Felician College
Advanced Clinical Pathophysiology
NURS 505
Dr. Tritak
November 14, 2015

“ I pledge my honor that I have neither given nor received inappropriate aid on this assignment”
Tay-Sach's Disease Disease and the deterioration it causes on the human existence is a tragic but inevitable phenomenon that man has dealt with throughout time. Death is unavoidable, yet the situation becomes evermore helpless when it strikes the young; the innocent who have not had their share of time, as is the case with a condition like Tay-Sachs disease. Fortunately, much childhood disease that plagued us for centuries has been eradicated due to the advances of modern science, and with the prospects of genetic technology today, the future is looking promising for those that have manage to elude scientists, like Tay-Sachs. However, Tay-Sachs is not a disease that can be considered in terms of science alone; it effects a unique ethnic population whose history and beliefs need to be considered in a sensitive manner. Tay-Sachs disease is a genetic disorder that is devastating in its deadliness.
This rare fatal disease is passed down through families. The disease’s hyphenated name is the result of two doctors, who worked independently of one another in the late 1800s. Dr. Warren Tay, an ophthalmologist, was the first to characterize one of the tell tale signs of the disease, the retina of the eye has a cherry red spot. A New York, neurologist, Dr. Bernard Sachs provided the first description of the biological mutations with Tay-Sachs disease. Tay-Sachs is a progressive neurodegenerative disorders. The individuals diagnosed with the disease experience a steady loss of the cell body in the central nervous system until the disease ends the patient’s life, usually before age five (Lew et al., 2014, p. 271). During brain development, in the early stages of life, gangliosides are naturally produced and broken down fast. Gangliosides, are found in the nerve cells and are a fatty substance that builds up in those who have Tay-Sachs. This accumulation causes the brain and spinal chord to destruct. Tay-Sachs sufferers lack Hexosaminidase A (Hex-A), which is protein that breaks down the gangliosides. This inability to produce Hex-A is what classifies the disease as a genetic disorder. In TSD, two copies of the abnormal gene are passed down, resulting from a mutation of the Hex-A on chromosome 15. TSD is one member of a group of metabolic disorders. One of the heterozygous genetic carriers is phenotypically normal. Both parents are carriers and 1:4 of pregnancies will be affected (Lew et al., 2014, p. 271). Tay-Sachs is part of a group classified as lysosomal storage disorders. Lysosomes contain approximately fifty various impaired enzymes that can break down proteins, DNA, RNA, sugars, and fats. Transfiguration in the genes that encrypt these enzymes are accredited to more than 30 various genetic disorders and diseases(Cooper, 2000). In these diseases, specific enzymes are affected in specific locations. These enzymes normally break down for reuse in the cells. If the enzymes are missing or malfunctioning, then the items build up and become toxic. In TSD the enzyme affects the brain. Tay-Sachs is actually one of the oldest known lysosomal diseases.
Scientifically, Tay-Sachs is known as a GM2 Gangliosidosis: Hexosaminidase alpha-subunit deficiency. Found on chromosome 15, the Gm2 gangliosides is impaired due to the Hex A deficiency, which is responsible for the -subunit of the enzyme, -Hexosaminidase A (Hex-A). Levels of severity in manifestation exist, from lethal childhood forms, to those compatible with survival into adulthood. The severity of manifestation has a positive correlation with the amount of residual Hex-A activity (Giraud et al., 2010, p. 599). As with other lysosomal hydrolases, Hex A, composed of and subunits in a 1:1 ratio, is synthesized through an intracellular pathway that involves the rough endoplasmic reticulum (ER), the ER lumen, and the Golgi apparatus which terminates in the lysosome, ready for secretion from the cell at the plasma membrane. Initial synthesis on the rough ER is propitiated through a hydrophobic distinctive peptide at the amino terminus of the and pro-polypeptides, which allows for translocation into the lumen of the ER. The signal is 22 amino acid residues long, and that of the consists of 42 amino acids. These signals are cleaved upon entry into the ER lumen, which allows translation to resume on both pro-polypeptide subunits. Once inside the lumen, through glycosylation on specific asparagine residues and formation of inter-polypeptide disulfide bonds, association of the and chains occurs (McManus & Mitchell, 2014, p. 882)
