TaySachs Disease

Tay-Sachs Disease
Tay-Sachs disease is a rare hereditary disease found mainly in infants but is also found in juveniles and adults. It is caused by the abnormal metabolism of fats and is characterized by mental deterioration, blindness, and paralysis. There is no available treatment for this disease.
The ethnic group of Ashkenazi Jews, is very tightly knit. Their religion teaches them to remain among their own small group. Ashkenazi Jews rarely marry outside of their group. Ashkenazi Jews have a carrier frequency of 1 in 25. As Tay-Sachs disease is inherited as autosomal recessive traits, two carriers must breed in order to produce and offspring with Tay-Sachs. Because of the high carrier frequency in Ashkenazi Jews, they are considered to be 10 times more likely to have Tay-Sachs disease than the general population. Carrier screening is recommended pre-pregnancy in all couples in whom at least one is an Ashkenazi Jew.
Lysosomes contain hydrolytic enzymes which function in the acid of the lysosome and are meant to be secreted not as wastes into the extracellular fluids, but as secretory proteins into an intracellular organelle. When one of these enzymes is dysfunctional, the catabolism of its macromolecule does not completely occur and there is a buildup of the macromolecule inside the lysosome. This results in great numbers of large lysosomes which begin to interfere with the normal functions of the cell. This disorder is called lysosomal storage disorder. These disorders can eventually lead to the dysfunction of the organs. The organs affected by the disorder are determined by two factors: 1) The location in the body where the macromolecules that are to be catabolized are found, and 2) The location where the catabolism occurs.
Tay-Sachs disease is a form of these lysosomal storage diseases. It is scientifically known as GM2 gangliosidosis: Hexosaminidase alpha-subunit deficiency. Three polypeptides encoded by three separate locations on the chromosome are needed for the catabolism of GM2 gangliosides. When these genes are mutated, the result is a buildup of the glycosphingolipid GM2 gangliosides. Over 50 mutations have been identified. Tay-Sachs disease is the most common form of gangliosidosis and results from a mutation of the alpha-subunit location on chromosome 15. This causes a severe dysfunction in the enzyme hexosaminidase A.
Glycosphingolipids, otherwise known as GSLs, are components of the plasma membrane of eukaryotic cells. They interact at the cell surface with toxins, viruses, bacteria, membrane-bound receptors, and enzymes. They participate in cell-type-specific adhesion processes. The products of GSL metabolism are ceramide and sphingosine. The second step of the GSL GM1 metabolism is where the buildup of GM2 gangliosides occurs.
Several alleles have been pinpointed at the alpha-subunit location. Each of these causes a variable degree of enzyme dysfunction in hexosaminidase A. These varying degrees cause varying symptoms. With the most severe allele, the infant would appear normal at birth but would begin to exhibit motor incoordination, increased startle reaction, and the cherry red spot. This would cause death by age 4. The cherry red spot is a characteristic of infantile-onset Tay-Sachs and is often used along with other characteristics for diagnosis. The juvenile-onset form is associated with ataxia and dementia. This would cause death by age 10 to 15. The adult-onset form is associated with clumsiness in childhood and motor weakness in adolescence; some patients are psychotic.
The catabolism of the glycosphingolipid GM2 gangliosides requires the enzyme hexosaminidase A. In Tay-Sachs disease, an inherited disorder, a mutation on the alpha-subunit location of chromosome 15 results in a dysfunction of hexosaminidase A. This causes an accumulation of GM2 gangliosides which results in the inability of the cell to function normally. This dysfunction manifests itself in three forms: the most common infantile-onset form, the juvenile-onset form, and the adult-onset form. Each of these forms has its own signs and symptoms. Each is inevitably fatal. There is no available treatment for Tay-Sachs disease.


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