Contributor: Gordon K. Klintworth
The GM2-gangliosidoses are a group of inherited disorders characterized by an excessive accumulation of GM2-ganglioside (and a few related glycolipids) in neurons. The degradation of GM2 gangliosides is complex and involves genes at three different loci that encode three different polypeptides. This sphingolipid accumulates are a result of a defect in hexosaminidase A, hexosaminidase B or GM2 activator. Three non-allelic variants of GM2-gangliosidosis are recognized: Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency. These disorders vary in age of onset, severity and clinical progression and are subclassified into infantile, late infantile, juvenile and adult cases based on age of onset. Cherry-red spots in the macula are features of Tay-Sachs disease and Sandhoff disease, but are not known to be prominent in the extremey rare GM2 activator deficiency. A mutation in HEXA results in a defective alpha chain in hexosaminidase A and Tay-Sachs disease, but a mutation in HEXB results in a defective beta-chain of hexosaminidase and a deficiency of both hexosaminidase A and hexosaminidase B causing Sandhoff disease. A mutation at the GM2 activator locus on human chromosome 5 (5q31.3-q33.1) causes a deficiency in GM2 activator protein.