The specific targeting of lysosomal enzymes, including Hex A, to the lysosome requires generation of phosphomannosyl recognition markers, formed by the action of phsohotransferase in the late ER and cis0golgi apparatus. Of the four oligosaccharides side chains in the -subunit, the first and fourth are preferentially phosphorylated to the second and third. This phoshotransferase has a specific affinity for lysosomal enzymes, and does not phosphorylate other glycoproteins. This serves as a mechanism for segregating proteins destined for the lysosome and those destined for elsewhere. The affinity is suspected to be caused by a common protein domain shared by lysosomal proteins, which allows them to bind the phosphotransferase. The protein domains seem not to be associated with a specific amino acid sequence, instead the precise placement of a lysine residue is responsible (Sandhoff & Harzer, 2013). Once in the trans-Golgi network, Hex a combines with a mannose-6-phosphate receptor to form a complex to be moved to the lysosome. Clathrin-coated vesicles to a transient prelysosomal/late endosome compartment that fuses with, or becomes, through acidification, a lysosome, deliver this lysosomal protein/mannose-6-phosphate receptor complex. Dissociation of this receptor-ligand complex occurs due to the increased acidity of the organelle. The released receptors are reprocessed towards the plexus of the trans-Golgi, in order to transfer additional ligands (Neote, Mahuran, & Gravel, 1991). Once in the lysosome, Hex-A undergoes substantial proteolytic and glycosidic modification. In the subunit, the 67 kD precursor that enters the lysosome is processed to a 7 kD N-terminal segment and a 54kD “mature” polypeptide. This is accompanied by the removal of 16 amino acid residues at the interval between the two sequences. Meanwhile, the 63 kD subunit is cleaved into p, a, and b polypeptides, also with the removal internal sequences. The reason for the aforementioned process is in not biologically imperative, as precursor forms are catalytically active as well. It is possible that to some degree, the susceptibility due to the acrid inner climate, the debased enzyme, is unyielding but still useful for the function of the lysosome (Paw, Kabac, & Neufeld, 1989).(Marcus, 2012) The function of the product Hex-A is multifaceted. Hex-A cleaves the gycosidic bond of terminal -N-acetylglucosmaine or -N-acetylgalactosamine moieties of fylcoconjugates, including glydocipids, glycoproteins, and glycosaminoglycans. Hex-A also has the unique ability among hexosaminidases to utilize negatively charged substrates, including primary substrate Gm2 ganglioside. This characteristic is due to a unique binding site on the subunit capable of accommodating the negatively charged group of the substrate. With the presence of a water soluble, lipid binding protein cofactor known as the Gm2 activator, a 1:1 complex occurs with the bound ganglioside which render the entire Hex-A enzymatic complex water soluble. With this unique characteristic, Hex-A hydrolyses other naturally occurring subdivision, similar to terminal linked N-acetylglucosamine-6-sulfate encompassed in keratin sulfate, which other hydrolases are incapable of. In short, Hex-A is a integral moiety in normal neuronal function. Without a supply of functional Hex-A, Gm2 ganglioside cannot be hydrolyzed and therefore accumulates, leading the to the characteristic symptoms of Tay-Sachs disease, the severity of which correlates with the level of residual Hex-A activity (Sandhoff & Harzer, 2013). Clinically, TSD is associated with a wide range of onset and manifestation of symptoms. It usually appears in early childhood, but there are occasions of it occurring during childhood, adolescence, or adulthood. In the infantile form, the most common form, the toxic build up the Gm2 ganglioside is so severe that it causes damage to the nerves even before birth. The disease starts to take it toll and becomes apparent when the child is approximately 3 - 6 months of age. The early indications include psychomotor retardation, weakness, visual disturbances, and an heightened startle response. The child frequently will have doll-like facial features and a bright red blemish seen on the macula. The cherry speck is found on almost all cases of TSD. The disease is classically diagnosed by an eye examination or by behavior observation. Later onset forms take widely different courses, and are dominated by different courses of deterioration. Variants include: mental deterioration, and convulsions, cerebral breakdown, abnormal spino cerebral decline, unnatural motor and nerve disorders, muscle twitching , and discerning psychosis. There is still no cure for the disease. Treatment is determined by the needs to make the patient comfortable. Many patients will need respiratory care, because mucus accumulates in their lungs. Children with TSD are also at a higher risk for respiratory infections, again which can affect their lungs, and contribute to breathing issues. Hence, careful monitoring and prompt treatment are necessary. Those with the disease may also need a variety of assisted devices. For instance, a Nasogastric tube or a Percutaneous Esophago-Gastronomy tube, to aid is swallowing, nutrition, and medication taking. Many of these people will be on anti-seizure medications. Physical therapy may also be given to prevent muscle rigidity and help maintain range of motion. The disease is classically diagnosed by an eye examination or by behavior observation. Other forms of diagnosis have been developed as well, such as finding swollen neuron in the CNS or an enzyme test measuring levels of the hexosaminidase protein. Polymerase chain reaction (PCR), is another test that can be used for determining the disease. Dor Yeshorim (Hebrew for “the generation of the