Medical Anthropology Paper-Tay Sachs Disease Essay Example

Medical Anthropology Paper Medical Anthropology Paper-Tay Sachs Disease Paper Medical Anthropology Paper-Tay Sachs Disease Paper A normal infant has the ability to develop healthy motor functions due to the synthesis of certain enzymes vital for clearing harmful materials that can interrupt the growth process. However, babies that inherit the gene coding for Tay-Sachs disease experience motor function disorders. Tay-Sachs disease is a rare genetic disorder inherited by individuals that causes the degradation of their central nervous system. This condition is not treatable. Moreover, it progresses continuously from infancy until early childhood, a point where the patient fails to survive. The disease occurs within a defined population, commonly found among eastern European Ashkenazi Jews. The said disorder results from genetic mutations whose effects are manifested from infancy and are highly fatal for affected babies. In addition, it is acquired through genetic inheritance and is detectable prior the childs birth (Lowden 575). The disease is due to a mutation at chromosome number 15 which results in a dysfunction of the lysosomal enzyme acid hydrolase. Deficiency of Beta Hexosaminidase A is characteristic among afflicted patients. This enzymatic absence can be attributed to the occurrence of a founder effect, which accounts for the unusually high frequency of an allele that is an identical copy carried by the individual who founded the population (Slatkin 282). Currently, there are neither treatments nor drugs that would cure Tay-Sachs disease. However, studies have shown that it is possible to prevent the manifestation of Tay-Sachs among potential patients. This leads to the interests of researchers in screening for the probability of passing this disease from heterozygous parents to offspring (Lowden 575). History The disease derived its name from a British ophthalmologist named Warren Tay (1843-1927) and an American neurologist named Bernard Sachs (1858-1944). Tay first provided the characteristic description of retinal cherry-red spot in the eyes while Sachs provided the earliest descriptions of the cellular modifications occurring among afflicted patients. It was also Sachs who first concluded that this disorder is acquired through inheritance from parental genes through studies conducted among numerous patients. His research revealed that this disease notably occurs among Ashkenazi Jews of Eastern European origin (www. ntsad. org). In the year 1900, Sachs collaborated with Dr. Isadore Strauss, who then served as Mount Sinais director of pathology. Their concerted work provided additional descriptions of Tay-Sachs patients, which included observations on the diseases neuropathology. By the middle part of the 1920s decade, Mount Sinai Hospital had finally established a laboratory for neuropathological studies headed by Dr. Joseph Globus. Through this program, scientists were able to identify that autonomic neurons in bowel mucosa are involved. This was used as a diagnostic test, as direct enzymatic assays were not yet discovered. These observations were highly used in determining Tay-Sachs cases and other associated genetic disorder â€Å"through the use of morphological studies of rectal biopsies† (Desnick and Kaback 18). Succeeding years relatively added few descriptions on the morphology of Tay-Sachs disease. But with the onset of the electron microscope during the 1960s, Terry and Korey were able to find numerous bodies bounded by membranes in the cytoplasm of neurons of patients with Tay-Sachs disease. The researchers used a formalin fixed brain specimen, where the tissues were poorly preserved. But the granular bodies that they detected were consistent with brain tissues that were not previously fixed in formalin but immediately placed in a frozen state. In 1963, Terry collaborated with a researcher named Weiss and their studies revealed that the disease is characterized by these granular bodies in the neuronal cytoplasm. Their research team discovered the nature of the lipids that accumulate within neurons, microglial cells, and pericytes. According to their biochemical findings, these deposits possess a ganglioside nature (Desnick and Kaback, 22). Also during the 1960s, an enzyme assay test was developed by Kaback in order to screen heterozygous individuals carrying the allele for Tay-Sachs disease. This test was proven reliable, as it statistically demonstrates low percentage of errors and false positives. The test historically started the determination of potential genetic diseases among offspring. This is essential in preventing diseases and eventually leading to close eradication of the disease among Ashkenazi Jews. Now, it is possible to identify whether couples are at risk in