these diseases is a lack of the ability of the cell to breakdown sphingolipids in
the lysosome. The accumulation of these macromolecules or partial derivatives
of these molecules in the lysosome results in the pathologic conditions associated
with the lysosomal storage diseases known as sphingolipidoses.
Proteins destined for the lysosome must contain certain carbohydrate sig-
nals. In I-cell disease the enzyme that catalyzes the addition of a mannose-6-
phosphate moiety to the protein is defective. Without the addition of this
mannose residue the proteins cannot be transported to the lysosome.
Tay-Sachs disease results from a deficiency in the enzyme hex-
osaminidase A (P-A-acetylhexosaminidase). The human gene for this enzyme
is found at chromosome position 15q23-q24. The deficiency in hex-
osaminidase A leads to the accumulation of ganglioside GM2 in the nerve cells
of the brain. Hexosaminidase A removes a terminal A-acetylgalactosamine
(GalNAc) residue from ganglioside GM2 to form ganglioside GM3 (Figure 28-4).
The inability of patients with Tay-Sachs disease to remove these sugar residues
results in the accumulation of gangliosides in the lysosome. This results in
swelling of the neurons containing these lipid-filled lysosomes and the dis-
ruption of neuronal function.
Figure 28-4. The reaction catalyzed by hexosaminidase A, the enzyme defi-
cient in patients with Tay-Sachs disease.
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