righteous”), is a program for Orthodox Jews that test community members for the more common Tay-Sachs mutations, in order to figure out if they are a carry of the disease. The Orthodox Jewish community, the ultimate source of Jewish law and interpretation of the scripture, relies on traditional use of biblical law and rabbinical responses to the questions raised concerning genetic issues. Historical Jewish scripture, the Bible and the Talmud being the paradigm, both contain genetic phenomena details. For example, the ancient text Mishneh Torah written by the Jewish scholar Maimonides in the middle ages goes into considerable depth about how and why it is prohibit to marry a female with a family history of seizures to avoid perpetuation of the illness to further generations. According to the 10th century scholar Rashi, any hereditary disease should be included in this prohibition (Rosner, 1995). This early proclamation most likely represents the first eugenic argument, almost a millennium before the recent controversy of the 1940s. Additionally, based on the greater amounts of flawed births from interfamilial unions, marriages amongst families were outlawed. The Jewish maintain laws regarding procreation, and do not feel that the risk of a genetic disorder is worthy enough to disobey the law. The Orthodox does not sanction abortion, so some prenatal testing may be frowned upon. The Dor Yeshorim sponsors the approach of confidential premarital screening, which is still commonplace in many Orthodox Jewish communities today. In 1983 Rabbi Eckstein, along with other community members established the Dor Yeshorim. Rabbi Eckstein had ten children, four of them afflicted with TSD. The goal of this group was to eliminate the disease from their community. Several acts were put into place through the group, including high school students (from their community) were tested to see if they were carriers or not. They were given a six-digit number to identify themselves. When members were thinking about dating and/or marriage, they were encourage to dial into the hotline, put in their number, then find out if based on their screening, they were compatible or incompatible. In 1993, eight thousand people were tested and eighty-seven of those couples changed their minds on marriage based on their compatibility results. Dor Yeshorim then expanded it service to Yeshiva University and sparked a controversy. It was felt that the population of the university was not a Chasidic population. Regardless of their morality, this group has been very effective. For Jewish communities to perform pre-implantation genetic screening of in vitro fertilized zygotes, those that were positive for the disease and discarded would not be thought of as an abortion .According to the Jewish law, the embryo is not viable until it is fixed to the uterus and thriving. Tay-Sachs disease is rare among the general population. French Canadians, Cajuns, and the Pennsylvanian Dutch have higher carrier rates than other ethnic groups (Strom et al., 2103, p. 61). That being said, it is most commonly thought of as a “Jewish Disease” The disease runs rampant in the Ashkenazi Jewish population. They have a carrier ration of 1:30. (Strom et al., 2103, p. 61). Often, it is said that the frequency of TSD in the Jewish population is directly related to the “founder effect” where “genetic disorders and mutations within a closely knit minority group are perpetuated over generations”. A concerted effort worldwide in the mid 197’s to identify the mutation responsible for the disease in the Ashkenazi population led to three separate, but simultaneous reports, that the mutation is at the donor splice site in intron 12. This mutation was shown to result in abnormal splicing, and thus instability in the mRNA. Without the normal mRNA, the -subunit cannot form properly, and thus the Hex-A loses it hydrolase function. More significant than the actual identification of the mutation was the remarkable discovery it was not the only one responsible for the infantile manifestation of the disease. It had been presumed that a single mutation was responsible, derived through a founder and the strict marriage practices of limiting partners to only other Jewish mates, and possibly perpetuated through a selective advantage among carriers. However, further research proved that TSD was more complicated than that. Three common mutations account for almost all of the mutations seen in the Ashkenazi Jewish Community (Curd et al., 2013, p. 139). The mutations are: a 4bp insertion in exon 11, the spice mutation in intron 12, and an amino acid substitution in exon 7. The first two together produce the infantile manifestation when the patient is homozygous for one or both of the first two mutations. The third mutation seen only in combination with one or both of the above two but never alone, produces the adult disease manifested in the second or third decade, even when heterozygous. After it was established that TSD was enzyme based, the reality that both an enzymatic diagnosis, and heterozygote deification was born . TSD became the first screening program on a community basis, hoping that the frequency of the disease would be eradicated or greatly reduced. The enzyme screening has