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A Review of Tay-Sachs Disease

Abstract
Tay-Sachs disease (TSD) is an uncommon genetic disease which causes the nervous system destruction. A mutation causes the symptoms normally in the early infantile stage, resulting in an early death. A mutation on the hexosaminidase A gene (HEXA), allows fats to build up and damage the cells of the nervous system. Out of the three forms of TSD, infantile, juvenile and late-onset, the infantile is the most common and severe. TSD is most commonly found in people from Jewish populations (Ashkenazi). Paralysis, seizures, a startle reflex, and red spots in the eye are some common features of this rare disease. The only real treatment for patients with TSD is to try to better the quality of life since there is no cure. The late-onset of this disease may be treated with medications to alleviate some of the symptoms, again to enhance the quality of life. Genetic tests are recommended for those in the high risk group being of eastern European descent. Blood tests can show if the HEXA gene is fully functional or not in a fetus, giving the mother a choice of terminating the pregnancy.

Tay-Sachs disease
A healthy baby is able to develop vision, movement, hearing, and other vital functions, because enzymes clear out fatty protein and other unwanted material that can interfere with growth.


But a baby with Tay-Sachs disease is born without one of those important enzymes, called Hexosaminidase A (Hex A). So, as those fatty proteins build up in the brain, they hurt the baby's sight, hearing, movement, and mental development.
A child can only get Tay-Sachs by inheriting it. The genetic trait is relatively common among certain ethnic groups, such as Ashkenazi Jews. Because the disease can be detected before a child is born, couples in those ethnic groups who are thinking of having children may want to get a blood test to find out whether their child would be likely to have the disease.
The child can only have Tay-Sachs disease if both parents are carriers of the gene. There is 50% chance that their child will be a carrier, but not have the disease, and 25% chance that their child will not be a carrier and not have the disease and 25% chance that their child will have the disease.
Patients with Tay-Sachs disease have red spot in the Retina of their eyes. This can be easily observed by a physician using an ophthalmoscope. This test is done after the doctor observes hearing, sight, and movement problems in the patient. The red spot is the area of the retina where excessive gangliosides surround retina ganglion cells (neurons of the central nervous system). This part is the only normal part of the retina. Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides [4].
There are three type of Tay-Sachs disease:
-Infantile TSD, Infants with TSD are normal for first six month of their life. Then, as nerves become distended with gangliosides the problems arises. The child becomes blind, deaf and unable to swallow. Muscles begin to atrophy. Death usually occurs before the age of 4 [9].
- Juvenile TSD: It is a rare disease; it is more in children of age 2 to10. These children develop cognitive, motor, speech and swallowing difficulties. The sufferers die at the age 5 to 15 years old [20].
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Adult Onset TSD: This is also a rare form of TSD. It occurs in patients in their 20s or early 30s. It is characterized by unsteadiness of gait. The symptoms also include speech and swallowing difficulties and difficulty to control the muscles, cognitive decline and psychiatric illness. Patients with this disease become wheelchair users in adulthood. But many can survive if the symptoms are controlled with medication [22].
The development of improved testing methods has allowed neurologists to diagnosis Tay-Sachs. Until the 1970s and 80s, when the molecular genetics of the disease was yet known, Tay-Sachs was often miss-diagnosed which leaded to more problems for patients.
Screening for Tay-Sachs disease was one of the first successes of the emerging field of genetic counseling and diagnosis. Israel was the first country to offer free genetic screening and counseling of Tay-Sachs, for all couples. Israel has become a leading center for research on genetic disease. Israel's success with Tay-Sachs disease has also opened several discussions and debates about the proper scope of genetic testing for other disorders.
Genetic screening for carriers of Tay-Sachs disease is possible because an inexpensive enzyme assay test is available. It detects lower levels of the enzyme hexosaminidase A in serum. The enzyme assay test is not as precise as genetic testing based on polymerase chain reaction (PCR) techniques. It is cost effective for much broader use and allows screening for a disease that is rare in most populations. Couples with positive or ambiguous test results on the enzyme assay test may be referred for more precise screening. PCR testing is more effective when the ancestry of both parents is known, allowing for proper selection of genetic markers. Genetic counselors, working with couples that plan to conceive a child, assess risk factors based on ancestry to determine which testing methods are appropriate. Proactive testing has been quite effective in eliminating Tay-Sachs occurrence among Ashkenazi Jews [2]. On January 18, 2005, the Israeli English language daily “Haaretz” reported that as a "Jewish disease" Tay-Sachs had almost been eradicated.
Pathological changes
The lysosomal storage mutation in Tay-Sachs inhibits the formation of beta-hexosaminidase A, an enzyme in the fat metabolism pathway. In absence of beta-hexosiaminidase A, nerve cells in the nervous system start to degenerate due to the increased levels of GM 2 ganglioside in the brain. More specifically the accumulation of these gangliosides is found prominently in the neurons, axons and glial cells [15].
Gangliosides are an important part of a cellular plasma membrane. They influence modulation of signal transduction in lipid rafts [9]. GM 2 gangliosides accumulate in the lysosomes which block important neural pathways. A continuous process results in the overall destruction of the cell. An accumulation of these dead cells leads to the devastating disease of Tay-Sachs [15].
There have been over 90 mutations encountered in the HEXA gene ranging from point mutations to base pair insertions and deletions. Each and every mutation results in a non-functional protein that inhibits the enzymatic breakdown of GM2 ganglioside.