having a child afflicted with the disease (Kaback 255). These efforts of Kaback, together with his team, led to the mass screening of potential disorders among individuals. This program was carefully organized and on May of 1971, approximately 18, 000 adults with Ashkenazi Jewish descent volunteered to be screened for possible heterozygosity. The said screening proved efficient and accurate in determining populations which are potentially at risk. In addition, the screening lasted and from 1969 until 1998, a total of 48,864 heterozygotes were already screened (Kaback 256). Clinical Description The degree of severity of Tay-Sachs manifestation can vary depending on the type of disease. An autosomal recessive disease, Tay-Sachs can cause â€Å"paralysis, dementia, and early death to a chronic adult form† (Genes and Disease 23). These adults afflicted by Tay-Sachs typically manifest psychosis and even neural dysfunction (Genes and Disease 23). Other manifestations of this disease include blindness and deafness early in life. Babies born with Tay-Sachs disease may develop normally during their first 3-6 months, but would eventually deteriorate mentally. They experience delay in mental progression as they experience loss of motor abilities. By the end of their first 12 months, patients rapidly regress mentally and physically. They are exposed to complications in swallowing, as well as in chest, and lung functions (Hauser 2171). Symptoms of this disease include cherry-red macular spots (see Figure 1), or a highly pronounced macular fovea centralis, and an enlarged heart. Babies with this genetic disorder experience disabled motor skills as they could poorly manage to control their heads, fail to crawl, sit and develop visual attention. They also characteristically assume a position that resembles those of frogs. Babies, supposedly at the stage of rapid development, lose their ability to maintain focus and eye contact, when Tay-Sachs starts to manifest. They also exhibit declining environmental interactions while gradually becoming unresponsive. They also develop inattention towards external stimuli until they reach a state that otherwise described vegetative. Hyperacusis, seizure, and macrocephaly are typical of Tay-Sachs disease (Kasper et al. 2318; lysosomallearning. com). There are three forms of Tay-Sachs disease. This includes the classic infantile, the juvenile form, and the adult form. Infants afflicted with Tay-Sachs do not produce Hexosaminidase A, while adults with this disease produce minimal enzymatic levels. Babies born with this disease experience both paralysis and muscle atrophy by six months of age and do not survive longer than five years. Most common ages when children manifest juvenile Tay-Sachs disease are those from 2 to 10 years old. The symptoms of patients are comparable to those with classic infantile form, but with a slower process. They develop dysarthria or speech problems, dysphagia or swallowing complications, ataxia or imbalance, and even spasticity. Patients generally die by their 15th year of age. The effects of the adult version are relatively milder than the classic infantile form, which attributes to their late onset in life. These individuals are otherwise known to possess chronic Tay-Sachs disease. Those with the adult-onset Tay-Sachs disease usually manifest symptoms by their adolescent stage, but it is also possible that these appear during childhood. Unlike babies with Tay-Sachs disease, adults with this disease do not experience blindness or deafness. Although the motor abilities are not completely degenerated, these individuals continuously experience mental weaknesses, including comprehension and memory problems. But different cases present various severity, as some can exhibit â€Å"slurred speech, muscle weakness, muscle cramps, tremors, unsteady gait and sometimes mental illness† (marchofdimes. com). Persons afflicted vary in life expectancy and some may not even to demonstrate the disease. Doctors determining the presence of this disease in individuals must consider investigating the following. Erythrocyte content of both carriers and afflicted individuals are considerably lower concentrations of sphingomyelin. Also, using the enzyme assay, serum or other cell cultures without or with less activities of Hexosaminidase A are a significant consideration. If these tests demonstrate abnormalities, then a DNA analysis must immediately be conducted. This is highly beneficial in determining other members of the family that are heterozygotes for this disorder. This has important implications in child-bearing options of couples and in diagnosing the disease prior a child’s birth. MRI are also commonly used in searching for cerebellar atrophy while electromyelogram is also used in detecting denervation and reinnvervation in