Tay-Sachs Disease Tay-Sachs disease is a rare inherited autosomal recessive disorder first discovered in 1881. It is a disease that is found in many populations, but commonly affects the populations of the Ashkenazi Jews. The disorder is caused when there is an absence of enzyme called beta hexosaminase A that is found on chromosome 15.
The most common mutation occurs in mostly 80 percent of Tay-Sachs patients is the four base pair addition (TATC) on exon 11 and a G to C inversion at the splice Junction of intron 12 which leads to a miss spliced and causes the messenger RNA to be unstable; and G to A inversion on exon 7 of the hexosaminase A gene. The insertion of this base pair causes the codon to stop early which then causes a hexosaminase A deficiency (Amos Frisch). Tay-Sachs is a lethal disease. Tay-Sachs disease was first discovered in 1881.
The man who discovered this genetic disorder was an ophthalmologist named Warren Tay, whom lived 1843-1947. He is most renowned for the discovery in his research of Tay-Sachs and the appearance of a “cherry-red spot” on the retina in the eyes of those infected with the disease. This is where the “Tay’ in Tay-Sachs comes from. The “Sachs” in Tay-Sachs comes from Bernard Sachs, a man from New York who lived from 1858-1944. He was a neurologist working at Mount Sinai Hospital. In 1887, Bernard Sachs discovered that people infected with Tay-Sachs had characteristic cellular changes.
He is also famous for realizing Ashkenazi Jews, or Jewish Eastern Europeans, are more likely than the overall population to develop the disease. Tay and Sachs made the first important observations of this disease, yet this was during a time of little genetic understanding. In the 1970s, many realizations were being made about genetics. At this time, studies began being produced to further was discovered that the cause for the neurological deterioration by Tay-Sachs was due to a genetic mutation in the HEXA gene on chromosome fifteen.
This causes a dysfunction in Hexosaminidase-A enzymes, responsible for the degradation of N- acetyl-galactosamine from gangliosides of nerve cells. By the year 2000, over 100 different mutations in the HEXA gene were discovered. Since Bernard’s discoveries, scientists have found prevalence of Tay-Sachs in not only Ashkenazi Jews, but also Louisiana Cajuns, French people of Quebec, and Irish- Americans. Scientists theorize the gene mutation can be traced back to a French couple from the 1700s based off genetic samples.
Because of Tay-Sachs prevalence in the Jewish population, concerns have lead to something positive. Israel had become the first country to offer free genetic testing to citizens. Also, in 1969 the National Tay- Sachs and Allied Disease Association of Delaware Valley was established to bring more of the Jewish-American population into awareness for the disease, as well as offer help to families suffering from the tragedies of this fatal disease.
In the review ournal of “GM2 gangliosidoses databases: Allelic variation at the HEXA, HEXB, and GM2A gene loci”, three relational locus-specific databases recording allelic variation at the HEXA, HEXB, and GM2A genes were developed. The databases are available online for users to search and retrieve information about specific alleles by a number of fields describing mutations, phenotypes, or author(s). For the method, a software and search engine was constructed using a software call “Red Hat Linux v5. 1 operating system”. The results, includes the mutation table “which provides specific molecular information on mutations identified.
Each of the mutation has an ID which is then assigned by its order of entry, a systematic name, an alternative name as well as information on the nucleotide change, the mutation type, the nucleotide position, the region of the gene involved and a description of mRNA and protein phenotypes (Paulo Cordeiro, 200). Included in this database is also the information on the submitter. The phenotype table in the database is designed to give details on clinical and biochemical phenotype, age of onset, and genotype and the ethnicity of patients harboring specific mutations. Molecular diagnostic method is also in this table.
The olecular diagnostic method is used to detect the mutation. The phenotype table can be search from any fields. All the three databases have online submission of new mutations. The submitters are asked to provide data for all fields. In this review, the information concerning the mutations on the manifestations of disease, a feature that is used to view mapped positions of the selected HEXA mutations onto the homology-modeled hexosaminidase was also developed (Paulo Cordeiro, 200, p. 321). A TSD mutation database was also constructed which included information regarding allele frequencies and numbers of alleles screen annually.
