RARE DISEASE
GM3 synthase deficiency
GM3 synthase deficiency
GM3 synthase deficiency
Synonyms: ST3GAL5-CDG
Synonyms: ST3GAL5-CDG
Synonyms: ST3GAL5-CDG
Drug discovery
0
drugs
With orphan designations
Overview
GM3 synthase deficiency is a rare autosomal recessive disorder caused by biallelic ST3GAL5 mutations, disrupting ganglioside biosynthesis essential for neurodevelopment. It presents with infantile-onset refractory epilepsy, profound intellectual disability, developmental regression, choreoathetosis, and sensory impairments. Characteristic hyper/hypopigmented skin lesions aid diagnosis. Neurodegeneration progresses despite symptomatic management, with mortality linked to seizure complications and systemic decline [1][2][5][16].
Burden
Morbidity: 100% require lifelong neurological/developmental support; cortical blindness/deafness common [5][13].
Mortality: Life expectancy unconfirmed, but many die in childhood from status epilepticus or aspiration [1][16].
Care complexity: High caregiver demands due to motor disabilities, feeding intolerance, and unrelenting seizures [9][13].
Therapies
Symptomatic care: Multi-drug antiseizure regimens (often refractory) [1][2], gastrostomy for dysphagia [9].
Experimental interventions: CNS-targeted rAAV9-ST3GAL5 gene therapy rescues ganglioside levels in preclinical models [3][7]; oral ganglioside supplementation shows transient developmental gains [11][17].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare skin diseases
Research Papers
29 drug discovery papers about GM3 synthase deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
29 drug discovery papers about GM3 synthase deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-03-02 | Study of GM3 Synthase Deficiency Knockout Models Treated with Recombinant Adeno-Associated Virus-Based Gene Therapy
Monosialodihexosylganglioside synthase deficiency (GM3SD) is a neurological disease that is caused by a loss-of-function mutation(s) in the ST3 betagalactoside alpha-2,3-sialyltransferase 5 (ST3GAL5) gene. Knockout (KO) models have been made to track biochemical and physiological phenotypes of GM3SD. However, recapitulation of disease pathophysiology, including mechanistic links in both models, requires additional research for full understanding. A gene therapy approach for GM3SD using recombinant adenoassociated viral vectors (rAAVs) is being worked on, and assessment of its efficacy is required before progressing to clinical trials. The goals of the current research are to 1) assess the ability of rAAV-treatment on rescuing a wellcharacterized hearing phenotype in the St3gal5-/- single-knockout (SKO) mouse model; 2) delve into potential cross-correction mechanisms observed in this specific neurological disease; and 3) use current advancements in glycolipid research for characterizing ganglioside profiles and assessing metabolic rescue in the disease models, with and without rAAV treatment. Taken together this research will help to further our understanding of GM3SD as a neurological and metabolic disorder, as well as how rAAV can rescue phenotypes associated with the disease.
2025-04-29 | Metabolic and Structural Consequences of GM3 Synthase Deficiency: Insights from an HEK293-T Knockout Model.
Background: GM3 Synthase Deficiency (GM3SD) is a rare autosomal recessive neurodevelopmental disease characterized by recurrent seizures and neurological deficits. The disorder stems from mutations in the ST3GAL5 gene, encoding GM3 synthase (GM3S), a key enzyme in ganglioside biosynthesis. While enzyme deficiencies affecting ganglioside catabolism are well-documented, the consequences of impaired ganglioside biosynthesis remain less explored. Methods: To investigate GM3SD, we used a Human Embryonic Kidney 293-T (HEK293-T) knockout (KO) cell model generated via CRISPR/Cas9 technology. Lipid composition was assessed via high-performance thin-layer chromatography (HPTLC); glycohydrolase activity in lysosomal and plasma membrane (PM) fractions was enzymatically analyzed. Lysosomal homeostasis was evaluated through protein content analysis and immunofluorescence, and cellular bioenergetics was measured using a luminescence-based assay. Results: Lipidome profiling revealed a significant accumulation of lactosylceramide (LacCer), the substrate of GM3S, along with increased levels of monosialyl-globoside Gb5 (MSGb5), indicating a metabolic shift in glycosphingolipid biosynthesis. Lipid raft analysis revealed elevated cholesterol levels, which may impair microdomain fluidity and signal transduction. Furthermore, altered activity of lysosomal and plasma membrane (PM)-associated glycohydrolases suggests secondary deregulation of glycosphingolipid metabolism, potentially contributing to abnormal lipid patterns. In addition, we observed increased lysosomal mass, indicating potential lysosomal homeostasis dysregulation. Finally, decreased adenosine triphosphate (ATP) levels point to impaired cellular bioenergetics, emphasizing the metabolic consequences of GM3SD. Conclusions: Together, these findings provide novel insights into the molecular alterations associated with GM3SD and establish the HEK293-T KO model as a promising platform for evaluating potential therapeutic strategies.
