Tay-Sachs disease (TSD) is a rare autosomal recessive genetic disorder that causes fatal neuro-degeneration in the brain and spinal cord and usually results in death by the age of 2 or 3. The disease is caused by the fatal accumulation of ganglioside glycosphingo lipids that are a component of the cell plasma membrane, in the nerve cells of the brain. This lysosomal storage disorder is pathologically evident in tissues of TSD patients that reveal enlarged neurons in the central nervous system. TSD is characterized early in infancy by a very specific set of symptoms and can be diagnosed clinically by visualizing a gray-white area on the retina due to the accumulation of lipids in ganglion cells along with a red spot in the center. Blindness results and the infant also experiences central nervous system problems such as developmental retardation, dementia, paralysis, seizures, and lack of motor control due to hypotonia, or decreased muscle tone and strength. There are also respiratory problems including aspiration of food and liquid, which may cause pneumonia. TSD is additionally characterized by an increased startle reaction, which is an exaggerated physical response to a sudden sound. The onset of these symptoms is at the infant stage of 3 to 6 months and gets markedly and progressively worse. The NCBI database puts incidence of TSD at about 1 in 3,900 births in Jewish persons and a lower rate of 1 in 320,000 in non-Jewish persons. The difference in frequency of TSD occurrence in these populations will be discussed later on.
TSD was first described in 1881 by Warren Tay, a British ophthalmologist, who observed the characteristic red spot on the retina of the eye of a child patient who suffered from neurological degeneration. The disease was also observed by Bernard Sachs, an American neurologist, who presented a detailed description of the disease in 1887. Sachs also recognized an increased frequency of TSD among persons of Ashkenazi Jewish descent as well as a tendency for the disease to occur in the same family, thus suggesting a genetic link.
[...] Since experimental history and research data of TSD are overwhelmingly concentrated on the classic infantile form of the disease, this paper will only focus on that form. The name TSD is implied to mean classic infantile TSD. Because TSD is an autosomal recessive disorder and affects both sexes equally, if both parents were carriers, they would have a 25% of having a child with TSD. An individual that receives both defective copies of the HEXA gene is thus unable to hydrolyze GM2 ganglioside. [...]
[...] de F., Poenaru, L., Couronne, F., Flori, E., Eibel, J. L., Deminatti, M. M., Savary, J. B., Lai, J. L., Gilgenkrantz, S., Pierson, M. Interstitial deletion of chromosome 15: two cases. Hum. Genet. 80: 401- Korneluk, R. G., Mahuran, D. J., Neote, K., Klavins, M. H., O'Dowd, B. F., Tropak, M., Willard, H. F., Anderson, M.-J., Lowden, J. A., Gravel, R. A. Isolation of cDNA clones coding for the alpha-subunit of human beta-hexosaminidase: extensive homology between the alpha- and beta-subunits and studies on Tay-Sachs disease. J. Biol. [...]
[...] Carrier and prenatal tests for TSD continue to help individuals of higher-risk populations as well as of the general population to learn their chances of having a TSD child or diagnose their child during pregnancy as having the disease or not. Carrier couples can meet with a genetic counselor or even consider assisted reproductive technology to help minimize their chances of having a TSD child. This is a modern technique that together with in-vitro fertilization allows embryos to be created in-vitro and then tested for TSD mutations. [...]
[...] Crystallographic structure of human beta- hexosaminidase interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis. J. Molec. Biol. 359: 913- Marchione, Marilynn. “Gene testing spurs decline of some dire diseases.” 17 Feb 2010. Associated Press.
[...] used a cDNA clone for in situ hybridization and confirmed the assignment of HEXA gene to 15q23-q24. In 1985, Myerowitz cloned the alpha chain of the HEXA gene from a human liver and found that the open reading frame contained 529 amino acids and that the molecular weight was 60kD. It was also discovered that the first 17 to 22 amino acids resembled a signal sequence. The alpha chain sequence was homologous to the amino acid sequence of the beta chain, which suggested that the alpha and beta shared a common ancestor. [...]
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