In this database, mutation would be recorded separately for Ashkenazi Jews and other individuals. This form on the database would be used by labs that are conducting community base Tay Sachs carrier screenings. Concluding, the HEXA, HEXB and GM2A database were constructed to help assist in regrouping scattered information into a centralized locations. Tay-Sachs disease is also referred to as a lysosomal lipid storage disorder. Tay-Sachs belongs to a family of lysosomal storage disorders that also includes Gaucher’s, Sandhoff, and Niemann-Picks disease to name a few. These lysosomal lysosomal product.
In the case of Tay-Sachs, there is a marked deficiency in the lysosomal acid hydrolase, hexosaminidase A, more commonly known as HEXA. The HEXA gene is located on chromosome 15. Mutations on both of the alleles on the gene locus lead to the deficiency of the HEXA activity. Beta-hexosiminidase enzyme A is one of the three isoenzymes from the beta-hexosiminidase family. These isoenzymes are all comprised of different association patterns of the alpha-beta subunits. HEXA specifically is an alpha-beta heterodimer. HEXA is the gene that encodes for the alpha-subunit of the beta-hexosaminidase A enzymes.
The beta- hexosaminidase A enzymes is composed of an alpha-subunit and a beta-subunit. The beta-hexosaminidase enzyme A is found in lysosomal cells. Lysosomes are organelles that break down larger molecules into smaller basic monomers that the cell can easily use. When there is a mutation on the beta-hexosaminidase A enzymes, the consequences occur in the neuronal lysosomes, which affect the nervous system. The beta-hexosaminidase is apart of a complex that breaks down the lipid GM2 ganglioside; The gangliosides are a specific type of phospholipids known as sphingolipids.
A sphingolipid is a phospholipid that has a sphingosine backbone instead of the typical glycerol backbone. The deficit of HEXA also causes the accumulation of abnormal metabolic productivity, specifically the accumulation of GM2 ganglioside. Gangliosides play an important role in the development and later differentiation of the Central Nervous System. In addition, they also have a role in the maintenance of tissue and repair after inflicted injury of the brain tissue. If marked for degradation, GM2 gangliosides are hydrolyzed and converted into GM3 ganglioside.
The complex hydrolyzes the GM2 ganglioside by removing the beta 1,4- inked N-acetylexosamine residue remaining from the GM2 ganglioside. This complex pertains to the onset of Tay-Sachs specifically because the alpha-subunit, which is encoded for by HEXA is the complex that is specialized for the hydrolysis of lipids. If there is a mutation on the HEXA gene, further mutation will affect the alpha-subunit of the beta-hexosaminidase A enzymes. When no alpha-subunit is produced, this signifies that there is no complex that can be formed with the GM2 activator protein.
Without the formation of this complex, the GM2 is unable to degrade and convert into GM3, thus causing an accumulation in the lysosomes. The accumulation of GM2 ganglioside is localized in the cytoplasm of the neurons in the brain. This buildup may cause severe blockages in other cellular pathways. The GM2 will begin to bulge and eventually burst open, resulting in an apoptotic death of the neurons. The trauma experienced in the neurons of the brain leads to the cause of such lethal symptoms. The detrimental symptoms of Tay-Sachs are caused by the trauma of the neurons in the brain, due to the buildup of the GM2 ganglioside.
There are three different stages of Tay-Sachs, which are: infantile, Juvenile, and adult stage. The three ifferent levels arise depending on the residual HEXA activity levels; there are several alleles of HEXA that cause different these clinical syndromes (Triggs-Raine, Akerman, Clarke & Gravel, 1991). The most common from of Tay-Sachs is the infantile stage. The infantile stage is also highly lethal. In the infantile stage, infants will start to show symptoms as early as the first three to five months of infancy.
The distinct symptom that usually surfaces first is the infamous ‘cherry red spot’ that is seen on the retina these macular cherry red spots. Many other symptoms that unveil include evelopmental arrest, hyperacusis, blindness, intractable seizures, progressive neurological deterioration- the child will stop smiling, crawling, being able to turn, losing the acquired ability to grasp and reach, and losing the awareness of the surroundings (Triggs-Raine, Akerman, Clarke & Gravel, 1991). Many other symptoms may emerge, which may ultimately lead to death.
