GM1 Gangliosidosis: Mechanisms and Management

Abstract

The lysosomal storage disorder, GM1 gangliosidosis (GM1), is a neurodegenerative condition resulting from deficiency of the enzyme β-galactosidase (β-gal). Mutation of the GLB1 gene, which codes for β-gal, prevents cleavage of the terminal β-1,4-linked galactose residue from GM1 ganglioside. Subsequent accumulation of GM1 ganglioside and other substrates in the lysosome impairs cell physiology and precipitates dysfunction of the nervous system. Beyond palliative and supportive care, no FDA-approved treatments exist for GM1 patients. Researchers are critically evaluating the efficacy of substrate reduction therapy, pharmacological chaperones, enzyme replacement therapy, stem cell transplantation, and gene therapy for GM1. A Phase I/II clinical trial for GM1 children is ongoing to evaluate the safety and efficacy of adeno-associated virus-mediated GLB1 delivery by intravenous injection, providing patients and families with hope for the future.

Fluorescent In Situ Staining and Flow Cytometric Procedures as New Pre-Diagnostic Tests for Sialidosis, GM1 Gangliosidosis and Niemann–Pick Type C

“…Biomarkers are also essential for monitoring and assessing outcomes in ongoing clinical trials [ 6 ]. Currently, FDA-approved treatments for patients with GM1 gangliosidosis and sialidosis [ 31 , 32 ] are limited to supportive care. The efficacy of substrate reduction therapy, pharmacological chaperones, enzyme replacement therapy, stem cell transplantation, and gene therapy for GM1 gangliosidosis is currently being evaluated [ 6 , 33 ].…”

GM1 Gangliosidosis—A Mini-Review

“…The progressive nature of the neurological disease in GM1 gangliosidosis requires close monitoring. Biomarkers in blood, urine, and CSF biomarkers may be potentially useful in this regard (Gray-Edwards et al, 2017a,b;Rha et al, 2021). Disease progression can also be monitored using minimally invasive neuroimaging.…”

“…Generalizations based on crystallographic structure of the β-GAL enzyme have been attempted (Ohto et al, 2012). Mutations associated with type I/infantile onset GM1 gangliosidosis, for the most part, are located in the core protein region causing β-gal instability, whereas mutations associated with milder phenotypes, such as types II and III GM1 gangliosidosis, tend to be on the protein surface (Morita et al, 2009;Ohto et al, 2012;Rha et al, 2021). Recently, the determination of the 3D structure of murine β-gal in complex with PPCA has revealed that some mutations at conserved amino acid residues found in GM1 gangliosidosis patients affect formation of the complex (Gorelik et al, 2021).…”

“…Bi-allelic mutations in GLB1 result in a reduction in β-GAL activity and the build-up of GM1 ganglioside in multiple tissues including the brain (Brunetti-Pierri and Scaglia, 2008;Karimzadeh et al, 2017;Rha et al, 2021) leading to severe neurodegeneration resulting in morbidity and premature mortality (Ferreira and Gahl, 2017). More than 200 diseasecausing mutations have been identified across the GLB1 gene, particularly in exons 2, 6, 15, and 16 (Figure 2).…”

“…Comprehensive reviews of GM1 gangliosidosis have been recently published (Regier et al, 1993;Breiden and Sandhoff, 2019;Lawrence et al, 2019;Lang et al, 2020;Rha et al, 2021). In this mini review, we will focus on the clinical spectrum of disease and genetic variants, our current understanding of disease pathogenesis, the utility of available animal models and approaches to therapy for these devastating disorders.…”