individuals with adult-onset of this disease (Tidy; Zaroff 2283). Pathogenesis The most essential organelle involved in Tay-Sachs disease is the lysosome. The biogenesis of this organelle is comprised of different steps synthesizing the following: lysosomal hydrolases, membrane constitutive proteins, and new membranes. The formation of lysosomes is initiated by the fusion of trans-golgi network and late endosomes. With the acidification of vesicles in progression, trans-Golgi network vesicles develop towards maturity. This process creates a gradient that promotes the facilitation of ligand and receptor dissociation. This is highly dependent on the pH levels of the system. Here, lysosomal hydrolases are also activated (Kasper 2318). Any form of interference or abnormalities in these steps of lysosomal biogenesis could result to enzymatic impairment and lead to lysosomal storage disorder. â€Å"Following leader sequence clipping, complex oligosaccharide modification occur during transit through the Golgi, including the mannose-6-phosphate modification of high-mannose oligosaccharide chains of many soluble lysosomal hydrolases† (Kasper 2318). Using various kinds of signals, the lysosomal integral or associated membrane proteins are sorted to the membrane or interior of the lysosome. Concurrently, other processes occur such as phosphorylation, sulfation, proteolytic processing, and macromolecular assembly of heteromers. These are all very crucial steps to ensure the normal functioning of enzymes. Defects of these processes could lead to multiple enzyme or protein deficiencies (Kasper 2318). These mentioned steps are all common for lysosomal storage diseases. But the final pathway is when particular macromolecules, under normal circumstances have high flux of these substrates, within tissues and cells accumulate. When enzymatic deficiency occurs, the most common and major cause are point mutations or genetic rearrangements at a locus that encodes a single lysosomal hydrolase (Kasper 2318). These consequently result in diseases that are passed on from one generation to another. An example of lysosomal storage disorder is the Tay-Sachs disease. This complication is considered an autosomal recessive disorder that is acquired through genetic inheritance. A lysosomal acid hydrolase, ? -N-Hexosaminidase A is a heterodimer composed of alpha and beta subunits. A point mutation occurring at the ? -chain subunit results in an enzymatic deficiency of ? -N-Hexosaminidase A (Myerowitz 3955). The disorders that arise from the mutation of the alpha subunit cause the dysfunction of ? -N-Hexosaminidase A activity. This also includes the abolition of the alpha and beta isozyme activities through the action of the remaining beta subunit (see Figure 2). Tay-Sachs disease is described as one of the earliest versions of human genetic sphingolipidoses where patients suffer from the accumulation of GM2-monosialoganglioside in neurons due to the mentioned ? -N-Hexosaminidase A deficiency (Ohno and Suzuki 18563). The comparison between a healthy neuron and a neuron affected by Tay-Sachs disease is illustrated in Figure 3. The abnormality of the ? -subunit can be attributed to the major deletion found at the 5 end of the gene coding for ? -N-Hexosaminidase A ? chain. It was also discovered that in the coding sequences of ? subunits in relatively mature stages, point mutations occur that consequently result to the synthesis of unique enzymes of GM2-gangliosidosis. In cases of Ashkenazi Jews, patients were observed to possess splicing defects located at the 5 end, where intron 12 is usually donated. This splicing complication was described by employing methods such as cloning, genomic sequencing, and identification of abnormal cDNAs (Ohno and Suzuki 18563). Tay-Sachs is actually a â€Å"group of disorders† (Myerowitz 3955) with varying degree of severity and biochemical parameters. Severity ranges from mild to fatal while the parameters include â€Å"residual enzyme activity, immunoprecipitable ? -chain polypeptide, and detectable ? -chain mRNA† (Myerowitz 3955). These mentioned variations are part of differential ? -chain genetic lesions. In the case of Ashkenazi Jews, this disease has a single clinical course that leads to early childhood death and same biochemical profiles. Scientists hypothesized that the severe form of this disease is caused by a single mutation (Myerowitz 3955). It has been established that Tay-Sachs is the result of accumulation of Ganglioside GM2 due to the cells inability to degrade these granular bodies. In the absence of GM2 activator protein, â€Å" the GalNAc and NeuAc in GM2 are refractory to hexosaminidase A and sialidase respectively† (Li et al. 10014). In the study, it was found that in analyzing the conformatino of these GM2, a rigid and compact structure of the