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Richard L Proia - One of the best experts on this subject based on the ideXlab platform.
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Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation
Journal of lipid research, 2018Co-Authors: Maria L. Allende, Cynthia J. Tifft, Emily K. Cook, Bridget C. Larman, Adrienne Nugent, Jacqueline Brady, Diane Golebiowski, Miguel Sena-esteves, Richard L ProiaAbstract:Sandhoff disease, one of the GM2 Gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 Gangliosidoses.
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The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy.
Pediatric endocrinology reviews : PER, 2016Co-Authors: Debra S Regier, Richard L Proia, Alessandra D'azzo, Cynthia J. TifftAbstract:The Gangliosidoses are lysosomal storage disorders caused by accumulation of GM1 or GM2 gangliosides. GM1 gangliosidosis has both central nervous system and systemic findings; while, GM2 gangliosidosis is restricted primarily to the central nervous system. Both disorders have autosomal recessive modes of inheritance and a continuum of clinical presentations from a severe infantile form to a milder, chronic adult form. Both are devastating diseases without cure or specific treatment however, with the use of supportive aggressive medical management, the lifespan and quality of life has been extended for both diseases. Naturally occurring and engineered animal models that mimic the human diseases have enhanced our understanding of the pathogenesis of disease progression. Some models have shown significant improvement in symptoms and lifespan with enzyme replacement, substrate reduction, and anti-inflammatory treatments alone or in combination. More recently gene therapy has shown impressive results in large and small animal models. Treatment with FDA-approved glucose analogs to reduce the amount of ganglioside substrate is used as off-label treatments for some patients. Therapies also under clinical development include small molecule chaperones and gene therapy.
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The GM2 Gangliosidoses: pathophysiology to therapy
International Congress Series, 2001Co-Authors: Richard L ProiaAbstract:Abstract A family of extremely severe diseases, known as the glycosphingolipidoses, is caused by inherited defects in the lysosomal degradation pathway for glycosphingolipids (GSLs). In most of these disorders, GSLs accumulate in lysosomes, causing neurodegeneration and a shortened life span. No effective treatment currently exists for most of these diseases, and their mechanisms of pathogenesis are only beginning to be understood. This review will discuss new findings for a representative group of these disorders—the GM2 Gangliosidoses—including the development of a new approach for treatment that targets the synthesis pathway of GSLs to retard their cellular accumulation.
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Targeting the hexosaminidase genes: mouse models of the GM2 Gangliosidoses.
Advances in genetics, 2001Co-Authors: Richard L ProiaAbstract:Publisher Summary This chapter deals with the study of mouse models of the G M2 Gangliosidoses. The onset of neurological symptoms in Tay-Sachs disease patients normally occurs by 3 to 5 months after birth. As a result of their β-hexosaminidase A deficiency, G M2 ganglioside accumulated in the brains of the Tay-Sachs mice in an age-dependent fashion. This G M2 ganglioside accumulation resulted in storage neurons with membranous cytoplasmic bodies (MCBs) that were identical to affected neurons in Tay-Sachs disease patients. In human cells, β -hexosaminidase A degrades G M2 ganglioside to form G M3 . In addition to this pathway, mouse cells also have a detour pathway where G M2 is converted to G A2 by the action of sialidase. G A2 can now be further degraded by β-hexosaminidase B (or A) and then by the action of other glycosidases to yield ceramide. In the Tay-Sachs mice the G M2 to G M3 conversion is blocked because of the absence of β-hexosaminidase A. Each of the human mucopolysaccharidoses involves the heritable absence of one of the enzymes that are required for the lysosomal degradation of glycosaminoglycans. The lack of a mucopolysaccharidosis phenotype in humans and mice with one β-hexosaminidase gene mutated is, therefore, due to functional redundancy in the enzyme system.
