Tay-Sachs+Disease

. __Tay-Sachs__ Tay-Sachs is an autosomal recessive disease (Mitchell, Capua, Clow, & Scriver, 1996). The disease is passed from parent to offspring when each parent passes the defective Tay-Sachs gene to their child. This gene is carried on chromosome 15 which is responsible for the production of hexosaminidase A. Hexosaminidase A is a protein that breaks down gangliosides. In the absence of this protein the gangliosides will build up in the nerve cells of the brain causing damage to the neurons. Tay-Sachs is a disease that is most prevalent in the Ashkenazi Jewish population (Tay-Sachs Disease, 2010).

Tay-Sachs is found in three different forms: common infantile, juvenile, and late onset. Infantile Tay-Sachs is the most common of the forms. At birth, the child appears normal and develops normally for about the first six months. Around six months is when the earliest symptoms arise and the child’s growth begins to slow. Over time the child losses motor functions one by one. By the age of two, the child has seizures and has lost most, if not all ,muscle and mental function. With this form, a child does not normally live past the age of five. Juvenile Tay-Sachs exhibits the same symptoms of the infantile form, except the age of on set is later in childhood. With this form, the earlier the first symptom appears the more quickly the disease progresses. This is still lethal within a few years of diagnosis. Late onset Tay-Sachs is diagnosed much later in life. With this form, mental health signs are normally the first to occur. Late onset Tay-Sachs is very rare and hard for most doctors to diagnose. This disease, like the two other forms, shortens life drastically (National Tay-Sachs and Allied Diseases).

__Symptoms__ • Deafness • Decreased eye contact/blindness • Loss of muscle strength • Delayed mental and social skills • Dementia • Increased startle reaction • Irritability • Listlessness • Loss of motor skills and coordination • Paralysis • Seizures • Slow growth Since there is no cure or well developed treatment of Tay-Sachs disease, it is very important to try and manage symptoms as much as possible, either to prolong life or just simply as comfort measures. (Tay-Sachs Disease, 2010) __Genetic Causes__ Tay-Sachs disease originates from a defect on a gene located on chromosome 15. Its exact cytogenic location is 15q24.1 as shown in figure 1. This gene codes for an enzyme called hexosaminidase-A or Hex-A (National Human Genome Research Institute, 2011). This Hex-A gene provides the code for the alpha subunit, which in turn attaches to a beta subunit to create a larger enzyme known as Beta-hexosaminidase A. This enzyme is essential in the central nervous system. It is found in the lysosomes of cells, which help to breakdown unwanted substances in the cells. Beta-hexosaminidase A functions in lysosomes to break down the fatty substance GM2 ganglioside. In Tay Sachs patients, the Hex-A is non-functional. This means that lysosomes, especially in the central nervous system are unable to breakdown GM2 ganglioside. This fatty matter builds up in the cell until it reaches a toxic level. Damage caused by the buildup of GM2 ganglioside eventually causes the destruction of the central nervous cells (US National Library of Medicine, 2008).

There are over 120 mutations that can occur in the Hex-A gene that cause Tay-Sachs disease. Some of these mutations are lethal mutations that can completely shut down the creation of the enzyme beta-hexosaminidase A. These mutations cause the infantile and juvenile forms of Tay-Sachs, which causes symptoms as early as six months and result in death within the first five years of life. Other mutations only reduce the functions of the enzyme beta-hexosaminidase A. These types of mutations are much rarer and result in late-onset Tay-Sachs disease (US National Library of Medicine, 2008).

Tay-Sachs disease is a recessive trait. Every person has two copies of the Hex A gene. A person with two non-mutated forms is a normal individual. A person with one normal and one mutated gene is phenotypically normal but is genetically said to be a carrier of the disease. A person with two mutated alleles has Tay-Sachs disease. As in any inherited trait, a person receives one allele form their mother and one from their father. Hex A mutations that cause Tay Sachs follow a mendelian inheritance pattern. This means if two people who are both carriers have a child they will have a 25 percent chance of a child with two normal alleles, a 50 percent chance of a child with only one mutated allele (a carrier), and a 25 percent chance of having a child with Tay-Sachs disease. This pattern is shown in figure 2. This is why it is so important for people at a high risk of being a carrier to be genetically tested before having children (National Tay-Sachs and Allied Disease Association of Delaware, 2006).

__ Victims of Tay-Sachs __ Tay-Sachs disease affects a large portion of the Ashkenazi Jewish population. Ashkenazi Jews are those who have ancestors from Eastern and Central Europe. There are two big reasons as to why Tay-Sachs affects so many Ashkenazi Jews. The first reason is known as the Founder Effect which is when a population is created by a small number of individuals. Most of today’s Ashkenazi Jews all originated from the same group of about a thousand Jews who lived in Eastern Europe a few hundred years ago. Therefore, if a few of the original founders of that population had a mutation, that defect would become amplified in the future generations and infect many more individuals. The second reason is due to genetic drift, which is where the inheritance of a particular gene is enhanced through random chance instead of natural selection. This explains why some non-beneficial genes have lasted through evolution. Also, due to political and religious reasons, the Ashkenazi Jews were isolated from the rest of that geographical population. This would lead to inbreeding among the Jewish race allowing for the mutated Tay-Sachs gene to be passed on through to their children (Katz). Ashkenazi Jew is not the only race that is affected by Tay-Sachs. One out of every twenty-seven Ashkenazi Jews is a carrier, but this rate is the same for French Canadians and Louisiana Cajuns. The Pennsylvania Dutch population is also highly effected by this mutated gene (Weiss).

