in children and is unfortunately associated with high mortality or the need for cardiac transplantation. B19V is also detected in up to 56% in adult patients with myocarditis [16]. More than one-third of patients with B19V-positive myocarditis are dual positive with enterovirus [17]. In general, B19V infections are asymptomatic or mild. Spontaneous B19V elimination from tissue does not always occur when infection is resolved, rather, the virus frequently becomes dormant within cardiac cells. Postmortem studies indicate that myocardial B19V DNAs is present in almost all apparently healthy individuals who might have previously been infected with B19V [18]. How latent B19V is reactivated and replicates and the mechanisms by which they induce inflammation in myocardium are not clear, but the latter likely involves the immune system in detecting B19V infected cells. B19V replication induces inflammation-mediated apoptosis in human endothelial cells via the non-structural B19V protein, NS1 that triggers the cascade of signaling pathways leading to synthesis of proinflammatory cytokines and caspase 3 [19,20]. In B19V myocarditis, abundant amounts of B19V DNA have been detected in the endothelium of coronary arteries [21,22] and associated with endothelial dysfunction, immune cell infiltration, disturbed coronary blood flow, and heart failure [22]. Such patients often present with clinical symptoms as normally present in myocardial infarction [16,22]. Following replication in cardiac endothelial cells, B19V enters nearby cardiomyocytes by binding to the glycosphingolipid globoside receptor, and then viral replication results in accumulation of NS1 protein, ultimately leading to inflammation and apoptosis [23]. Therapeutic interventions in B19V-positive myocarditis aim to preserve left ventricular function and to reduce B19V viral load. Specific antiviral agents and vaccines are in very early stages of development and focus on preventing viral entry, reducing viral replication, and inhibiting NS1 protein effector function. Interferon-beta and intravenous immunoglobulin are currently used to reduce viral load and help maintain left ventricular function [23,24].