scholarly journals Molecular heterogeneity in the infantile and juvenile forms of Sandhoff disease (O-variant GM2 gangliosidosis).

1986 ◽  
Vol 261 (27) ◽  
pp. 12680-12685 ◽  
Author(s):  
B F O'Dowd ◽  
M H Klavins ◽  
H F Willard ◽  
R Gravel ◽  
J A Lowden ◽  
...  
Keyword(s):  
Sandhoff Disease ◽  
Molecular Heterogeneity ◽  
Gm2 Gangliosidosis

Two patients from Turkey with a novel variant in the GM2A gene and review of the literature

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Aslı İnci ◽  
Filiz Başak Cengiz Ergin ◽  
Gürsel Biberoğlu ◽  
İlyas Okur ◽  
Fatih Süheyl Ezgü ◽  
...  
Keyword(s):  
Sandhoff Disease ◽  
Pathogenic Variant ◽  
Protein Deficiency ◽  
Gm2 Gangliosidosis ◽  
Infantile Form ◽  
Rare Form ◽  
Inborn Errors ◽  
Activator Protein ◽  
Gm2 Activator ◽  
Gm2 Activator Protein

Abstract Objectives GM2 gangliosidosis is a rare form of inborn errors of metabolism including Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency. GM2 activator protein deficiency is an ultra-rare form of GM2 gangliosidosis. To date, 16 cases of GM2 activator protein deficiency have been reported in the literature, and among them, 11 cases were the infantile form of the disease. Here we report the first two patients from Turkey with the infantile form of the disease with a novel likely pathogenic variant. Case presentation A boy of eight months old presented to the metabolic department with very mild neurological deterioration, although he had achieved early developmental milestones at the appropriate time. The parents also had a daughter who had lost skills progressively before one year of age. The boy was evaluated and bilateral cherry-red spots were found with no abnormality in either metabolic screening including β-hexosaminidase or cranial magnetic resonance imaging. A novel homozygous likely pathogenic variant in GM2A was detected in a next-generation sequence panel revealing GM2 activator protein deficiency. His sister was investigated after he was diagnosed with GM2 activator deficiency and it was found that she had the same variant as her brother. Conclusions This case report emphasizes that in the event of normal β-hexosaminidase activity, GM2 activator protein deficiency could be underdiagnosed, and further molecular analysis should be performed. To the best of our knowledge, this boy is one of the youngest patient diagnosed with very mild symptoms. With this novel pathogenic variant, these patients have expanded the mutation spectrum of GM2 activator protein deficiency.

Molecular Heterogeneity in O-Variant GM2 Gangliosidosis

1986 ◽  
pp. 779-784 ◽  
Author(s):  
Brian F. O’Dowd ◽  
Maris H. Klavins ◽  
Huntington F. Willard ◽  
Roy Gravel ◽  
J. Alexander Lowden ◽  
...  
Keyword(s):  
Molecular Heterogeneity ◽  
Gm2 Gangliosidosis

Validity of Lymphoid Cell Line for Enzymatic Studies of GM2-Gangliosidosis Variant 0 (Sandhoff Disease)

Enzyme ◽  
1985 ◽  
Vol 34 (1) ◽  
pp. 48-56 ◽  
Author(s):  
Michel Hardy ◽  
Michèle Vuillaume ◽  
Gilbert Lenoir ◽  
Louis Douste-Blazy ◽  
Arlette Maret ◽  
...  
Keyword(s):  
Cell Line ◽  
Lymphoid Cell ◽  
Sandhoff Disease ◽  
Gm2 Gangliosidosis ◽  
Lymphoid Cell Line

scholarly journals GM2 Gangliosidosis: Clinical Features and Current Therapies

2020 ◽  
Author(s):  
Andres Felipe Leal ◽  
Eliana Benincore-Flórez ◽  
Daniela Solano-Galarza ◽  
Rafael Guillermo Garzón Jaramillo ◽  
Olga Yaneth Echeverri-Peña ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protein Transport ◽  
Current Knowledge ◽  
Sandhoff Disease ◽  
Substrate Reduction Therapy ◽  
Gm2 Gangliosidosis ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Central Nervous System Dysfunction