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quantification of mrnas encoding proteins of the glycosphingolipid catabolism in mouse models of GM2 Gangliosidoses and sphingolipid activator protein precursor prosaposin deficiency
Biochimica et Biophysica Acta, 2000Co-Authors: Astrid Potratz, Silke Huttler, Uwe Bierfreund, Richard L Proia, Kunihiko Suzuki, Konrad SandhoffAbstract:Abstract We have investigated the mRNA amounts of six lysosomal proteins (β-hexosaminidase α- and β-subunit, sphingolipid activator protein precursor, GM2 activator protein, lysosomal sialidase, β-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.
Terry D. Butters - One of the best experts on this subject based on the ideXlab platform.
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Lysosomal storage of oligosaccharide and glycosphingolipid in imino sugar treated cells
Glycoconjugate Journal, 2010Co-Authors: Stephanie D. Boomkamp, James Samuel Shane Rountree, David C. A. Neville, George W J Fleet, Raymond A. Dwek, Terry D. ButtersAbstract:Sandhoff and Tay-Sachs disease are autosomal recessive GM2 Gangliosidoses where a deficiency of lysosomal β-hexosaminidase results in storage of glycoconjugates. Imino sugar (2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol) inhibition of β-hexosaminidase in murine RAW264.7 macrophage-like cells led to lysosomal storage of glycoconjugates that were characterised structurally using fluorescence labelling of the free or glycolipid-derived oligosaccharides followed by HPLC and mass spectrometry. Stored glycoconjugates were confirmed as containing non-reducing GlcNAc or GalNAc residues resulting from the incomplete degradation of N-linked glycoprotein oligosaccharide and glycolipids, respectively. When substrate reduction therapeutics N -butyl-deoxynojirimycin ( N B-DNJ) or N -butyldeoxygalactonojirimycin ( N B-DGJ) were applied to the storage phenotype cells, an increase in glucosylated and galactosylated oligosaccharide species was observed due to endoplasmic reticulum α-glucosidases and lysosomal β-galactosidase inhibition, respectively. Hexosaminidase inhibition triggered a tightly regulated cytokine-mediated inflammatory response that was normalised using imino sugars N B-DNJ and N B-DGJ, which restored the GM2 ganglioside storage burden but failed to reduce the levels of GA2 glycolipid or glycoprotein-derived N -linked oligosaccharides. Using a chemically induced gangliosidosis phenotype that can be modulated with substrate lowering drugs, the critical role of GM2 ganglioside in the progression of inflammatory disease is also demonstrated.
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Glycosphingolipid disorders of the brain.
Sub-cellular biochemistry, 2008Co-Authors: Stephanie D. Boomkamp, Terry D. ButtersAbstract:Glycosphingolipids, comprising a ceramide lipid backbone linked to one/more saccharides, are particularly abundant on the outer leaflet of the eukaryotic plasma membrane and play a role in a wide variety of essential cellular processes. Biosynthesis and subsequently degradation of these lipids is tightly regulated via the involvement of numerous enzymes, and failure of an enzyme to participate in the metabolism results in storage of the enzyme’s substrate, giving rise to a lysosomal storage disease. The characteristics, severity and onset of the disease are dependent on the enzyme deficient and the residual activity. Most lysosomal storage disorders found thus far are caused by a defect in the catabolic activity of a hydrolase, causing progressive accumulation of its substrate, predominantly in the lysosome. Storage of gangliosides, sialic acid containing glycosphingolipids, mostly found in the central nervous system, is a hallmark of neuronopathic forms of the disease, that include GM1 and GM2 Gangliosidoses, Gaucher type II and III and Niemann-Pick C. Models for these diseases have provided valuable insight into the disease pathology and potential treatment methods.
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NSAIDs increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin.