Children usually do not survive no more than the first five years of life. In the Juvenile form, symptoms become evident during the ages of two through ten years old. Symptoms of the Juvenile form include he loss of coordination, deterioration in speech, cognition, and motor skills, seizures, vision loss, and progressive dementia. The adult stage of Tay-Sachs disease usually includes progressive motor and mental impairment. Abnormal findings in the adult stage of Tay-Sachs include symptoms such as personality changes, depression, and psychosis.
Tay-Sachs disease is also recognized as an autosomal recessive disorder. An autosomal recessive disorder means that the gene that is being affect is located on one of the autosomal chromosome pairs from 1-22. For this particular disease, the affected chromosome is chromosome 15. An autosomal recessive disorder is one that follows an autosomal recessive inheritance pattern. This particular inheritance pattern signifies that in order for the disease to have an affect, possibly lethal, the progeny must inherit two “faulty’ copies of the gene from both of the parents.
Recessive means that two copies of the gene are needed for the child to have the trait. An autosomal recessive trait would at time be expressed in equal frequency in both sexes. However, the traits can only appear when the affected individual has received the faulty allele from each parent. In the chart, one can have two eterozygous parents, which means they are carriers that pass down the gene to their children. In this case, only one out of four (25%) would have the disease while two out of four would likely have a 50% chance of having the traits but will not have the disease they would be heterozygous.
In addition, one out of four would be a non- carrier this child would be homozygous. However, if only one parent is carrying the gene there would be a 50/50 percent chance that two out of the four children are non-carriers and the other two are genetic carriers (LEWI). HEXA gene mutation, some scientists believe there are possible benefits to being a eterozygous carrier of a Tay-Sachs disease allele. In the 1960s through 1970s, scientists argued that the prevalence of carriers of Tay-Sachs disease in the Ashkenazi Jews population was due to overdominance.
Overdominance is a hypothesis that states crossing of inbred strains results in combinations of alleles that are beneficial to heterozygotes. This can then result in the survival of alleles that are harmful for homozygous carriers. Scientists at this time saw how overdominance was the reason why the sickle cell anemia allele was prevalent in populations where malaria was common. Carrying this allele helped a person survive with malaria longer than a person who did not carry this allele. Scientists therefore applied this same concept to heterozygous carriers of Tay-Sachs disease.
In the 1970s through 1980s, scientists questioned whether heterozygous carriers of Tay-Sachs disease had an advantage over non-carriers when it comes to the survival of tuberculosis. The reason scientists questioned this was because the Ashkenazi Jews are descendants from populations that were forced to live in crowded ghettos. Because of the unhygienic living conditions and crowdedness in these hettos, tuberculosis spread like wildfire. Survivors of these conditions were thought to have an advantage by carrying the Tay-Sachs affected fifteenth chromosome.
Yet since then, a few statistical studies showed that grandparents of the known affected allele carriers were Just as likely to die from tuberculosis as the grandparents of those who were non-allele carriers. More recently, scientists began to theorize a new possible advantage of being a heterozygous carrier of a Tay-Sachs disease allele. Some scientists theorize heterozygous carriers of lipid storage diseases, such as Tay-Sachs, have genes that ay improve dendrite growth. They believe this type of dendrite growth increases intelligence.
Increased intelligence would have been a selective advantage because the Ashkenazi Jews were only allowed to have intellectual occupations at that time. Recently, scientists have been focusing on the theory of the founder effect. They theorize that the high frequency of the HEXA gene mutation is actually a result of genetic drift, caused from population bottlenecking. There is another theory among scientists for the prevalence of the Tay-Sachs allele among the Ashkenazi Jews. They ay it could stem from parents losing a child because they are infected and die from Tay-Sachs, and then they try to compensate by producing many more children.
In the research paper, “Origin and Spread of the 1278insTATC Mutation Causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis,” it was concluded that the 1278insTATC mutations is the most widespread mutation on the beta-hexosaminidase gene that causes Tay-Sachs disease. Tay-Sachs disease is a lysosomal storage disease that occurs quite often amongst the Ashkenazi Jewish population. In order to investigate this particular genetic history, a sample size of 55 individuals was used, in order to try to locate the 1278insTATC chromosome.
