2026-06-26 | Infantile GM1 Gangliosidosis with Epilepsy Associated with a Same-Codon GLB1 Variant (c.808T>G/c.808T>C).
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by a deficiency of β-galactosidase due to pathogenic variants in the GLB1 gene. Almost 300 pathogenic or likely pathogenic variants have been identified, associated with a phenotypic spectrum ranging from GM1 gangliosidosis to mucopolysaccharidosis type IVB. Disease severity is largely determined by the extent to which specific variants impair enzymatic catalytic activity, particularly through disruption of substrate recognition and binding within the active site. We report a patient with GM1 gangliosidosis type I harboring two pathogenic missense variants, c.808T>G (p.Tyr270Asp) and c.808T>C (p.Tyr270His), in a compound heterozygous state. To the best of our knowledge, this specific allelic combination has not been previously described. Both variants affect the same codon, resulting in distinct amino acid substitutions at position 270, a residue critically involved in maintaining the structural and functional integrity of the catalytic domain of β-galactosidase. Disruption at this site is expected to severely compromise enzymatic activity. Comparative analysis with previously reported cases carrying variants at the same residue, in either homozygous or compound heterozygous states, demonstrates a possible consistent association with the infantile form of GM1 gangliosidosis, characterized by a rapidly progressive neurodegenerative course and multisystem involvement. Collectively, these findings provide additional support for the hypothesis that codon 270 can be regarded as a critical functional hotspot within GLB1, where even distinct amino acid substitutions can result in profound enzymatic dysfunction and a severe early-onset phenotype.
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2026-06-08 | Identification of novel compound heterozygous mutations in the GLB1 gene by whole-exome sequencing in a case of infantile GM1 gangliosidosis: a case report.
GM1 gangliosidosis was a rare, fatal autosomal recessive lysosomal storage disorder caused by biallelic mutations in the GLB1 gene. Whole-exome sequencing (WES) was increasingly utilized to identify novel pathogenic variants in the GLB1 gene among undiagnosed pediatric cases. We reported a 9-month-old male infant with developmental delay, hepatomegaly, extensive Mongolian spots, and hypotonia. WES identified two novel compound heterozygous GLB1 variants: a paternal c.792 + 1G > A splice-site mutation and a maternal c.1572_1573insC(p.Gly525Argfs*7) frameshift mutation. Both were classified as pathogenic by ACMG guidelines. β-galactosidase activity was markedly deficient, confirming the diagnosis. The family received genetic counseling and opted for prenatal diagnosis in a subsequent pregnancy. At age 2 years, the patient exhibited an inability to speak or walk and had a history of recurrent severe pneumonia requiring multiple hospitalizations, with his overall condition currently managed supportively. Two novel pathogenic GLB1 mutations expanded the mutational spectrum of infantile GM1 gangliosidosis. WES with enzymatic validation enabled precise diagnosis, genetic counseling, and prenatal management. The development of targeted therapies remained imperative to alter the disease's natural course.
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2026-03-28 | Impact of Sinbaglustat on Neurons of the Medial Nucleus of the Trapezoid Body in a Murine Model of Human GM1-Gangliosidosis.
Background: GM1-gangliosidosis (GM1) is a lysosomal storage disorder caused by mutations in the Glb1 gene, resulting in reduced β-galactosidase activity and accumulation of GM1 gangliosides in neuronal lysosomes. Effective therapeutic strategies for this disease remain limited. Substrate reduction therapy using small molecules targeting glucosylceramide synthase (GCS) and non-lysosomal glucosylceramidase (GBA2), such as sinbaglustat, represents a promising approach. Methods: Structural and electrophysiological properties of principal neurons of the medial nucleus of the trapezoid body (MNTB) were investigated in 7-month-old Glb1-/- mice. Animals received long-term treatment with either low (LD; 10 mg/kg) or high (HD; 300 mg/kg) doses of sinbaglustat and were compared with untreated Glb1-/- (KO) and untreated wild-type (WT) mice. Results: Sinbaglustat treatment reduced lysosomal storage material in MNTB neurons. Basal membrane properties were largely unchanged across groups. However, action potential halfwidth was significantly increased in untreated KO and LD mice compared to untreated WT animals but was normalized in HD mice. After-hyperpolarization duration was prolonged in Glb1-/- mice relative to WT. Temporal precision during high-frequency stimulation was reduced in untreated KO mice and improved following sinbaglustat treatment. Conclusions: These findings indicate that GM1-gangliosidosis is associated with functional alterations in MNTB neurons and suggest that long-term sinbaglustat treatment can partially restore neuronal electrophysiological properties, supporting its therapeutic potential in GM1.
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2025-09-16 | MRI brain volumetric analysis of type II GM1 gangliosidosis patients treated with gene therapy
Motivation: Type II GM1 gangliosidosis is a rare disease that lacks reliable quantitative neural biomarkers to monitor disease progression. Goal(s): With the advent of gene therapy in treating GM1, we sought to quantify volumetrics of different brain regions known to be affected in GM1 patients. Approach: We quantified and tracked brain volumetric changes longitudinally on specific brain structures at different timepoints using MRI to evaluate disease progression/regression in GM1 patients treated with gene therapy and compared them to untreated patients and healthy controls. Results: We demonstrated the utility of brain volumetrics in assessing longitudinal brain region changes in gene therapy treated GM1 patients. Impact: Our study addressed the need for quantitative neural biomarkers in type II GM1 gangliosidosis which correlated with clinical markers. Through longitudinal brain volumetric analysis using MRI, we demonstrated the efficacy of gene therapy in monitoring disease progression/regression in GM1 patients.
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2025-07-29 | β-Galactosidase inhibition explored by biochemical methods and in silico studies for plant polyphenols.
β-Galactosidase is a lysosomal enzyme whose deficiency is associated with genetic disorders such as GM1 gangliosidosis, prompting the search for novel enzyme modulators with therapeutic potential. The current study evaluated the inhibitory potential of selected natural polyphenols against β-galactosidase using a combined approach of biochemical assays and computational modeling. Sixteen plant-derived compounds were initially screened through molecular docking against Aspergillus oryzae β-galactosidase. Among these, hesperidin, rutin, and chlorogenic acid exhibited the most favorable interactions and were subsequently assessed through in vitro enzyme inhibition assays and MM/GBSA binding energy calculations. These compounds showed potential inhibitory effects and stable binding within the enzyme's active site. Although classical pharmacological chaperone activity was not directly demonstrated, the observed modulation of enzyme function suggests potential for further development of these polyphenols as structurally distinct β-galactosidase inhibitors. The findings provide a basis for future investigations aimed at natural product-based strategies to manage lysosomal storage disorders such as GM1 gangliosidosis.
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