Annals of neurology, 2004Co-Authors: Mylvaganam Jeyakumar, David C. A. Neville, Terry D. Butters, Raymond A. Dwek, David Smith, Ian M. Williams, Mario Cortina Borja, Frances M. PlattAbstract:The GM2 Gangliosidoses are caused by incomplete catabolism of GM2 ganglioside in the lysosome, leading to progressive storage and a neurodegenerative clinical course. An inflammatory response (microglial activation, macrophage infiltration, oxidative damage) has been found to be a consequence of GM2 storage in the brain, although it remains unclear whether this contributes to pathogenesis or disease progression. In this study, we treated Sandhoff disease mice with nonsteroidal antiinflammatory drugs (indomethacin, aspirin, and ibuprofen) and antioxidants (L-ascorbic acid and -tochopherol acetate). The treated mice lived significantly longer than untreated littermates (12–23%, p < 0.0001) and showed a slower rate of disease progression (p < 0.001). When aspirin treatment was combined with substrate reduction therapy, synergy resulted (11%, p < 0.05) with a maximum improvement of 73% in survival (p < 0.00001). This study demonstrates that inflammation contributes to disease progression and identifies antiinflammatory and antioxidant therapies as a potential adjunctive approach to slow the clinical course of this and related disorders.
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central nervous system inflammation is a hallmark of pathogenesis in mouse models of gm1 and GM2 gangliosidosis
Brain, 2003Co-Authors: Mylvaganam Jeyakumar, Elena Elliotsmith, Aarnoud C Van Der Spoel, Hugh V Perry, Terry D. Butters, Rhodri Thomas, Raymond A. Dwek, Alessandra Dazzo, David A. Smith, Frances M. PlattAbstract:Mouse models of the GM2 Gangliosidoses [Tay‐Sachs, late onset Tay‐Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro‐inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor α (TNFα), transforming growth factor (TGFβ1) and interleukin 1β (IL1β)]; and (iii) studied blood‐brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF‐R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the Gangliosidoses.
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Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Mylvaganam Jeyakumar, Terry D. Butters, Richard L Proia, Ra Dwek, Mario Cortina-borja, V Hunnam, V H Perry, Frances M. PlattAbstract:Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the β-subunit of β-hexosaminidase. GM2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS). There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the GM2 Gangliosidoses. One strategy for treating this and related diseases is substrate deprivation. This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS. In this study, we have evaluated whether this drug also could be applied to the treatment of diseases with CNS storage and pathology. We therefore have treated a mouse model of Sandhoff disease with the inhibitor N-butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease.
David A. Wenger - One of the best experts on this subject based on the ideXlab platform.
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Usefulness of 4‐methylumbelliferyl‐6‐ sulfo‐2‐acetamido‐2‐deoxy‐β‐D‐glucopyranoside for the diagnosis of GM2 Gangliosidoses in leukocytes
Clinical genetics, 2008Co-Authors: Koji Inui, David A. WengerAbstract:4-Methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-D-glucopyranoside was synthesized and tested as a substrate for the diagnosis of GM2 Gangliosidoses using leukocytes. Less than 2% of normal activity was measured in homogenates from patients with typical Tay-Sachs disease and from a patient with a variant form having 37% Hexosaminidase A by heat denaturation using the usual fluorogenic substrate. An adult patient had 8.5% of normal activity. Three patients with Sandhoff disease were found to have values ranging from 17% to 37% of normal. These values overlap the range found for carriers of Tay-Sachs disease, and suggest that the usefulness of this substrate, while excellent for diagnosing B variants of GM2 gangliosidosis, requires further study. Perhaps when used together with 4-methylumbelliferyl-2-acetamido-2-deoxy-β-D-glucopyranoside excellent discriminations of patients, carriers and controls will be realized.
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usefulness of 4 methylumbelliferyl 6 sulfo 2 acetamido 2 deoxy β d glucopyranoside for the diagnosis of GM2 Gangliosidoses in leukocytes
Clinical Genetics, 2008Co-Authors: Koji Inui, David A. WengerAbstract:4-Methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-D-glucopyranoside was synthesized and tested as a substrate for the diagnosis of GM2 Gangliosidoses using leukocytes. Less than 2% of normal activity was measured in homogenates from patients with typical Tay-Sachs disease and from a patient with a variant form having 37% Hexosaminidase A by heat denaturation using the usual fluorogenic substrate. An adult patient had 8.5% of normal activity. Three patients with Sandhoff disease were found to have values ranging from 17% to 37% of normal. These values overlap the range found for carriers of Tay-Sachs disease, and suggest that the usefulness of this substrate, while excellent for diagnosing B variants of GM2 gangliosidosis, requires further study. Perhaps when used together with 4-methylumbelliferyl-2-acetamido-2-deoxy-β-D-glucopyranoside excellent discriminations of patients, carriers and controls will be realized.