oligosaccharide head group was revealed. This is concluded to be the factor responsible for the resistance of GM2 from degradation or enzymatic hydrolysis (Li et al. 10014). All these abnormal processes are primarily attributable to mutations that occur on chromosome 15. Mutations include insertions and deletions of different base pairs, splice site mutations, point mutations, and other forms. With every modification resulting from mutation processes result in the alteration of the protein or enzymatic product, which causes the inhibition of its function. One of the most commonly observed and noted mutations are those of the Ashkenazi Jews where four base pairs are inserted in exon 11. The result is the classic infantile Tay-Sachs disease that can also be found in other ethnicities (Ohno 18563). Etiology This disease is commonly passed on from carrier parents to their offspring. Children that possess both alleles for Tay-Sachs manifest and suffer from the disease. The human body is composed of 23 pairs of chromosomes, therefore 46 chromosomes in total. These chromosomes contain genetic instructions that always come in pairs, from both maternal and paternal inheritance. But when these genes experience alterations or any form of modification, a mutation occurs and the gene loses its normal functions. Since each individual has two chromosomes, those with only one copy of the dysfunctional gene will be able to continue to function correctly as the normal gene would compensate for the impairment of the other. But if an individual acquires two recessive alleles, the individual will manifest the symptoms characteristic of the disease (Branda et al. 174; www. dnadirect. com). In cases when both parents are heterozygous for the Tay-Sachs gene, there is a 25% probability of passing the disease to the offspring, while a 50% probability of bearing a carrier individual and a 25% chance of a phenotypically and genotypically normal child (see Figure 4). In situations when only one parent is a carrier, there are 0% chances of having an afflicted child. However, they still have a 50% risk of having an offspring carrying the gene for Tay-Sachs (Branda et al. 174; www. dnadirect. com). Epidemiology Tay-Sachs disease is one of the most renowned genetic disorders associated with a certain population. This is a metabolic disorder typically acquired through genetic inheritance and occurs most frequently among Ashkenazi Jews of Eastern Europe. However, the disease is not confined within this group as it is also found among French Canadians that inhabit the South-eastern portion of Quebec and among Cajuns that live in the South-western part of Louisiana (Genes and Disease 23). One of the causes that scientists propose on the emergence of this disease is founder effect. Founder effect is a potential cause for a high frequency allele within a population in isolation. This is the case if the allele selectively remains in neutrality and if it has identical copies of the original carrier that founded the subpopulation. This is also applicable in conditions where an allele simply arose by later mutating (Slatkin 282). In explaining the phenomenon of the occurrence of high frequency alleles, experts have always employed this founder effects hypothesis. Most disease associated alleles are likely to be non-neutral. However, even alleles with mild deleterious effects could gain high levels of frequency due to founder effects. Today, another explanation is widely accepted in the scientific community in accounting for Tay-Sachs disease. This is the heterozygote advantage. This hypothesis is basically supported by the fact that most disease associated with alleles result from sphingolipid storage dysfunction. This outcome is not commonly observed in the general population. These two hypotheses were highly acknowledged prior the 1990s. But until recently, the heterozygote advantage was questioned and the founder effect has gained a relatively greater acceptance. This is due to several research studies conducted that argued in favour of founder effects as the actual cause of lipid storage diseases in the Ashkenazi Jewish population. The heterozygote advantage is unlikely as some non-lipid storage diseases (NLSDs) are due to dominant instead of recessive alleles and that these NLSDs do not benefit from the presence of disease associated alleles (Slatkin 282). The study on the debate between genetic drift and selection were further investigated by Risch et al. (p. 812). It has been established that Ashkenazi Jews have higher tendencies to acquire lysosomal storage diseases (LSDs), and in this study, four were found to occur at high frequencies. It was suggested that this condition is a result of having natural selection, otherwise termed as carrier advantage, as an impetus. The researchers compared