The major contributor of the death of these nerve cells is caused by activated macrophages, microglia, astrocytes, complement, and a family of proinflammatory cytokines. Inflammation is also a leading cause of nuerodegeneration in TSD [1].
The fact that the brain of Tay Sachs patients can more than double its weight in less than a year expresses the severity of GM 2 ganglioside built-up[19].
Out of the 14 exons on the alpha chain, the most common exon mutation in Ashkenazi Jews is on exon 11 on chromosome 15. These mutations in the HEXA gene cause an insufficient expression of the alpha chain of the Beta-hexosaminidase A, which causes the over accumulation of GM 2 gangliosides in the CNS. TSD is an autosomal recessive disease. It requires the HEXA gene from both parents to inherit the disease. If only one of the defected genes is inherited then the good gene compensates for the mutated gene, manufacturing significant amounts of beta-hexosaminidase A to maintain a normal lipid metabolism [8].
Three clinical variations of this disease are of relevance. Type I- infantile onset, type II- juvenile and type III, adult onset. The main difference of these three onsets is in the infantile type. The activity of beta-hexosaminidase is completely insufficient. This leads to an early infantile death. As for the juvenile and adult form, the beta-hexosaminidase is not completely deficient. In all three forms of this lysosomal storage disease an MRI will show an increasing dissipation of both grey and white matter of the nervous system [17].
The main function of lysosome is to degrade cellular metabolites in the cell. The enzyme of defect in Tay-Sachs that is required for this process is beta-hexosaminidase A. As the breakdown of molecules slows down in nerve cells, an accumulation of partially metabolized waste builds up in these cells causing mental retardation [16].
Biochemical Aspects
The HEXA gene and the beta-hexosaminidase A enzyme are the most important biological factors in TSD. The location of the Beta-hexosaminidase A can be found in cellular lysosomes [2].
Beta-hexosaminidase A is a heterodimer that consists of both an alpha and a beta chain. The HEXA gene is found on the alpha subunit located on chromosome 15. The 1700 BP alpha chain is defective in Tay-Sachs disease [6]. Beta-hexosaminidse A catalyzes the deletion of N-acetyl-galactosamine from the GM 2 ganglioside. As seen in the illustration [5].
For a functional beta-hexosaminidase A, both alpha and beta subunits are necessary. A complex is formed from this enzyme in which degradation of the GM 2 ganglioside occurs from the binding of the GM 2 activator protein. The GM 2 can then be hydrolizized, assuming that all participants are properly functional. As the hydrolization occurs in the GM 2 ganglioside, the beta 1,4 linked N-acetylhexosamine portion is removed [8]. The GM 2 ganglioside is changed into a GM3 ganglioside. The alpha residue is responsible for the complete degradation of the ganglioside from GM 2 to GM 3. With out a functional alpha residue as seen in Tay-Sachs disease, a build up of GM 2 ganglioside occurs. Although the beta subunit is not responsible for the hybridization of the ganglioside, its absence of malfunctioning also results in a non-functional complex that cannot be hydrolyzed further [9]. So the importance of both of these subunits is illustrated in the complete complex needed for the functional hydrolization of the GM 2 ganglioside.
This illustration shows the degradation mechanisms of the GM 2 ganglioside by beta-hexosaminidase A. First the GM 2 activator protein attaches itself to the GM 2 ganglioside on the phospholipid membrane of the lysosome. A complex is formed between beta-hexosaminidase A and the alpha subunit. Then the hydrolization of the 1,4 linked N-acetylhexosamine occurs. GM 2 ganglioside transitions to GM3 ganglioside. The activator protein disembarks from the GM3 ganglioside and the cycle is complete [16].
The terminal GalNAc and the GM2 activator in addition with a cofactor aid in the dysfuntional catabolism of ganglioside GM2 (GalNAc 1 4(Neu5Ac 2 3)Gal 1 4GlcCer). Not only does the GalNAc require the GM2 activator protein, also the Neu5Ac in the enzymatic chemical reaction requires it [21].The Gal has both the GalNAc and the Neu5Ac attached to it to assemble GalNAc 1 4 (Neu5Ac 2 3) -Gal -, and thus a GM2 epitope is created. The unsusceptible hydrolysis of the GM2 ganglioside with the implemation of GalNAc and the Neu5Ac could be due to the interaction between the GM2 epitope and the GM2 activator. This may make the GalNAc and the Neu5Ac approachable to sialidase and beta-hexosaminidase A [16].
The alpha chain is about 35 KB found on 14 exons. The sequence is close to that of the TATA and CAAT motifs that are usually involved in regulating transcription at the 5' end of the gene. There is a different transcriptional process which occurs at both the different alpha motifs causing a difference in the transcriptional process. The 3' exon consists of two different mRNA sequences that result in a dissimilar non-translated region on the exon. One of the exons of this gene sequences the alpha chain part that is deleted or mutated during the maturation stage of the enzyme [9]. This results in the domain to become non-functional as a precursor to Tay-Sachs disease.
Treatment
There are no treatments currently available to treat those affected with Tay-Sachs disease, aside from supportive measures. Treatments are being developed such as gene therapy, stem cell therapy, and enzyme replacement [1].
Prevention
There are a few methods to preventing, and possibly eliminating, Tay-Sachs disease. These involve genetic screening and selective abortion, partner selection, and embryo screening.
The genetic screening is simple. Carriers of Tay-Sachs disease can be detected through an enzyme assay test. As Tay-Sachs disease has a 25 percent chance of afflicting a newborn, if both parents are carriers, parents with this information can be given an opportunity to choose whether or not to conceive [18]. Doing early testing of the fetus can show whether or not the fetus is afflicted with Tay-Sachs disease. If it is selective abortion can be preformed, removing the fetus while it is in its early stages of development, minimizing harm to the mother [6].
Another method is embryo screening following in vitro fertilization. The embryos can be tested for Tay-Sachs disease. Those carrying Tay-Sachs disease can be removed and a healthy embryo can be implanted into the womb. This will result in an embryo with no risk of being afflicted with Tay-Sachs disease, and provide no risk for the parents to consider a possible abortion [22].
With these methods the possibility of having offspring affected with Tay-Sachs disease can be eliminated.

