Since the advent of the microscope in the 18th century, advances in the practice and sophistication of science have permitted human colonization and growth of all landmasses: colonization of the Western Hemisphere was difficult by sea, where lack of nutritious food led to metabolic deficiencies such as scurvy; while entire populations were wiped empty with the spread of plague. Nowadays, countries support ever increasing populations with medicinal treatments and health pandemics are neutralized with international vaccination campaigns. However, numerous incurable diseases still affect members of the general population. This is especially true of diseases of genetic origin, where alteration of an individuals DNA is necessary to restore wild-type phenotypes. Unfortunately, the technology for curing DNA diseases has not yet been perfected.
Commonly known as lipid storage diseases, gangliosidoses remain relatively rare in the worldwide population. Gangliosidoses involve the erroneous accumulation of lipids in cellular compartments known as vacuoles due to the cells impotence in synthesizing enzymes required for lipid catabolism. Accumulation of gangliosides in cells leads to excessive swelling at the cellular level. Neuronal cells are commonly affected by excessive lipid accumulation and results in deterioration of neuronal processes, which results in are loss of physical manipulation, loss of vision, and mental retardation.
Pathophysiologically, most gangliosidoses share common symptoms which prohibit the identification of the disease responsible. Additionally, evidence has proved that the deficient enzymes not only cleave lipids but vast arrays of products with common features as well. It was Konrad Sandhoff, discover of Sandhoff disease, who suggested the usage of enzymatic assays to attribute specific enzyme deficiencies to particular disease.
Before understanding how these enzymes cleave gangliosides, an overview of ganglioside is prudent. Gangliosides contain hydrophobic ceramide residues attached to hydrophillic oligosaccharide chains. Catabolism of gangliosides always begins from the hydrophillic oligosaccharide end until ceramide cleavage occurs. Three general classes exist for the classification of catabolised gangliosides: GM1, GM2, and GM3 gangliosides.
Transitioning from GM1 to GM3 involves enzymatic activation of enzymes specific for cleaving each subsequent product. For further analysis, focus will be given to the GM2 defiency Sandhoff's disease, promptly named after is discover Konrad Sandhoff in 1973?
Sandhoff disease arises from loss of enzymatic function necessary for cleavage of GM2 gangliosides to GM3 for further processing. Two enzymes are responsible for GM2 cleavage: N-acetly-BETA-D-Hexoaminidase A and B.
After isolation, it was determined that Hexosaminidase A had an isoelectric point at pH 4.9 and Hexosaminidase had an isoelectric point at pH 7.3. Despite their differences, both Hexosaminidase A and B have an...