the LSDs and NLSDs in terms of their levels of mutations, allelic frequency distribution, and mutation coalescence dates. It was found that there were no differences in the distribution nor any regular distribuion patterns were observed between LSDs and NLSDs occurring in different geographic areas. But the scientists discovered a more interesting concentration of two particular Tay-Sachs mutations in central and eastern Europe. Such an observation is an indication that genetic drift or the founder effect is the driving force that affected the population. It is the primary determinant of the genetic mutations that occur in Ashkenazi Jews (Risch et al. 812). Treatment and Screening An effective treatment or cure is currently not available for Tay-Sachs disease. Due to this, scientists are exploring on various possibilities that would enable them to formulate the appropriate treatment and management of this disease. Through intensive research projects using therapeutic approaches and clinical trials, experts have discovered a potential cure. This is by employing enzyme replacement therapy in order to compensate for the deficiency of ? -N-Hexosaminidase A absent among afflicted infants and even among adult patients. But this proposal entails several complications as it can affect the brain neurons that receive protection from the blood-brain barrier. Other current studies include gene therapy, pharmacological chaperone therapy, and neural stem cell therapy. Another alternative research is conducted on stem cell transplantation employing the blood of umbilical cord, but all these mentioned potential cure are still under the process of scientific research (www. nstad. org). These stem cell research studies investigate the potential of transplanting bone marrow in treating classic Tay-Sachs disease. These stem cells are immature cells that can differentiate into any form of cell (see Figure 5). In this case, scientists are seeking to produce blood cells from these stem cells either from a bone marrow donor or umbilical cord blood. But this remains unsuccessful in causing the reversal of brain damage that is fatal for afflicted patients. Drug options are also being explores by medical experts, which includes the miglustat drug. This has the ability to cause fatty build up reduction in the brain cells of Tay-Sachs disease patients (Escolar et al. , 2; Bembi 278; marchofdimes. com). The enzyme replacement therapy proposal is basically applicable to most lysosomal storage disorders. The objective is to perform an enzymatic replacement, a procedure comparable to that of injecting insulin to diabetics. The problem in this procedure is that HEXA enzymes are relatively too large to penetrate the blood-brain barrier. This causes the development of blood vessel junctions in the brain, which leads to neuronal cell damage. Alternate pathways were also tested such as injecting the enzyme to the cerebrospinal fluid, but this treatment is still left ineffective (www. freepatentsonline. com). As mentioned in the historical background of this disease, screening for potential carriers is very essential in preventing the manifestation of Tay-Sachs. This is very vital for populations such as Ashkenazi Jews, French Canadians, Louisiana Cajuns, and even Pennsylvania Dutch. This procedure is recommended to be conducted prior conceiving an offspring. But even after the end of an individuals childbearing years, it is still important to be screened for ones status as a carrier as it would make a tremendous difference in the lives of immediate family and close relatives (www. nstad. org). Prenatal tests are currently available such as amniocentesis and chorionic villus sampling. These tests determine the existence of the disease prior a childs birth. Typically conducted between the 15th and 20th week of pregnancy, women can choose amniocentesis where a needle is inserted to the mothers abdomen to obtain amniotic fluid samples. Fetal cells are contained within this fluid and therefore can be tested whether they possess ? -N-Hexosaminidase A. Another test usually conducted between the 10th and 12th weeks of pregnancy is CVS. This is done through the retrieval of placental cells either through tube insertion on the vagina or needle penetration through the maternal abdominal area. Again, the objective is to obtain fetal cells that would be tested for the presence of ? -N-Hexosaminidase A. If these tests reveal the absence of ? -N-Hexosaminidase A, the infant will eventually manifest the classic Tay-Sachs disease. These tests are currently being offered especially to couples who are positive for carrying the allele, and most often to those who resort to in vitro fertilization (www. marchofdimes. com). Conclusion One of the clinical considerations of this disease is that it is caused by an