accounted for a 90% decrease in new cases of TSD (Strom et al., 2103, p. 61-62). After the initiation of the population based screening, it was noted that certain unaffected individual who were tested, actually had Hex-A levels in the positive level. As a result, more mutations of specific DNA were identified, which are now known as pseudo deficiency alleles. Concluding that molecular testing is required for anyone thought to be a carrier. No matter what one’s race or ethnicity molecular testing is necessary. In addition, we know of five more mutations that result in a phenotype, known as B1 variant, where Hex-A shows standard or close enough to standard activity against the test substance, but are lacking in vivo against the normal substrate. As a result, individual heterozygous for this genotype will show may not have a positive result or equivocal, but they are in fact, still carriers for the disease. This also means, that there could be tragic results without further molecular testing(Strom et al., 2103, p. 62). The most significant non-genetic reason for mistaken genetic assessment is related to the hormones of pregnancy, or use of oral contraceptives. Often early-unexpected pregnancies, depending on the location of the genetic testing, account for the noteworthy number of screened. During pregnancy or oral contraceptive use, a placental type of hexosaminidase, Hex-P, appears. It contains both Hex-A and Hex-B properties. This isozyme has thermo ability proprieties the same as Hex-B, leading to the reduction of some of Hex-A . Therefore, pregnant woman are mistakenly diagnosed as carriers. An alternative enzyme-based procedure is available which involves preparing leukocytes and performing a thermal fractionation assay on cell supernatants, because this white blood cells makeup does not change with fertilization. This option is irrelevant with unplanned pregnancies. Additionally, the procedure can only be done manually and is very tedious and expensive, however, if a father tests positive, then the future mother will be tested. With such drawback and limitations to the enzyme -based assay, the scientific community of the 1980s longed for a more reliable method of TSD screening. With the advances in PCR technology and the initiation of the Human Genome Project this became a reality. DNA-based screening gives geneticists the opportunity to screen with little or no error, but it subsequently gave an efficient means to discover unheard of or unfamiliar TSD deviations. Through the use of PCR technology, the identification of a large number of mutant genes requires acquaintance of the array of the dosing part of the gene and the area of the exon-intron horizons. However, the background of the patient indicates the mutant alleles are most likely for them. For example, as discussed earlier, infantile Ashkenazi Jewish patients, the most frequent mutations are seen on the 4 bp insertion in exon 11 and the splice mutation in intron 12, which accounts for the majority of their cases. Meanwhile, the French Canadian patients, exhibit a 6 bp deletion in exon 5.Currently, the Hex-A locus has over 40 mutations identified , each corresponding to a different geographical location or ethnic group, though it must be emphasized that many of these cases are quite rare, and again, over 90% of those diagnosed are of Ashkenazi descent. With the above knowledge in mind, the common practice among geneticists is to test the patient’s DNA samples for an average of three of the most common alleles appropriate to the phenotype and/or the roots of the patient. To date, there has been no cure for Tay-Sachs disease. Research studies are constantly being done to look for a cure. Some of the potential areas of research are bone marrow transplant, enzyme replacement, and gene therapy. Currently on clinicaltrials.gov, there is a recruiting trial at Duke that is utilizing umbilical cord blood (UBC) transplant of inherited metabolic diseases with administration in intrathecal UBC derived Oligodendrocyte-like cells, with having Tay-Sachs part of the eligibility criteria. Duke has also performed several bone marrow transplants on TSD patients, with minimal success. Enzyme replacement therapy has also not met with much success. Unfortunately, relating to its size, the enzyme cannot cross the blood brain barrier. Researchers have also tried to inject cerebrospinal fluid, with the enzyme but again, the cells failed to engage the enzyme. Gene therapy could theoretically cure TSD if the defective genes in the brain were replaced. However, the transport of the genes into neurons would be as difficult, if not more, as transporting the enzymes. Viral vectors, which are currently at the cutting edge of Glioblastoma research, are also being researched to act as transporters of DNA. Pharmalogical treatments are also being studied. Tay-Sachs is as devastating as it is deadly. While to date, there has been no effective cure or treatment found, however, great strides have been made. Although there are still new cases being diagnosed, the numbers have been drastically reduced. Research is continually ongoing and scientists are pioneering breakthroughs to end this fatal and overwhelming disease.

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