GM1 Gangliosidosis—A Mini-Review

Abstract

GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).

Abnormal DaTscan in GM1‐Gangliosidosis Type III Manifesting with Dystonia‐Parkinsonism

“…This ultimately accounts for disruption of the autophagy lysosomal pathway and neuronal damage, which has increasingly been recognized as a pathophysiological mechanism underlying Parkinson's disease and other neurodegenerative disorders 8,9 . Against this background, substrate reduction therapy with the N‐alkylated sugar miglustat, which inhibits the enzyme glucosylceramide synthase and ultimately glycosphingolipid biosynthesis, has been proposed for the treatment of GM1 gangliosidis based on proven efficacy in reducing disease progression in other lysosomal storage disorders (ie, Gaucher disease type 1, Niemann‐Pick disease type C) as well as in reducing GM1 ganglioside in the central nervous system of a mouse model of GM1 gangliosidosis and patients’ cultured skin fibroblasts 1 …”

Gene editing is suitable to treat GM1 Gangliosidosis: a proof-of-concept study

“…Gene therapy for GM1 gangliosidosis may be able to slow down or stop disease progression but cannot reverse damage already caused by the disease 19,22 . There is currently no curative treatment for GM1 gangliosidosis.…”

“…Here, we investigated whether BE may constitute an alternative strategy to cure GM1 gangliosidosis. Indeed, there are currently no effective therapies and only supportive treatments can be offered 19 . GM1 gangliosidosis is an autosomal recessive, lysosomal storage disorder estimated to occur in 1 in 100,000 to 200,000 newborns 20 .…”

GM1 Is Cytoprotective in GPR37-Expressing Cells and Downregulates Signaling

“…This time and dose discrepancy between transient and stably overexpressing cell lines might reflect the cellular stress induced by transfection or, for the concentration, be attributable to the reduced endogenous levels of GM1 in stable N2a GPR37-eGFP . While GM1 is mostly known for cytoprotective actions, increased levels of GM1 leads to neurodegeneration clinically [ 42 ]. Furthermore, as seen by qPCR, GPR37 expression was unaltered with GM1 treatment, indicating that the effects seen on signaling, and not expression levels, were responsible for the effect.…”