2024-08-09 | Dietary gangliosides rescue GM3 synthase deficiency outcomes in mice accompanied by neurogenesis in the hippocampus.
Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GM3SD) causes an absence of GM3 and all downstream biosynthetic derivatives, including all the a-, b-, c-series gangliosides, commonly found in neural tissues. The affected individuals manifest with severe irritability, intractable seizures, hearing loss, blindness, and profound intellectual disability. It has been reported that oral ganglioside supplementation has achieved some significant improvements in clinical symptoms, growth parameters, and developmental and cognitive scores in GM3SD patients. To gain insight into the molecular mechanisms of this supplementation, we performed supplementation of oral bovine milk gangliosides to GM3 synthase-deficient mice from early weaning periods. The oral milk ganglioside preparations were dominated by GM3 and GD3 gangliosides. Oral milk ganglioside supplementation improved the decreased cognitive function observed in GM3 synthase-deficient mice. The improvement in cognitive function was accompanied by increased ganglioside levels and neurogenesis in the hippocampus in the supplemented animals.
2023-09-11 | Ganglioside GM3 deficiency enhances mast cell sensitivity.
Mast cells are a significant source of cytokines and chemokines that play a role in pathological processes. Gangliosides, which are complex lipids with a sugar chain, are present in all eukaryotic cell membranes and comprise lipid rafts. Ganglioside GM3, the first ganglioside in the synthetic pathway, is a common precursor of the specifying derivatives and is well known for its various functions in biosystems. Mast cells contain high levels of gangliosides; however, the involvement of GM3 in mast cell sensitivity is unclear. Therefore, in this study, we elucidated the role of ganglioside GM3 in mast cells and skin inflammation. GM3 synthase (GM3S)-deficient mast cells showed cytosolic granule topological changes and hyperactivation upon IgE-DNP stimulation without affecting proliferation and differentiation. Additionally, inflammatory cytokine levels increased in GM3S-deficient bone marrow-derived mast cells (BMMC). Furthermore, GM3S-KO mice and GM3S-KO BMMC transplantation showed increased skin allergic reactions. Besides mast cell hypersensitivity caused by GM3S deficiency, membrane integrity decreased and GM3 supplementation rescued this loss of membrane integrity. Additionally, GM3S deficiency increased the phosphorylation of p38 mitogen-activated protein kinase. These results suggest that GM3 increases membrane integrity, leading to the suppression of the p38 signalling pathway in BMMC and contributing to skin allergic reaction.
2023-09-07 | Neural-specific alterations in glycosphingolipid biosynthesis and cell signaling associated with two human ganglioside GM3 synthase deficiency variants
Abstract GM3 Synthase Deficiency (GM3SD) is a neurodevelopmental disorder resulting from pathogenic variants in the ST3GAL5 gene, which encodes GM3 synthase, a glycosphingolipid (GSL)-specific sialyltransferase. This enzyme adds a sialic acid to the terminal galactose of lactosylceramide (LacCer) to produce the monosialylated ganglioside GM3. In turn, GM3 is extended by other glycosyltransferases to generate nearly all the complex gangliosides enriched in neural tissue. Pathogenic mechanisms underlying the neural phenotypes associated with GM3SD are unknown. To explore how loss of GM3 impacts neural-specific glycolipid glycosylation and cell signaling, GM3SD patient fibroblasts bearing one of two different ST3GAL5 variants were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to neural crest cells (NCCs). GM3 and GM3-derived gangliosides were undetectable in cells carrying either variant, while LacCer precursor levels were elevated compared to wildtype (WT). NCCs of both variants synthesized elevated levels of neutral lacto- and globo-series, as well as minor alternatively sialylated GSLs compared to WT. Ceramide profiles were also shifted in GM3SD variant cells. Altered GSL profiles in GM3SD cells were accompanied by dynamic changes in the cell surface proteome, protein O-GlcNAcylation, and receptor tyrosine kinase abundance. GM3SD cells also exhibited increased apoptosis and sensitivity to erlotinib-induced inhibition of epidermal growth factor receptor signaling. Pharmacologic inhibition of O-GlcNAcase rescued baseline and erlotinib-induced apoptosis. Collectively, these findings indicate aberrant cell signaling during differentiation of GM3SD iPSCs and also underscore the challenge of distinguishing between variant effect and genetic background effect on specific phenotypic consequences.