__ Treatment and Prevention __ There is no definite cure for Tay - Sachs disease; however, there are ways to prevent it from occurring. There are on-going research projects that include stem cell research, gene therapy and medications to help find ways of preventing this disease. The main type of prevention is the genetic testing of individuals who may be carriers for Tay-Sachs (Weiss). A recommended test for preventing this disease is screening for the HEXA mutation. This test is simple and can use blood, saliva, or sweat. Couples in the high risk groups that are considering having children should both be tested to see if they are carriers for Tay-Sachs. If they both test positive, they would have a 25 percent chance of having a baby who develops this disease (NHS choices). Tay-Sachs disease causes inflammation and storage of GM2 gangliosides in the central nervous system. This can cause problems for attempts at treatment. Scientists have experimented with mice infected with the Sandoff disease, a disease with a similar cause to Tay-Sachs, by treating them with allogeneic bone marrow transplants. This treatment prolonged the life of the effected mice but did not cure the disease. However, this treatment was not as successful in humans with Tay-Sachs. Another experiment was conducted by delivering gene therapy directly to the brain. This therapy reduced the amount of storage and inflammation significantly and prolonged the lifespan of the person. However, it again did not cure that individual of Tay-Sachs and the symptoms eventually returned (Gonzalez, Wang, Lynch, Ziegler, Cheng, Cox).

__Current Research going on in Tay-Sachs__ Tay-Sachs disease can be tested for by doing a screening with Hexosamidase A or Hex A serum. The individual being tested will show a defiency in the HEX A gene. This has cut the occurances of Tays-Sachs in infants by 90% (Schneider et al., 2009). Experimental gene therapy in mice is now being used to try to find a cure for a disease closely related to Tay-Sachs called Sandhoff's disease. It is also a deficiency in Hex A. This gene therapy is being done on mice that have Sandhoff's which means they lack the function of the Hex beta subunit. This experimentation prolonged the lives of these mice, but not by much as none of them lived past five months. The gene therapy is delivered directly to the brain. This was shown to delay the onset of negative effects of Tay-Sachs. However the treatment did not rid the body of Tay-Sachs. One case of Tay-Sachs involving a young girl has reasearchers looking closer. She was experiencing extreme effects of Tay-Sachs. By the age of 14 months, her white matter and basal nuclei showed mildly high signal intensity and her thalamus showed low intensity. These effects are being considered to be the result of accumulation of Gm2 ganglioside within the cytoplasm of the neurons. The neurons that are being infected are located in the basal ganglia and the cerebral cortex (Hagase et al., 2009). These new discoveries and advances in research of the disease will only better the chances for a treatment or cure. Studying effects like these will also help lead to better prevention methods.

Other research topics that are found on The Cure Tay-Sachs foundation website are: cord blood transplants,chaperone therapy, stem cell therapy, and enzyme replacement. Cord blood transplant has the goal of bringing in new Hex-A blood into the brain. Chaperone therapy is the use of human created molecules that allow for better absorption of the mutated Hex-A. Stem cell theory is hoping that stem cells can help create new Hex A genes. The last reserach that is being worked on is Enzyme replacement. This theory is close to stem cell theory, it is having trouble crossing the blood brain barrier (Pusateri, 2007). =Bibliography=

Cachon-Gonzalez, Begona M., Wang, Susan Z., Lynch, Andrew, Ziegler, Robin, Cheng, Seng H., Cox, Timothy M. “Effective Gene Therapy in an Authentic Model of Tay-Sachs-Related Diseases.” PNAS. 103-27 (2006): 10373-10378.

Hagase, T., Shimizu, J., Goto, T., Yasuyuki, N., Mori, M., Takahashi, N., Namba, E., Yamagat, T., and Momoi, M.Y. (2009). Unilaterally and rapidly progressing white matter lesion and elevated cytokines in a patient with Tay-Sachs disease. //Brain and Development.// (32)3. []

Katz, Lisa. "Jewish Genetic Disorders." //About.com Judaism//. Web. 03 Apr. 2012. [].

Mitchell, J. J., Capua, A., Clow, C., & Scriver, C. R. (1996, 7 10). //Twenty-Year Outcome Analysis of Genetic Screening Programs for Tay-Sachs and 3-Thalassemia Disease Carriers in High Schools//. Retrieved 4 1, 2012, from [] //National Human Genome Research Institute.// (2011, March 17). Retrieved April 1, 2012, from [|http://www.genome.gov/page.cfm?pageID=10001220#NHGRI]

//National Tay-Sachs and Allied Disease Association of Delaware.// (2006). Retrieved April 2, 2012, from Tay-Sachs Disease: []

//National Tay-Sachs and Allied Diseases.// (n.d.). Retrieved April 3, 2012, from []

Pusateri, Michael. (2007). "The Cure Tay-Sach Foundation." Retrieved April 5, 2012. []

Schneider, A., Nakagawa, S., Keep, R., Dorsainville, D., Charrow, J., Aleck, K., Hoffman, J., Minkoff, S., Finegold, D., Sun, W., Spencer, A., Lebow, J., Zhan, J., Apfelroth, S., Schreiber-Agus, N., and Gross, S. (2009). Population-based Tay-Sachs screening among Ashkenazi Jewish young adults in the 21st Century: Hexosaminidase A enzyme assay is essential for accurate testing. //American Journal of Medical Genetics Part A// 149A:2444 – 24 "Tay-Sachs Disease - PreventionÂ ." //Tay-Sachs Disease//. Web. 26 Mar. 2012. []. //Tay-Sachs Disease//. (2010, 11 17). Retrieved 4 1, 2012, from PubMed Health: [] //US National Library of Medicine.// (2008, September). Retrieved April 1, 2012, from Genetics Home References: [].

Weiss, Robin E. "Tay-SachsÂ Disease." //About.com Pregnancy & Childbirth//. Web. 26 Mar. 2012. [].