Mghf

Huntingtons disease is an autosomal dominant (Harper et al, 1991) neurodegenerative disorder characterized by involuntary movements, cognitive loss, and psychiatric problems as described by Martin and Gusella (1986). These symptoms are related to the death of medium spiny projection neurons in the caudate nucleus, putamen, and the cortex (Reiner et al, 1988). In later stages of the disease, take down areas such as the hippocampus and hypothalamus gets affected as well (Kassubek et al, 2004). Huntingtons disease has a prevalence rate of approximately 1 in 10,000 Caucasic populations (Harper et al, 1991).Patients with Huntingtons disease most typic tout ensembley display a choreic movement disorder involving involuntary writhing movements observed by George Huntington himself. The age of onset of Huntingtons disease seem to be normally distributed around the average age of 35 to 42, with small number of cases exploitation in patients younger than 20 old age of age or older than 60 geezerhood of age (Andrew et al, 1993). The majority of juvenile patients, whose disease onset are at age 20 years or less, have inherited the paternally defected gene (Andrew et al, 1993).Patients usually died within 15 to 20 years of disease onset. Gusella et al (1983) first determined the kettle of fish of the genetic mutation in Huntingtons disease to be the short arm of chromosome 4. It was afterwards another 10 years did the researchers of The Huntingtons Disease collaborative Research Group (1993) able to discover that a gene in chromosome 4 containing a trinucleotide repeat of CAG was abnormally expanded in diseased individuals. The IT15 (interesting imitation 15) gene, dubbed the huntingtin gene by the group, codes for the huntingtin gene.This CAG repeat, which translates into a poly-glutamine stretch, is highly polymorphic among the population ranging from 11 to 34 copies on normal individuals. However, in individuals with Huntingtons disease it expanded to to a great er extent than 42 repeats and increasing to upwards of 100 (The Huntingtons Disease Collaborative Research Group, 1993). This provides evidence showing that the mutant huntingtin protein seems to be toxic to its native booths and confers a disease state to individuals with an extended length of repeats. There is overly a correlation between the CAG length and disease onset as shown by Andrew et al (1993).The mutated elongated huntingtin protein is cut by enzymes into fragments and the fragments begin to form abnormal clusters, neuronal intranuclear inclusions (NIIs), inside cells. These clusters goat to a fault act to recruit normal proteins to adhere unneurotic as well (Davies et al, 1997). This was originally thought to cause the pathogenesis of Huntingtons disease. However, more recent studies have shown that the presence of NIIs is actually a coping response to the perniciousness of mutant huntingtin proteins and acts to prolong the life of the cells and reduce intracellular mutant huntingtin in neighbouring neurons (Arrasate et al, 2004).The exact function of the wild-type huntingtin protein are unclear, however many efforts have been made in understanding its native functions. Nasir et al (1995) showed that homozygous huntingtin homologs in mice died before embryogenesis could occur and that heterozygotes displayed similar deficits as diseased human patients. Wild-type huntingtin is also crucial for establishing and maintaining neuronal identity, particularly in cortex and striatum (Reiner et al, 2001).Current data can provide the conclusion that normal huntingtin protein has actions classic for phylogeny in mammals. In vitro, wild-type huntingtin have been shown to act to cheer mentality cells from apoptotic stimuli, such as serum deprivation, mitochondrial toxins, or the transfection of death genes (Cattaneo et al, 2005). Wild-type huntingtin protein, not mutated, stimulates brain-derived neurotrophic factor (BDNF) production by acting at leve l of Bdnf transcription. BDNF is very important for survival of striatal neurons (Cattaneo et al, 2005).Intracellularly, huntingtin protein has been found to associate with various organelles such as the nucleus, endoplasmic reticulum, and Golgi complex (Cattaneo et al, 2005). It has also been found in neurites and at synapses, where it associates with vesicular structures and microtubules (Li et al, 2003). This characteristic has been shown to enhance vesicular transport of BDNF along microtubules (Gauthier et al, 2004). On a similar note, huntingtin interacts with a number of cytoskeletal and synaptic vesicle proteins that are essential for exo- and endocytosis at synaptic terminals.Wild-type huntingtin binds instantaneously to the Src homology 3 domain of postsynaptic density protein 95, which binds NMDA and kainite receptors. This activity is decreased in mutant proteins and can lead to overactivation or sensitization of NMDA receptors (Cattaneo et al, 2005). Aside from the tox icity of the mutated huntingtin protein, the loss of normal huntingtin protein also seems to add to the pathogenesis of Huntingtons disease. Presence of completely mutant huntingtin protein results in massive apoptotic cell death in the testes of male mice (Leavitt, 2001).However, no apoptosis can be seen in testes of mice expressing human mutant huntingtin when wild-type huntingtin is expressed as well (Leavitt, 2001). It was also seen that in mice, the absence of wild-type huntingtin protein led to a worsening of striatal atrophy and neuronal loss, and a significant decrease in neuronal cross-sectional area compared to mice that had wild-type huntingtin present (Cattaneo et al, 2005). Huntingtons disease still system incurable to this day. However, many treatments are usable for treatments of its symptoms.Chorea, the hallmark of the disease is a major target for many treatments. Such drugs include dopamine-depleting agents, dopamine antagonists, benzodiazepines, glutamate antag onists, acetylcholinesterase inhibitors, dopamine agonists, antiseizure medications, cannabinoids, lithium, deep brain stimulation and fetal cell transplantation (Frank and Jankovic, 2010). One notable drug afoot(predicate)ly in use is Tetrabenazine, which is the only US FDA-approved drug for treatment of Huntingtons disease (Frank and Jankovic, 2010).The drug acts by reversibly inhibiting the central vesicular monoamine transporter type 2, this cause a depletion of dopamine (Bagchi, 1983). The main area of effect for tetrabenazine is in the caudate nucleus, putamen, and the nucleus accumbens, all areas known to be responsible for the major pathology of the disease. The Huntington Study Group (2006) was able to demonstrate the efficacy of tetrabenazine in a double-blind, placebo-controlled trial. Subjects who received tetrabenazine showed a change from the baseline in the maximal chorea score of the UHDRS.Compared to the baseline, treatment resulted in a diminution of 5. 