GM1 gangliosidosis: A modern view of its etiopathogenesis, phenotypic heterogeneity, and innovative therapeutic strategies

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Abstract
GM1 gangliosidosis is a rare autosomal recessive hereditary disorder caused by mutations in the GLB1 gene. The deficient activity of the enzyme β-galactosidase leads to the pathological accumulation of GM1 ganglioside, primarily in the cells of the central nervous system and visceral organs, resulting in progressive neurodegeneration and systemic symptoms. The clinical presentation is highly heterogeneous and can include neurological deterioration, epilepsy, skeletal abnormalities, facial dysmorphism, organomegaly, and ophthalmological manifestations. This clinical polymorphism, along with the variable age of onset and the differing degrees of neurological and systemic involvement, is attributed to the specific mutations and their impact on the residual enzyme activity. Based on this, three types of GM1 gangliosidosis are distinguished: the infantile, juvenile, and late-onset forms. This article reviews current knowledge on the etiology, biochemical defects, pathogenesis, and clinical manifestations of GM1 gangliosidosis. It also analyzes novel potential therapeutic approaches for patients, with insights from animal model studies. While no effective cure for GM1 gangliosidosis currently exists, several strategies show significant promise. The most advanced therapeutic approaches include enzyme replacement therapy, substrate reduction therapy, chaperone therapy, hematopoietic stem cell transplantation, and gene therapy using adeno-associated viral vectors, some of which have already progressed to clinical trials.

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