organelle dysfunction, particularly lysosomes. Most cells have a limited life span and therefore must be continuously replaced. Without the proper amount of lysosomal enzymes as typically attributable to a genetic disorder, the result is an abnormal accumulation of glycogen and lipids that could destroy the tissue. This case is demonstrated by Tay-Sachs disease, together with other disorders such as Gauchers disease and glycogen storage. Due to this accumulation, myelin sheaths are destroyed which would lead to the different clinical manifestations of Tay-Sachs disease. (Van de Graaff 370). The Tay-Sachs gene occurs one in every 30 Ashkenazi Jews, making almost 3% of this population as carrier of this disease. Due to lysosomal storage dysfunction, the individual becomes deficient of an enzyme called Hexosaminidase A, which codes for the metabolism of lipid molecules in cellular systems. This fatal neurodegenerative disease has an infantile form and manifests through symptoms such as macrocephaly, loss of motor skills, increased startle reaction, and a macular cherry red spot. Patients exhibiting ataxia and dementia, the juvenile-onset form of Tay-Sachs causes the death of afflicted individuals between ages 10 and 15. The adult onset of this disease is characterized by â€Å"clumsiness in childhood, progressive motor weakness in adolescence, and additional spinocerebellar, lower motor neuron symptoms, and dysarthria in adulthood† (Kasper 2318). Patients commonly demonstrate psychosis and their intelligence continuously declines. Bembi, B. â€Å"Substrate Reduction Therapy in the Infantile Form of Tay-Sachs Disease. † Neurology, 66 (2006): 278-280. Branda KJ, Tomczak J, Natowicz, MR. 2004. â€Å"Heterozygosity for Tay-Sachs and Sandhoff diseases in non-Jewish Americans with ancestry from Ireland, Great Britain, or Italy. † Genet Test 8 (2004):174-180 Desnick, R. , and Kaback, M. Tay-Sachs Disease. Ed. USA: Academic Press, 2001. â€Å"Tay Sachs Disease. † 29 January 2008 dnadirect. com/patients/tests/ashkenazi/tay_sachs. jsp. Escolar, Maria L. , Michele D. Poe, James M. Provenzale, Karen C. , Richards, M. D. , June Allison, R. N. , Susan Wood, P. N. P. , David A. Wenger, Daniel Pietryga, Donna Wall, Martin Champagne, Richard Morse, William Krivit and Joanne Kurtzberg, M. D. â€Å"Transplantation of Umbilical-Cord Blood in Babies with Infantile Krabbes Disease. † The New England Journal of Medicine, 352 (2005):2069-2081. â€Å"Compositions and method for treating lysosomal storage disease. † 30 January 2008 freepatentsonline. com/6066626. html â€Å"Cord Blood. † 4 February 2008 cordbloodusa. org/articles-a1-Cord_Blood. htm. â€Å"Genes and Disease. † Bethesda (MD): National Library of Medicine (US), NCBI. 29 January 2008 ncbi. nlm. nih. gov/books/bv. fcgi? rid=gnd. section. 238. Hauser SL, Longo DL, Harrison’s Principles of Internal Medicine. Ed. 14th ed. New York: McGraw-Hill; 1998; p. 2171. Kasper, D. L. , A. S. Fauci, D. L. Longo, E. Baraunwald, S. Hauser, S. L . Jameson, Harrison’s Principles of Internal Medicine 16th Ed. USA: McGraw-Hill Companies, Inc. 2005. Li, Y. , S. Li, , A. Hasegawa, H. Ishida, M. Kiso, A. Bernardi, P. Brocca, L. Raimondi, and S. Sonnino. â€Å"Structural basis for the resistance of Tay-Sachs Ganglioside GM2 to enzymatic degradation. † The Journal of Biological Chemistry, 274:10014-10018, 1999. Lowden, J. A. â€Å"Role of the physician in screening for carriers of Tay-Sachs disease. † CMA Journal 119 (1978):575-585. â€Å"Tay-Sachs Disease. † 29 January 2008 marchofdimes. com/professionals/14332_1227. asp. Myerowitz, R. â€Å"Splice junction mutation in some Ashkenzi Jews with Tay-Sachs disease. † Natl. Acad. Sci. USA, 85 (1998):3955-3959. â€Å"National Tay-Sachs and Allied Diseases Association. † 29 January 2008 ntsad. org/. National Eye Institute. 4 February 2008 nei. nih. gov/resources/eyegene/redeye. jpg Society for Neuroscience. 4 February 2008 sfn. org/SiteObjects/published/0000BDF20016F63800 FD712C3158BA55/0000BDF200000

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Writing Contests and Competitions Writing Contests and Competitions Writing Contests and Competitions By Daniel Scocco This page will be updated regularly with the latest writing contests and competitions from around the web and the world! Make sure to bookmark it. If you are promoting a writing contest, or are aware of one that is not listed here, please send the details to info@dailywritingtips.com and well include it here as soon as possible. Last update: 08/24/2016 Upcoming Contests and Competitions Name: Atlantis Short Story Contest Prizes: $450 total, first prize is $300 Entry fee: starts from $10 Deadline: November 30, 2016 Description: Authors from all around the world are welcome to enter the one and only contest that offers a criqitue for every participating story! Name: