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Tay-Sachs Disease

Genetic Basis And Clinical Manifestations Of Tay-sachs Disease

Tay–Sachs disease is inherited from asymptomatic carrier parents and is, therefore, an autosomal recessive disorder. The defective gene produces a protein, specifically an enzyme, that is important for speeding up a specific biochemical reaction. The enzyme, hexosaminidase A (Hex-A) and the defective activity leads to the accumulation of the substrate (precursor) it breaksdown called GM2 gangliosides, a fatty substance found enriched in nerve cells of the brain. Gangliosides are synthesized and rapidly degraded during brain development. Accumulation of GM2 ganglioside leads to the deterioration of both mental and physical development and children become blind, deaf, and unable to swallow food, and eventually paralysis due to muscular degeneration. The cherry-red spot on the retina is a typical finding caused by accumulation of the fatty acid material in lipid-rich cells around the retina. This fatty substance can accumulate even during pregnancy, where the first destructive effects take place, although the clinical significance does not appear until the first few months after birth The symptom vary in severity and time at which they are evident. Failure to develop, loss of vision, and a characteristic abnormal startle reaction to sounds are often helpful considerations in making a diagnosis. There is also another hexosaminidase, or Hex-B, and if it is also defective, it leads to a distinct disorder called Sandhoff's disease.

Although Tay–Sachs disease primarily affects infants, juvenile and adult forms of Tay-Sachs disease also exist. A rarer form occurs in affected individuals that are in their late twenties or early thirties of life and is characterized by progressive neurological degeneration with the first recognized abnormality being an unsteady gait.

Tay-Sachs is a homozygous recessive genetic disorder caused by a defective gene on chromosome 15. In homozygous recessive genetic disorders, two defective alleles, or copies of the gene, one from each parent, must be passed on to produce the disease. If two people who each carry a defective copy of the gene have a child, the chances are one in four that the child will have Tay-Sachs disease. Certain populations are known to be at a higher risk for carrying a defective Hex-A gene, however, anyone in a population can be a carrier of Tay-Sachs disease. The defective Tay-Sachs allele is prevalent in Jews of Eastern European descent. About 1 in 27 people of this descent are thought to be carriers, and about 1 in 3600 Jewish infants are born with this disease, accounting for approximately 90% of all Tay-Sachs cases worldwide. Among non-Jews, about one in 300 people are carriers of the defective allele. Carriers do not have symptoms of Tay-Sachs, although their levels of the hexosaminidase A enzyme may be reduced as much as 50%. This reduction, however, is not sufficient to produce symptoms.

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