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Review
. 2021 Apr 9:14:209-233.
doi: 10.2147/TACG.S206076. eCollection 2021.

GM1 Gangliosidosis: Mechanisms and Management

Allisandra K Rha  1 , Anne S Maguire  1   2 , Douglas R Martin  1   2
Affiliations
Review

GM1 Gangliosidosis: Mechanisms and Management

Allisandra K Rha et al. Appl Clin Genet. .

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.

Keywords: GLB1; GM1 gangliosidosis; LSD; biomarkers; chaperone; gene therapy.

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Conflict of interest statement

Dr Douglas R Martin reports grants from National Institutes of Health, during the conduct of the study; stock options from Lysogene, and personal fees from Axovant, outside the submitted work. The authors report no other potential conflicts of interest for this work.

Figures

Figure 1
Figure 1
Transmission Electron Microscopy (TEM) images of feline CNS tissue. Normal axon in cross-section surrounded by thick myelin sheath (A). Multiple axons in cross-section of GM1 white matter, surrounded by disjointed and unravelling myelin layers (B). Normal oligodendrocyte with round nuclear envelope and prominent cytocavitary network (C). GM1 oligodendrocyte with multiple swollen mitochondria (black arrows) and irregularly-shaped nuclear envelope (white arrow) (D). Scale bars are 1μm. Transmission electron micrographs in panels A, B, and D, reproduced with permission Gray-Edwards HL, Maguire AS, Salibi N, et al. 7T MRI predictsamelioration of neurodegeneration in the brain after AAV genetherapy. Mol Ther - Methods Clin Dev. 2020;17:258–270. © 2019 Elsevier.
Figure 2
Figure 2
An example of data collected from Magnetic Resonance Spectroscopy (MRS) and MRI of normal and GM1 cats. Cerebellar voxel defined in the cat for measurement of 1H MRS (open white square) (A). Example 1H spectrum with metabolites labeled and data output for the respective metabolites (B). Transverse T2w images of the cerebral cortex and cerebellum in normal and GM1 cats at 2 and 8 months of age. The isointensity of gray and white matter is prominent at 8 months for both the cerebral cortex and cerebellum of GM1 cats compared to normal controls. In GM1 cats, atrophy is mild and unilateral ventriculomegaly is apparent in the provided example (also occurs in normal controls) (C).
Figure 3
Figure 3
Management of GM1 Gangliosidosis. Clockwise, beginning on the left: Pharmacological chaperones for enzyme enhancement and small molecules for substrate reduction therapy (1–7), stem cell transplantation, gene therapy, and enzyme replacement (RCSB PDB ID: 3THC).
See this image and copyright information in PMC

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