Rare Disease Highlight: GM1 Gangliosidosis

GM1-gangliosidosis is a rare disorder passed from parents to children causing mutations in the GLB1 gene, which encodes for an enzyme known as beta-galactosidase. This mutation results in the enzyme’s decreased activity and the consequential accumulation of certain substrates, causing swelling and damage to cellular contents, as well as organ dysfunction [1, 2]. Three types of GM1-gangliosidosis are recognized with the symptoms ranging from mild to severe. A hallmark of this disorder is central nervous system (CNS) degeneration, which is where the synthesis of one of the accumulating substrates, ganglioside, is highest. Depending on the disease type, CNS symptoms may include disturbances in the development of movements and speech, seizures, and difficulty eating. GM1-gangliosidosis type 1 (infantile), the most common form, and type 2 (late infantile/juvenile) are severe conditions, which, in most cases, result in the death of the patients before adulthood, while the prognosis of type 3 GM1-gangliosidosis is largely dependent on the degree of neurological impairment [2]. Overall, about 200, 50, and 70 cases of type 1, type 2, and type 3 GM1-gangliosidosis have been reported to date, respectively [3].

GM1-gangliosidosis remains a rare disease with significant unmet medical need, as patients only have access to symptomatic and supportive treatments. No clinical practice guidelines for GM1-gangliosidosis have been published, so the current standard-of-care (SOC) consists of evaluation, treatment, and monitoring by various specialists knowledgeable about GLB1-related disorders [2]. Thus, based on the absence of FDA-approved treatment and the dismal quality-of-life and outcomes, new treatment interventions for GM1-gangliosidosis are greatly needed [2, 4].

1.         Brunetti-Pierri, N. and F. Scaglia, GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab, 2008. 94(4): p. 391-396.

2.         Regier, D.S., C.J. Tifft, and C.E. Rothermel, GLB1-Related Disorders, in GeneReviews(®), M.P. Adam, et al., Editors. 2021, University of Washington, Seattle | Copyright © 1993-2021, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.: Seattle (WA).

3.         Caciotti, D.A., D.M.A. Donati, and D.A. Morrone. Orphanet: GM1 gangliosidosis 2012  [cited 2021 12/09]; Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=354.

4.         Ferreira, C.R., et al., The skeletal phenotype of intermediate GM1 gangliosidosis: Clinical, radiographic and densitometric features, and implications for clinical monitoring and intervention. Bone, 2020. 131: p. 115142.

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