Conclusion
Tay-Sachs disease, in the most common form is a fatal genetic condition resulting in the death of neurons in the nervous system. The deficiency of hexosaminidase A causes a GM2 gangliosides to build-up in neural tissues of the brain. Progressive brain damage is a result of the lake of this vital enzyme. Both the alpha and beta subunits of beta-hexosaminidase A are needed for the ennzyme to degrade GM2 ganglioside into GM3 ganglioside. In the occurrence of a mutation as seen in TSD, GM2 gangliosides build up in the brain tissues due to the insufficient HEXA gene. In result the the beta 1,4 linked N-acetylhexosamine portion is not removed from the GM2 ganglioside. This causes serious consequences for the function of the nervous system. The defective gene for HEXA that occurs in TSD is on chromosome 15. There are 2 copies to this gene, so if one is healthy and the other is defective than the person is healthy, but is a carrier of the gene. If both parents pass the faulty gene to their child then the child will develop TSD. So if both parents are carriers of the gene the child with have a 50 percent chance of also being a carrier and a 25 percent chance of having the disease. There is no cure for this disease, nor is there an efficacious treatment. Scientists are working hard on finding a solution for a replacement therapy or transplantation therapy. As far as research has come, there has not yet been any successful outcome of reversing or slowing down the damage that occurs to the nervous system. Prevention and testing is the only dependable and preventative solution for Tay-Sachs disease.