0 units in chorea compared with a 1. 5 unit reduction for the placebo group. A second symptom targeted for treatment to allow patients to function normally is the psychiatric problems. Dopamine receptor blocking agents are commonly used as anti-psychotics in order to treat psychosis associated with Huntingtons disease (Frank and Jankovic, 2010). There are many ethical issues that have been associated with Huntingtons disease patients, in particular pertaining to the application of genetic testing.The expanded CAG repeats associated with Huntingtons disease (Gusella et al, 1983) are used as a predictive testing to determine the gamble of a person for developing inherited HD gene. The debate of ethics with respect to genetic testing for Huntingtons disease seems to lie on several major factors including autonomy, beneficence, confidentiality, and justice (Huggins et al, 1990). The question remains whether or not the current use of genetic predictive testing is ethical. Autonomy refers to th e respect for the individuals right to make an informed ratiocination about an action that may have a profound effect on his or her life.The patients should feel no pressure from doctors or institutions with regards to their decision for genetic testing. Also, they should also have a full understanding of the consequences and implications of their decisions. This would require physicians to provide all the necessary teaching to the patients so that they are informed about the testing. If a woman refuses to get tests done for her baby even though her relatives are with her insisting on getting it performed, the physician cannot allow the testing to be performed.Beneficience is summarized by the phrase first do no harm (Huggins et al, 1990). This is an important factor when the results of the test may reveal genetic cultivation about oneself. This implies not only avoiding harm to patient but also preventing harm to other individuals, which may include family members of patients. Due to the genetic characteristics of Huntingtons disease, family members can be both directly and indirection influenced by the results of the test.If for example a pregnant woman decides to get an ultra sound for her baby in order to find out if the baby has spina bifida, and upon stay by the physician decides that she wants to give birth at home as opposed to in a hospital where the baby could be treated flop in order to minimize the risk of the disease. The physician should take any action he can in order to avoid any risk to the health of the baby. Confidentiality with genetic tests applies the same as with any other form of personal information. It should not be disclosed to any other third parties, which includes family members as well.For example, if two siblings were to go and receive a CAG repeat test at the same time and one sibling asks the physician about the results of the other sibling. The physician cannot disclose any information or they will violate the confident iality of the patient. Justice simply means equal entree to health services and information to all. This also includes long-term support and guidelines for testing as a medical service so that the service is not difficult to obtain if needed. For example, even though cystic Fibrosis is mostly only prominent in Caucasians, the testing should still be offered to regnant women of other ethnicities as well. Other ethical dilemmas still exist with current genetic testing technologies. One particularly pertaining to Huntingtons disease is whether or not the information is obtained even though there is no cure for the disease. In diseases such as phenylketonuria (PKU), after newborn screening, dietary interventions will allow the individuals with the condition to lead healthy and normal personifys (Lea et al, 2005). However, for Huntingtons disease, even after knowing that the disease will affect the individual what can be done?Therefore, would it be better to not know at all? By testing and finding out that an individual has the mutation that will eventually lead to the development of Huntingtons disease, the individual can attend to the initial development of symptoms and as a result may be treated much earlier. This can result in a more favourable prognosis. Similarly, the individual can live more cautiously as to prevent further exacerbation of their condition. On a more subjective level, the individual may use the experience to live a more fulfilling life knowing that he or she may not live as long as the rest of the population.Conversely, the information can also be used negatively. There can be a lot of discrimination in terms of applying for employment and health insurance. This information would also impact the ambition and life goals of the individual, the amount of psychological harm that comes with eventually developing an incurable and lethal neurodegenerative disease is extremely large. Similarly, would they still tag to have a family and children i f they knew that they had a very high risk of dying at a young age? This particular issue should be unflinching by following the ethical factors listed before.As long as the individual is informed, are being prevented from harm, information not shared with any third party members, and has access to healthcare services, then being tested for Huntingtons disease will be ethically correct. This knowledge will give them insight on how to live the rest of their life. Another dilemma that has Harper, P. S. , Morris, M. J. , Quarrell, O. , Shaw, D. J. , Tyler, A. , and Youngman, S. (1991). The epidemiology of Huntingtons disease. J. Med. Genet. 89 365-376. Martin, J. B. , and Gusella, J. K. (1986).Huntingtons disease pathogenesis and management. N. Engl. J. Med. 315 1267-1276. Andrew, S. E. , Goldberg, Y. P. , Kremer, B. , Telenius, H. , Theilmann, J. , Adamn, S. , Starr, E. , Squitieri, F. , Lin, B. , Kalchman, M. A. , Graham, R. K. , and Hayden, M. R. (1993). The relationship between tr inucleotide (CAG) repeat length and clinical features of Huntingtons disease. Nat Genet. 4 398-403. The Huntingtons Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons disease chromosomes.Cell. 72 971-983. Gusella, J. F. , Wexler, N. S. , Coneally, P. M. , Naylor, S. L. , Anderson, M. A. , Tanzi, R. 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