GM2 gangliosidosis are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidosis have been described: Tay-Sachs disease, Sandhoff disease, and AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidosis patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidosis, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g. intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidosis, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

scholarly journals Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

2021 ◽  
Author(s):  
Davide Sala ◽  
Francesca Ornaghi ◽  
Francesco Morena ◽  
Chiara Argentati ◽  
Manuela Valsecchi ◽  
...  
Keyword(s):  
Lentiviral Vector ◽  
Combined Therapy ◽  
Treatment Strategies ◽  
Sandhoff Disease ◽  
Neurological Impairment ◽  
Therapeutic Benefit ◽  
Gm2 Gangliosidosis ◽  
Peripheral Tissues ◽  
Sequential Administration ◽  
The Brain

The GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease (SD) are respectively caused by mutations in the HEXA and HEXB genes encoding the α and β subunits of β-N-acetylhexosaminidase (Hex). The consequential accumulation of ganglioside in the brain leads to severe and progressive neurological impairment. There are currently no approved therapies to counteract or reverse the effects of GM2 gangliosidosis. Adeno-associated vector (AAV)-based investigational gene therapy (GT) products have raised expectations but come with safety and efficacy issues that need to be addressed. Thus, there is an urgent need to develop novel therapies targeting the CNS and other affected tissues that are appropriately timed to ensure pervasive metabolic correction and counteract disease progression. In this report, we show that the sequential administration of lentiviral vector (LV)-mediated intracerebral (IC) GT and bone marrow transplantation (BMT) in pre-symptomatic SD mice provide a timely and long-lasting source of the Hex enzyme in the central and peripheral nervous systems and peripheral tissues, leading to global rescue of the disease phenotype. Combined therapy showed a clear therapeutic advantage compared to individual treatments in terms of lifespan extension and normalization of the neuroinflammatory and neurodegenerative phenotypes of the SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in the brain tissues that single treatments failed to achieve. Our results highlight the complementary and synergic mode of action of LV-mediated IC GT and BMT, clarify the relative contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of enzymatic activity that is required to achieve a significant therapeutic benefit, with important implications for the monitoring and interpretation of ongoing experimental therapies, and for the design of more effective treatment strategies for GM2 gangliosidosis.

scholarly journals Canine GM2-Gangliosidosis Sandhoff Disease Associated with a 3-Base Pair Deletion in theHEXB Gene

2017 ◽  
Vol 32 (1) ◽  
pp. 340-347 ◽  
Author(s):  
P. Wang ◽  
P.S. Henthorn ◽  
E. Galban ◽  
G. Lin ◽  
T. Takedai ◽  
...  
Keyword(s):  
Base Pair ◽  
Sandhoff Disease ◽  
Gm2 Gangliosidosis ◽  
Base Pair Deletion

scholarly journals Membrane lipids and their degradation compounds control GM2 catabolism at intralysosomal luminal vesicles

2019 ◽  
Vol 60 (6) ◽  
pp. 1099-1111 ◽  
Author(s):  
Susi Anheuser ◽  
Bernadette Breiden ◽  
Konrad Sandhoff
Keyword(s):  
Membrane Lipids ◽  
Lysosomal Storage Diseases ◽  
Sandhoff Disease ◽  
Water Soluble ◽  
Lysosomal Storage ◽  
Gm2 Gangliosidosis ◽  
Activator Protein ◽  
Anionic Lipids ◽  
Gm2 Activator ◽  
Gm2 Activator Protein

The catabolism of ganglioside GM2 is dependent on three gene products. Mutations in any of these genes result in a different type of GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease, and the B1 and AB variants of GM2 gangliosidosis), with GM2 as the major lysosomal storage compound. GM2 is also a secondary storage compound in lysosomal storage diseases such as Niemann-Pick disease types A–C, with primary storage of SM in type A and cholesterol in types B and C, respectively. The reconstitution of GM2 catabolism at liposomal surfaces carrying GM2 revealed that incorporating lipids into the GM2-carrying membrane such as cholesterol, SM, sphingosine, and sphinganine inhibits GM2 hydrolysis by β-hexosaminidase A assisted by GM2 activator protein, while anionic lipids, ceramide, fatty acids, lysophosphatidylcholine, and diacylglycerol stimulate GM2 catabolism. In contrast, the hydrolysis of the synthetic, water-soluble substrate 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-d-glucopyranoside was neither significantly affected by membrane lipids such as ceramide or SM nor stimulated by anionic lipids such as bis(monoacylglycero)phosphate added as liposomes, detergent micelles, or lipid aggregates. Moreover, hydrolysis-inhibiting lipids also had an inhibiting effect on the solubilization and mobilization of membrane-bound lipids by the GM2 activator protein, while the stimulating lipids enhanced lipid mobilization.—

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