Frances M. Platt - One of the best experts on this subject based on the ideXlab platform.
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NSAIDs Increase Survival in the Sandhoff Disease Mouse: Synergy with N-butyldeoxynojirimycin
2016Co-Authors: Frances M. PlattAbstract:The GM2 Gangliosidoses are caused by incomplete catabolism of GM2 ganglioside in the lysosome, leading to progressive storage and a neurodegenerative clinical course. An inflammatory response (microglial activation, macrophage infiltra-tion, oxidative damage) has been found to be a consequence of GM2 storage in the brain, although it remains unclear whether this contributes to pathogenesis or disease progression. In this study, we treated Sandhoff disease mice with nonsteroidal antiinflammatory drugs (indomethacin, aspirin, and ibuprofen) and antioxidants (L-ascorbic acid and -tochopherol acetate). The treated mice lived significantly longer than untreated littermates (12–23%, p < 0.0001) and showed a slower rate of disease progression (p < 0.001). When aspirin treatment was combined with substrate reduction therapy, synergy resulted (11%, p < 0.05) with a maximum improvement of 73 % in survival (p < 0.00001). This study demonstrates that inflammation contributes to disease progression and identifies antiinflammatory and antioxidant ther-apies as a potential adjunctive approach to slow the clinical course of this and related disorders. Ann Neurol 2004;56:642–649 The glycosphingolipid (GSL) lysosomal storage dis-eases arise due to inherited defects in the genes en-coding the enzymes, or their cofactors, responsible for the catabolism of GSLs in the lysosome.1,2 Withi
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Critical role of iron in the pathogenesis of the murine Gangliosidoses.
Neurobiology of disease, 2009Co-Authors: Mylvaganam Jeyakumar, I. D. Williams, David Smith, Timothy M. Cox, Frances M. PlattAbstract:Abstract Neurodegeneration is a prominent feature of the Gangliosidoses, a group of lysosomal storage diseases. Here we show altered iron homeostasis in mouse models of both GM1 and GM2 Gangliosidoses, which are characterized by progressive depletion of iron in brain tissue. This finding contrasts with the findings in many other neurological disorders, where excess iron deposition has been reported. We found that key regulators of iron homeostasis, hepcidin and IL-6, were increased in Gangliosidoses mice. In the brain, the principal iron transport and delivery protein transferrin was reduced, accompanied by a progressive inability of the brain to acquire iron from the circulation. Expression of the transferrin receptor was up-regulated reciprocally. Despite the deregulation of iron homeostasis administration of iron prolonged survival in the diseased mice by up to 38%, with onset of disease delayed and motor function preserved.
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NSAIDs increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin.
Annals of neurology, 2004Co-Authors: Mylvaganam Jeyakumar, David C. A. Neville, Terry D. Butters, Raymond A. Dwek, David Smith, Ian M. Williams, Mario Cortina Borja, Frances M. PlattAbstract:The GM2 Gangliosidoses are caused by incomplete catabolism of GM2 ganglioside in the lysosome, leading to progressive storage and a neurodegenerative clinical course. An inflammatory response (microglial activation, macrophage infiltration, oxidative damage) has been found to be a consequence of GM2 storage in the brain, although it remains unclear whether this contributes to pathogenesis or disease progression. In this study, we treated Sandhoff disease mice with nonsteroidal antiinflammatory drugs (indomethacin, aspirin, and ibuprofen) and antioxidants (L-ascorbic acid and -tochopherol acetate). The treated mice lived significantly longer than untreated littermates (12–23%, p < 0.0001) and showed a slower rate of disease progression (p < 0.001). When aspirin treatment was combined with substrate reduction therapy, synergy resulted (11%, p < 0.05) with a maximum improvement of 73% in survival (p < 0.00001). This study demonstrates that inflammation contributes to disease progression and identifies antiinflammatory and antioxidant therapies as a potential adjunctive approach to slow the clinical course of this and related disorders.
