The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy

Abstract

The gangliosidoses are lysosomal storage disorders caused by accumulation of GM1 or GM2 gangliosides. GM1 gangliosidosis has both central nervous system and systemic findings; while, GM2 gangliosidosis is restricted primarily to the central nervous system. Both disorders have autosomal recessive modes of inheritance and a continuum of clinical presentations from a severe infantile form to a milder, chronic adult form. Both are devastating diseases without cure or specific treatment however, with the use of supportive aggressive medical management, the lifespan and quality of life has been extended for both diseases. Naturally occurring and engineered animal models that mimic the human diseases have enhanced our understanding of the pathogenesis of disease progression. Some models have shown significant improvement in symptoms and lifespan with enzyme replacement, substrate reduction, and anti-inflammatory treatments alone or in combination. More recently gene therapy has shown impressive results in large and small animal models. Treatment with FDA-approved glucose analogs to reduce the amount of ganglioside substrate is used as off-label treatments for some patients. Therapies also under clinical development include small molecule chaperones and gene therapy.

Figure 1.. Sphingolipid Catabolism

GM1 ganglioside is metabolized by β-galactosidase to form GW2 ganglioside. Abnormalities of this metabolic step lead to accumulation of GM1 ganglioside and GM1 gangliosidosis. GM2 ganglioside is converted to GM3 ganglioside by the action of β-hexosaminidase A. Deficiencies of this enzyme result in the accumulation of GM2 ganglioside and Tay-Sachs or Sandhoff disease

Figure 2.. GM1 Gangliosidosis

NEU1, PCCA, and β-GAL assemble in the lysosome. This complex is required for β-GAL to convert GM1 to GM2 ganglioside. Alternate splicing of BGAL leads to formation of EBP. This forms a membrane-associated complex with PCCA and NEU1 to metabolize tropoelastin to elastin fibers

Figure 3.. GM2 Gangliasidoses

Deficiencies in β-hexosaminidase A resulting from mutations in either HEX A (β subunit) or HEX B (β subunit) lead to Tay Sachs or Sandhoff disease respectively. Mutations in GM2A (GM2 activator protein) lead to GM2 activator deficiency.