Works Cited (Reference)
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[4] Gravel, Roy A., et al. "The GM2 Gangliosidoses." In The Metabolic and Molecular Bases of Inherited Diseases, 8th ed., Charles R. Scriver, Arthur L. Beaudet, William S. Sly and David Valle, eds. New York: McGraw-Hill, 2001.
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[7] Li, Yu-Teh, Su-Chen Li, and Et Al. “Structural Basis for the Resistance of Tay-Sachs Ganglioside GM2 to Enzymatic Degradation.” Journal of Biological Chemistry 274.15, 10014-10018 (Apr. 1999).
[8] Moe, MD, Paul G. & Tim A. Benke, MD, PhD (2005). "Neurologic & Muscular Disorders", Current Pediatric Diagnosis & Treatment, 17 th
[9] Neudorfer O, Pastores GM, Zeng BJ, Gianutsos J, Zaroff CM, Kolodny EH (2005). "Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients". Genetics in Medicine (2): 119-23
[10] Proia, R. L.; Soravia, E. “Organization of the gene encoding the human beta-hexosaminidase alpha-chain”. J. Biol. Chem. 262: 5677-5681, 1987.
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[12] “Stem Cells Act Through Multiple Mechanisms to Benefit Mice with Neurodegenerative Disease.” Burnham Institute for Medical Research. 27 Mar. 2007. 28 Nov. 2007 .
[13] Suzuki, Kunihiko. “The Genetic Lysosomal Diseases: Tay-Sachs Disease as the Prototype.” Mental Retardation and Developmental Disabilities Research Reviews 2.3 (Dec. 1998): 167-176.
[14] Tanaka, A.; Punnett, H. H.; Suzuki, K. “A new point mutation in the beta-hexosaminidase alpha subunit gene responsible for infantile Tay-Sachs disease in a non-Jewish Caucasian patient (a Kpn mutant).” Am. J. Hum. Genet. 47: 567-574, 1990.
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[18] “Tay Sachs Disease.” Mount Sinai Center for Jewish Genetic Diseases. 26 Nov. 2007 .
[19] “Tay-Sachs Disease.” Wikipedia. 28 Nov. 2007. 28 Nov. 2007 .
[20] “Tay-Sachs Disease Information Page.” National Institute of Neurological Disorders and Stroke (February 14, 2007). Retrieved on 2007-11-27
[21] Triggs-Raine, B. L.; Akerman, B. R.; Clarke, J. T. R.; Gravel, R. A. “Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.” Am. J. Hum. Genet. 49: 1041-1054, 1991.
[22] Weinstein, Lenore B. “Selected Genetic Disorders Affecting Ashkenazi Jewish Families.” Family & Community Health 30.1 (Fall 2007): 50-62.

[23] Willner JP, Grabowski GA, Gordon RE, Bender AN, and Desnick RJ (July 1981). "Chronic GM2 gangliosidosis masquerading as atypical Friedreich



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