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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
The clinical phenotype of Sandhoff disease may be indistinguishable from that of Tay-Sachs disease (Chapter 88), but there may be hepatosplenomegaly in Sandhoff disease. The distinction between the two conditions was delineated by Sandhoff et al. [1] in 1968, in a patient who was unusual in that he stored ganglioside not only in the brain but also in other viscera, in contrast to patients with Tay-Sachs disease. The activity of total hexosaminidase was found to be deficient [1]. Hexosaminidase B is a glycoprotein homopolymer with four identical subunits; its structure is designated β2β2 [2, 3]. Hexosaminidase A is a heteropolymer of α and β subunits. Activity of the Hex-A and Hex-B isozymes are defective because of a defective β subunit. The disease has also been referred to as GM2 gangliosidosis (variant O). The Hex-B gene is located on chromosome 5q13 [4]. Heterogeneity has been observed in the mutations in the gene for Hex-B [5]. Most mutations lead to the most severe infantile onset phenotype. The causative mutations in these patients tend to be deletions, nonsense mutations, or splice site mutations. The most common is a 16 kb deletion that includes the promoter, exons 1 to 5, and part of the intron [6].
Lysosomal, sterol and lipid disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
In this disorder there is a deficiency of the hexosaminidase β-subunit. This subunit is required to form the enzymes hexosaminidase A and hexosaminidase B, which are needed to break down fatty materials known as GM2 gangliosides. If there is a deficiency or an absence of these enzymes, GM2 gangliosides will accumulate in the nerve cells of the brain and the organs of the body. This afects the ability of the central nervous system to function and leads to the symptoms of the condition. This disorder is very similar to Tay-Sachs disease (see p. 69), except that in the latter condition there is only a deiciency of hexosaminidase A.
The Cerebellar Ataxias and Hereditary Spastic Paraplegias
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Hexosaminidase A deficiency (GM2 gangliosidosis) is an autosomal recessive disorder, which usually causes a fatal cerebromacular degeneration of infancy (Tay–Sachs disease). However, rare patients have a later onset ataxia associated with eye movement abnormalities, facial grimacing, anterior horn cell disease or neuropathy. The diagnosis is established by measurements of hexosaminidase A.
Network pharmacology-based analysis of the mechanism of Saposhnikovia divaricata for the treatment of type I allergy
Published in Pharmaceutical Biology, 2022
Xiangsheng Li, Hui Li, Tingting Wang, Yang Zhao, Yuxin Shao, Yizhao Sun, Yanfen Zhang, Zhongcheng Liu
The release of β-hexosaminidase (β-HEX) was measured as a marker of degranulation. RBL-2H3 cells (3 × 105 cells/well) were seeded into 24-well plates and randomly divided into a control group, a model group, a positive group (KF, 30 μM), a negative control, groups treated with SD (0.5, 1, and 2 mg/mL) and POG (10, 40, and 80 μg/mL). Twenty-four hours later, except for the negative group, each group was sensitised overnight by 500 μL DMEM containing 0.4 μg/mL anti-DNP-IgE antibody, while negative group was given 500 μL DMEM. Twelve hours later, the treated, positive and negative groups were replaced with 1 mL of DMEM (containing drugs), and the other groups were replaced with 1 mL of DMEM. After 12 h, the treated, positive and model groups were given 200 μL PIPES (containing 0.4 μg/mL DNP-BSA), and the other groups were given 200 μL PIPES. Incubate for 1 h and ice bath for 10 min, collect supernatant. A 50 μL aliquot of each sample was added to a 96-well plate, 50 μL β-HEX substrate solutions (p-nitrophenyl-N-acetyl-β-d-glucosaminide) was added, and the plate was incubated at 37 °C for 1 h. The reaction was stopped by adding 200 μL sodium carbonate buffer and the optical density (OD) value for the release of β-HEX was measured at 405 nm. The experiment was repeated six times. The inhibition rate of β-Hex in each group was calculated according to the following formula:
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Manuel González-Cuesta, Irene Herrera-González, M. Isabel García-Moreno, Roger A. Ashmus, David J. Vocadlo, José M. García Fernández, Eiji Nanba, Katsumi Higaki, Carmen Ortiz Mellet
N-Acetyl-β-hexosaminidase (Hex; EC 3.2.1.52) is a member of the glycosyl hydrolase family 20 (GH20) that catalyses the removal of terminal, non-reducing N-acetyl-β-d-glucosamine (GlcNAc) or galactosamine (GalNAc) residues from gangliosides, glycoproteins or glycosaminoglycans1. In humans two Hex isoforms are readily detectable, namely HexA and HexB. The first one is a heterodimer formed by α and β subunits, encoded respectively by the evolutionary related HEXA and HEXB genes, whereas the second one is the ββ homodimer2. The thermodynamically less stable αα homodimer (HexS) is also formed, but only reaches measurable levels when the β subunit is deficient. Although the α and β subunits possess independent active sites, dimerisation is a prerequisite for their in vivo biological function. Exclusively the α-subunit of HexA can hydrolyse the GM2 ganglioside (GM2), an intermediate in the biosynthesis and degradation of higher brain gangliosides, in lysosomes by specifically interacting with the GM2 activator protein (GM2AP) co-factor3. Disabling mutations in HEXA, HEXB or the gene encoding for GM2AP results in Tay-Sachs disease (TSD; OMIM #272800), Sandhoff disease (SD; OMIM #268800) or the less common AB variant (OMIM #272750), respectively, a subset of lysosomal storage disorders (LSDs) collectively referred to as GM2 gangliosidosis4. All the three are autosomal recessive conditions associated with phenotypic neurodegeneration and devastating consequences. Currently, there are no effective treatment options for any of these diseases5.
Anti-allergic actions of a Chinese patent medicine, huoxiangzhengqi oral liquid, in RBL-2H3 cells and in mice
Published in Pharmaceutical Biology, 2021
Jianbin Sun, Sixing Huang, Yao Qin, Ping Zhang, Ziwei Li, Li Zhang, Xin Wang, Ruijun Wu, Shaorong Qin, Jiayong Huo, Kunquan Xiao, Weizao Luo
β-Hexosaminidase (β-HEX) release assay was conducted as previously described (Tewtrakul et al. 2008). Briefly, RBL-2H3 cells were sensitized with IgE (0.45 µg/mL) for 24 h and then preincubated with HXZQ-OL (0–4397 µg/mL) for 30 min, followed by addition of 10 µg/mL DNP-BSA at 37 °C for 10 min to stimulate the cells to degranulate. The supernatant (50 µL) was mixed with 50 µL PNAG in 0.1 M citrate buffer (pH4.5) and then incubated for 1h at 37 °C. At the end of the reaction terminated by stop solution, the absorbance was measured at 405 nm using a microplate reader.