GM2gangliosider

GM2 ganglioside, or GM2, is a major glycosphingolipid found in cell membranes, with highest abundance in the nervous system. It consists of a ceramide lipid tail linked to a complex oligosaccharide headgroup that includes a sialic acid residue, classifying it as a ganglioside. GM2 is synthesized in the Golgi apparatus, formed from GM3 by the action of GM2 synthase, and is distributed to membranes and lysosomes.

The catabolic pathway for GM2 requires the enzyme beta-hexosaminidase A (HEXA) in combination with the GM2 activator protein GM2A. When HEXA or GM2A is deficient, GM2 accumulates within lysosomes, particularly in neurons, leading to cellular dysfunction. The lysosomal buildup of GM2 is a key feature of certain neurodegenerative disorders known as GM2 gangliosidoses.

GM2 gangliosidoses comprise a spectrum of diseases. The most common form, Tay-Sachs disease, results from biallelic mutations in HEXA; Sandhoff disease arises from HEXB mutations; and a rarer AB variant is due to GM2A deficiency. Onset can range from infancy to childhood, with hallmark features including progressive motor and cognitive decline, exaggerated startle response in infancy, initial hypotonia followed by spasticity, seizures, and visual impairment.

Diagnosis typically involves biochemical assays showing reduced HEXA activity in leukocytes or fibroblasts and genetic testing of HEXA, HEXB, and GM2A genes. Some cases may employ measurement of GM2-derived metabolites in body fluids or supportive neuroimaging findings. There is currently no disease-modifying therapy approved; management is primarily supportive and multidisciplinary.

Research efforts focus on gene therapy, substrate reduction strategies, and chaperone therapies in preclinical models, with ongoing exploration of biomarkers for diagnosis and monitoring of disease progression.