A golden retriever dog is described with total hexosaminidase deficiency and raised GM2-ganglioside in CSF. The animal represents a model for human Sandhoff disease.
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Unifying biology of neurodegeneration in lysosomal storage diseases.
J Inherit Metab Dis
January 2025
Department of Life Sciences, Manchester Metropolitan University, Manchester, UK.
There are currently at least 70 characterised lysosomal storage diseases (LSD) resultant from inherited single-gene defects. Of these, at least 30 present with central nervous system (CNS) neurodegeneration and overlapping aetiology. Substrate accumulation and dysfunctional neuronal lysosomes are common denominator, but how variants in 30 different genes converge on this central cellular phenotype is unclear.
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medRxiv
December 2024
Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, 10 Center Drive, Bethesda MD USA.
GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants in encoding the α-subunit and Sandhoff disease is caused by variants in encoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable.
View Article and Find Full Text PDFDysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease.
Cells
January 2025
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS and periphery. The NLRP3 inflammasome is an important coordinator of pro-inflammatory responses, and we have investigated its regulation in murine SD.
View Article and Find Full Text PDFIntracerebroventricular administration of a modified hexosaminidase ameliorates late-stage neurodegeneration in a GM2 mouse model.
PLoS One
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BioMarin Pharmaceutical Inc., Novato, CA, United States of America.
The GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease, are devastating neurodegenerative disorders caused by β-hexosaminidase A (HexA) deficiency. In the Sandhoff disease mouse model, rescue potential was severely reduced when HexA was introduced after disease onset. Here, we assess the effect of recombinant HexA and HexD3, a newly engineered mimetic of HexA optimized for the treatment of Tay-Sachs disease and Sandhoff disease.
View Article and Find Full Text PDFReactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease.
Neurobiol Dis
January 2025
Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address:
Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function.
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