Tay-Sachs is a disease caused by a mutation to the gene which codes for Hex A. Without Hex A, a cell cannot degrade GM2 ganglioside into GM3 ganglioside. This results in a build up of ganglioside’s in lysosomes of neurons. The result is varying degrees of mental deterioration. New DNA-based screening is currently being developed to replace the enzyme-based screening techniques that have been used since 1969. This will not only speed up the diagnosis, but also allow for earlier detection of Tay-Sachs by using the parents genotypes.
Tay-Sachs disease is one of three autosomal recessive, lysosomal storage disorders, collectively known as the GM2 gangliosidoses. They result from accumulation of GM2 ganglioside in lysosomes, primarily of neurons. The clinical symptoms of Tay-Sachs vary from infantile lethal neurodegenerative disease to less severe adult onset forms. The latter are often characterized by motor neuron impairments. The recognition of the high incidence of this disease among Ashkenazi Jews and the identification of the deficiency of hexosaminidase A as the basic defect were essential findings leading to the establishment of mass carrier screening programs for this disease . Recently, research has focused on the DNA-based diagnostics that are anticipated to play a role in future carrier screening programs .
GM2 ganglioside hydrolysis
The lysosomal hydrolase, beta-hexosaminidase, occurs predominantly in two forms, hexosaminidase A (Hex A) and hexosaminidase B (Hex B). Hex A is comprised of one alpha and one beta subunit while Hex B is comprised of two beta subunits . While both subunits contain similar active sites, only the alpha subunit can hydrolyze GM2 ganglioside. Dimer formation is required for either subunit to become active.
The Hexosaminidase A activity that is blocked in Tay-Sachs disease is that of cleaving the terminal N-acetylgalactosamine off of GM2 ganglioside.
GalNAc-Gal-Glc-Cer ---------> Gal-Glc-Cer + GalNAc
GM2 Ganglioside GM3 Ganglioside
Fig. 1 Shows the action of Hex A cleaving the GalNAc off of the GM2 ganglioside and converting it to the GM3 ganglioside. This is the blocked reaction in Tay-Sachs disease. (GalNAc=N-acetylgalactosamine; Gal=Galactose; Glc=Glucose; Cer=Ceramide; NANA=Sialic Acid ) [ 6 ]
There is also a third protein required for GM2 ganglioside hydrolysis called the GM2-activator. It has been demonstrated that the GM2-activator extracts ganglioside GM2 from micelles or liposomes and forms a ganglioside activator complex. This complex is required for the...