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central nervous system inflammation is a hallmark of pathogenesis in mouse models of gm1 and GM2 gangliosidosis
Brain, 2003Co-Authors: Mylvaganam Jeyakumar, Elena Elliotsmith, Aarnoud C Van Der Spoel, Hugh V Perry, Terry D. Butters, Rhodri Thomas, Raymond A. Dwek, Alessandra Dazzo, David A. Smith, Frances M. PlattAbstract:Mouse models of the GM2 Gangliosidoses [Tay‐Sachs, late onset Tay‐Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro‐inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor α (TNFα), transforming growth factor (TGFβ1) and interleukin 1β (IL1β)]; and (iii) studied blood‐brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF‐R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the Gangliosidoses.
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Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin.
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Mylvaganam Jeyakumar, Terry D. Butters, Richard L Proia, Ra Dwek, Mario Cortina-borja, V Hunnam, V H Perry, Frances M. PlattAbstract:Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the β-subunit of β-hexosaminidase. GM2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS). There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the GM2 Gangliosidoses. One strategy for treating this and related diseases is substrate deprivation. This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS. In this study, we have evaluated whether this drug also could be applied to the treatment of diseases with CNS storage and pathology. We therefore have treated a mouse model of Sandhoff disease with the inhibitor N-butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease.
Koji Inui - One of the best experts on this subject based on the ideXlab platform.
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Usefulness of 4‐methylumbelliferyl‐6‐ sulfo‐2‐acetamido‐2‐deoxy‐β‐D‐glucopyranoside for the diagnosis of GM2 Gangliosidoses in leukocytes
Clinical genetics, 2008Co-Authors: Koji Inui, David A. WengerAbstract:4-Methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-D-glucopyranoside was synthesized and tested as a substrate for the diagnosis of GM2 Gangliosidoses using leukocytes. Less than 2% of normal activity was measured in homogenates from patients with typical Tay-Sachs disease and from a patient with a variant form having 37% Hexosaminidase A by heat denaturation using the usual fluorogenic substrate. An adult patient had 8.5% of normal activity. Three patients with Sandhoff disease were found to have values ranging from 17% to 37% of normal. These values overlap the range found for carriers of Tay-Sachs disease, and suggest that the usefulness of this substrate, while excellent for diagnosing B variants of GM2 gangliosidosis, requires further study. Perhaps when used together with 4-methylumbelliferyl-2-acetamido-2-deoxy-β-D-glucopyranoside excellent discriminations of patients, carriers and controls will be realized.
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usefulness of 4 methylumbelliferyl 6 sulfo 2 acetamido 2 deoxy β d glucopyranoside for the diagnosis of GM2 Gangliosidoses in leukocytes
Clinical Genetics, 2008Co-Authors: Koji Inui, David A. WengerAbstract:4-Methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-D-glucopyranoside was synthesized and tested as a substrate for the diagnosis of GM2 Gangliosidoses using leukocytes. Less than 2% of normal activity was measured in homogenates from patients with typical Tay-Sachs disease and from a patient with a variant form having 37% Hexosaminidase A by heat denaturation using the usual fluorogenic substrate. An adult patient had 8.5% of normal activity. Three patients with Sandhoff disease were found to have values ranging from 17% to 37% of normal. These values overlap the range found for carriers of Tay-Sachs disease, and suggest that the usefulness of this substrate, while excellent for diagnosing B variants of GM2 gangliosidosis, requires further study. Perhaps when used together with 4-methylumbelliferyl-2-acetamido-2-deoxy-β-D-glucopyranoside excellent discriminations of patients, carriers and controls will be realized.