The cause of Tay-Sachs disease is best described by which of the following?
|A||Excess of a lysosomal enzyme in blood due to defective uptake .|
|B||Deficiency of a lysosomal enzyme that digests proteoglycans .|
|C||Deficiency of a, membrane receptor that take up proteoglycans.|
|D||Deficiency of a mitochondrial enzyme that degrades glycogen.|
a. The lysosomal enzyme hexosaminidase A is deficient in Tay-Sachs disease. The enzyme cleaves amidohexose groups from gangliosides, complex lipids formed from ceramide (a derivative of sphingosine)
b. Ceramide is synthesized in the endoplasmic reticulum from palmitoyl coenzyme A (16-carbon acyl CoA) and serine in a reaction catalyzed by pyridoxal phosphate.
c. Uridine diphosphoglucose (UDP-glucose) or UDP-galactose moieties and sialic acid groups are then added in the Golgi apparatus and the gangliosides contribute to myelin in nerve cells.
d. Neuro lipidoses like Tay-Sachs disease lack certain lysosomal enzymes necessary to degrade the gangliosides, causing severe effects on nerve cells (neuro degeneration).
e. A parallel group of disorders called mucopolysaccharidoses result from the absence of lysosomal enzymes that degrade complex carbohydrate chains and their associated proteins (called proteoglycans).
f. Proteoglycans are more widely distributed than gangliosides, occurring in the ground substance of many tissues.
g. Accumulation of the glycosaminoglycans from these proteoglycans thus causes a wide spectrum of symptoms including coarsening of the face and hair, cardiopulmonary problems, and bony deformities such as kyphosis (beaked spine).
h. There is a specific lysosomal receptor that recognizes mannose-6-phosphate on certain lysosomal enzymes and targets them to lysosomes.
i. Mutations in this receptor can cause increased blood levels and lysosomal deficiencies of several enzymes that are normally targeted to lysosomes. One such disease is I (inclusion) cell disease (252500).
j. The slow accumulation of abnormal gangliosides in lipidoses and of abnormal proteoglycans in mucopolysaccharidoses causes a characteristic clinical course of normal early development that plateaus and then regresses.
k. The age of regression and life span vary widely among the lysosomal storage dis eases, with Tay-Sachs being one of the most severe.