2026-03-02 | Study of GM3 Synthase Deficiency Knockout Models Treated with Recombinant Adeno-Associated Virus-Based Gene Therapy
Monosialodihexosylganglioside synthase deficiency (GM3SD) is a neurological disease that is caused by a loss-of-function mutation(s) in the ST3 betagalactoside alpha-2,3-sialyltransferase 5 (ST3GAL5) gene. Knockout (KO) models have been made to track biochemical and physiological phenotypes of GM3SD. However, recapitulation of disease pathophysiology, including mechanistic links in both models, requires additional research for full understanding. A gene therapy approach for GM3SD using recombinant adenoassociated viral vectors (rAAVs) is being worked on, and assessment of its efficacy is required before progressing to clinical trials. The goals of the current research are to 1) assess the ability of rAAV-treatment on rescuing a wellcharacterized hearing phenotype in the St3gal5-/- single-knockout (SKO) mouse model; 2) delve into potential cross-correction mechanisms observed in this specific neurological disease; and 3) use current advancements in glycolipid research for characterizing ganglioside profiles and assessing metabolic rescue in the disease models, with and without rAAV treatment. Taken together this research will help to further our understanding of GM3SD as a neurological and metabolic disorder, as well as how rAAV can rescue phenotypes associated with the disease.
2025-04-29 | Metabolic and Structural Consequences of GM3 Synthase Deficiency: Insights from an HEK293-T Knockout Model.
Background: GM3 Synthase Deficiency (GM3SD) is a rare autosomal recessive neurodevelopmental disease characterized by recurrent seizures and neurological deficits. The disorder stems from mutations in the ST3GAL5 gene, encoding GM3 synthase (GM3S), a key enzyme in ganglioside biosynthesis. While enzyme deficiencies affecting ganglioside catabolism are well-documented, the consequences of impaired ganglioside biosynthesis remain less explored. Methods: To investigate GM3SD, we used a Human Embryonic Kidney 293-T (HEK293-T) knockout (KO) cell model generated via CRISPR/Cas9 technology. Lipid composition was assessed via high-performance thin-layer chromatography (HPTLC); glycohydrolase activity in lysosomal and plasma membrane (PM) fractions was enzymatically analyzed. Lysosomal homeostasis was evaluated through protein content analysis and immunofluorescence, and cellular bioenergetics was measured using a luminescence-based assay. Results: Lipidome profiling revealed a significant accumulation of lactosylceramide (LacCer), the substrate of GM3S, along with increased levels of monosialyl-globoside Gb5 (MSGb5), indicating a metabolic shift in glycosphingolipid biosynthesis. Lipid raft analysis revealed elevated cholesterol levels, which may impair microdomain fluidity and signal transduction. Furthermore, altered activity of lysosomal and plasma membrane (PM)-associated glycohydrolases suggests secondary deregulation of glycosphingolipid metabolism, potentially contributing to abnormal lipid patterns. In addition, we observed increased lysosomal mass, indicating potential lysosomal homeostasis dysregulation. Finally, decreased adenosine triphosphate (ATP) levels point to impaired cellular bioenergetics, emphasizing the metabolic consequences of GM3SD. Conclusions: Together, these findings provide novel insights into the molecular alterations associated with GM3SD and establish the HEK293-T KO model as a promising platform for evaluating potential therapeutic strategies.
2024-08-09 | Dietary gangliosides rescue GM3 synthase deficiency outcomes in mice accompanied by neurogenesis in the hippocampus.
Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GM3SD) causes an absence of GM3 and all downstream biosynthetic derivatives, including all the a-, b-, c-series gangliosides, commonly found in neural tissues. The affected individuals manifest with severe irritability, intractable seizures, hearing loss, blindness, and profound intellectual disability. It has been reported that oral ganglioside supplementation has achieved some significant improvements in clinical symptoms, growth parameters, and developmental and cognitive scores in GM3SD patients. To gain insight into the molecular mechanisms of this supplementation, we performed supplementation of oral bovine milk gangliosides to GM3 synthase-deficient mice from early weaning periods. The oral milk ganglioside preparations were dominated by GM3 and GD3 gangliosides. Oral milk ganglioside supplementation improved the decreased cognitive function observed in GM3 synthase-deficient mice. The improvement in cognitive function was accompanied by increased ganglioside levels and neurogenesis in the hippocampus in the supplemented animals.
2023-09-11 | Ganglioside GM3 deficiency enhances mast cell sensitivity.
Mast cells are a significant source of cytokines and chemokines that play a role in pathological processes. Gangliosides, which are complex lipids with a sugar chain, are present in all eukaryotic cell membranes and comprise lipid rafts. Ganglioside GM3, the first ganglioside in the synthetic pathway, is a common precursor of the specifying derivatives and is well known for its various functions in biosystems. Mast cells contain high levels of gangliosides; however, the involvement of GM3 in mast cell sensitivity is unclear. Therefore, in this study, we elucidated the role of ganglioside GM3 in mast cells and skin inflammation. GM3 synthase (GM3S)-deficient mast cells showed cytosolic granule topological changes and hyperactivation upon IgE-DNP stimulation without affecting proliferation and differentiation. Additionally, inflammatory cytokine levels increased in GM3S-deficient bone marrow-derived mast cells (BMMC). Furthermore, GM3S-KO mice and GM3S-KO BMMC transplantation showed increased skin allergic reactions. Besides mast cell hypersensitivity caused by GM3S deficiency, membrane integrity decreased and GM3 supplementation rescued this loss of membrane integrity. Additionally, GM3S deficiency increased the phosphorylation of p38 mitogen-activated protein kinase. These results suggest that GM3 increases membrane integrity, leading to the suppression of the p38 signalling pathway in BMMC and contributing to skin allergic reaction.
2023-09-07 | Neural-specific alterations in glycosphingolipid biosynthesis and cell signaling associated with two human ganglioside GM3 synthase deficiency variants
Abstract GM3 Synthase Deficiency (GM3SD) is a neurodevelopmental disorder resulting from pathogenic variants in the ST3GAL5 gene, which encodes GM3 synthase, a glycosphingolipid (GSL)-specific sialyltransferase. This enzyme adds a sialic acid to the terminal galactose of lactosylceramide (LacCer) to produce the monosialylated ganglioside GM3. In turn, GM3 is extended by other glycosyltransferases to generate nearly all the complex gangliosides enriched in neural tissue. Pathogenic mechanisms underlying the neural phenotypes associated with GM3SD are unknown. To explore how loss of GM3 impacts neural-specific glycolipid glycosylation and cell signaling, GM3SD patient fibroblasts bearing one of two different ST3GAL5 variants were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to neural crest cells (NCCs). GM3 and GM3-derived gangliosides were undetectable in cells carrying either variant, while LacCer precursor levels were elevated compared to wildtype (WT). NCCs of both variants synthesized elevated levels of neutral lacto- and globo-series, as well as minor alternatively sialylated GSLs compared to WT. Ceramide profiles were also shifted in GM3SD variant cells. Altered GSL profiles in GM3SD cells were accompanied by dynamic changes in the cell surface proteome, protein O-GlcNAcylation, and receptor tyrosine kinase abundance. GM3SD cells also exhibited increased apoptosis and sensitivity to erlotinib-induced inhibition of epidermal growth factor receptor signaling. Pharmacologic inhibition of O-GlcNAcase rescued baseline and erlotinib-induced apoptosis. Collectively, these findings indicate aberrant cell signaling during differentiation of GM3SD iPSCs and also underscore the challenge of distinguishing between variant effect and genetic background effect on specific phenotypic consequences.
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