The 1278insTATC mutation was detected in the DNA samples using a polymerase chain reaction amplification and a heteroduplex analysis that followed the Shore and Myerowitz methods. An approach for analysis entailed for the analysis of the linkage disequilibrium between the flanking polymorphic dimension for when the mutation surfaced, sometime during the 8th and 9th century. Based on the geographic distribution of the Ashkenazi Jews at the time, it is rgued that the 1278insTATC is also consistent with this movement, originating from one ancestral chromosome.
Based on this argument, it is highly suggested that the mechanism behind this occurrence is founder’s effect. In response to the earlier mentioned review paper, the techniques of the former have profusely advanced. With the aid of online databases, one is able to “book keep” all the specified details that in turn are needed for analysis of genetics and genetic diseases. Unfortunately, there is currently no cure for Tay-Sachs disease. The major hindrance that impedes the opportunity for effective treatment of Tay-Sachs is the ossibility of penetration the blood-brain barrier with the interference of potential therapeutic agents.
Some methods of treatment that are currently being worked on include enzyme replacement therapy and substrate deprivation therapy (Tandon, 2002). The objective of enzyme replacement therapy is to clear the accumulated GM2 gangliosides. In the enzyme replace method, the goal is to replace HEXA. One approach involves using viral vectors. These viral vectors are able to deliver a particular gene to the host cell via cell surface receptors. The virus will then use the ellular apparatus of the host cell in order to replicate its own genome, which carries the “wild type alpha-subunit” (Tandon, 2002).
This “wild type” would potentially permit a functional HEX A to form and clear the GM2 ganglioside. Another approach to enzyme replacement therapy is by the means of using neural progenitor cells. The idea behind the progenitor cells is to produce stem cells that are able to produce regenerating clones of cells. These genetically engineered cells would possibly be able to create and express new functioning HEX A. Another option in terms of treatment methods includes substrate deprivation herapy. Its objective is to regulate and decrease the amount of the GM2 ganglioside substrate that is being synthesized.
In Tay-Sachs, this approach would reduce the biosynthesis of the gangliosides in order to match the altered rate of catabolism (Tandon, 2002). Amos Frisch, R. C. (1993). Mutations of the Hexosaminidase A GENE in Ashkenazi and Non-Askkenazi Jews. Biochemical Medicine and Metabolic Biology, 22. Barlow-Stewart, K. (2007). Tay-sachs disease and other conditions more common in the ashkenazi Jewish community. Retrieved from http://www. genetics. edu. au Greenberg, D. A. & Kaback, M. M. (1982). Estimation of the frequency of hexosaminidase a variant alleles in the american Jewish population.
LEWI, D. (2011, September 8). What is autosomal recessive inheritance. Retrieved from Cats- foundation: http://www. cats-foundation. org/blogs/what-is-autosomal-recessive- inheritance/ Lloyd, Emma. Bright Hub, The History of Tay-Sachs Disease. 26 July 2010. Myrianthopoulos, N. C. , & Aronson, S. M. (n. d. ). Population dynamics of tay-sachs disease. i. reproductive fitness and selection. ” “. National Tay-Sachs and Allied Diseases. “-“. News Medical. November 2012. ” “. National Tay-Sachs and Allied Diseases Association of Delaware Valley. Navone, Nicole.
Flipper e Nuvola. June 2010 Paulo Cordeiro, P. H. (200). The GM2 gangliosidoses databases: Allelic variation at the HEXA, HEXB and GM2A loci. Genetics Medicine, 321. Tandon , A. (2002). Therapeutic options for tay-sachs disease. The Einstein Quarterly Journal of Biology and Medicine, Triggs-Raine, B. L. , Akerman, B. R. , Clarke, J. T. R. , & Gravel, R. A. (1991). Sequence of dna flanking the exons of the hexa gene, and identification of mutations in tay-sachs disease. Willicx. Division of Genetics and Metabolism, University of Florida. 18 September 2011.