The Gene of Huntington's Disease - Report Example

Running Head: Huntingtons Disease GENETICS Huntingtons disease appears here] of appears here] GENETICS Huntingtons disease When a DNA marker closely linked to the gene of Huntingtons disease was discovered in 1983, a world was opened up, not only for families suffering from Huntingtons disease, but for all those with genetic illness. Localizing a gene whose chromosomal origin was unknown confirmed the practical value of a novel strategy applicable to almost all hereditary disorders. Gene mapping, aimed at spanning the genome at regular intervals, or the fine-point charting of interstices between intervals, is proceeding at a furious pace, and a complete map of the human genome will be in place in the not too distant future. But as this molecular cartography advances, clinical medicine is turning topsy-turvy in its wake. Huntingtons disease is an autosomal dominant neurodegenerative disease. Appearing usually in the third or fourth decade of life, it can begin in early childhood or old age. A triad of disturbances is pathognomonic: uncontrolled involuntary movements usually including chorea, intellectual decline, and psychiatric disturbance, mostly depression. The disease progresses for twenty years toward an inevitably fatal outcome, and therapy is palliative at best. Families, scientists, and clinicians involved with research on or treatment of Huntingtons disease have been .aware that their development of counseling and diagnostic program using DNA markers could be as precedent-setting as the discovery of the marker itself. They have been trying to act with caution and sensitivity, at the same time making the test available. The Tests offered. Presymptomatic and prenatal testing can now be carried out with a number of different markers to enable risks to be changed from 50 percent to 96 percent or higher of being positive or negative for the gene of Huntingtons disease. Even though there has been some uncertainty as to the exact location of the gene within the most telomeric band on chromosome 4, there are sufficient markers to alter a persons risk significantly if a family is genetically informative. Initially, less than half of all families listed on the National Huntingtons Disease Roster at Indiana University had such an appropriate structure. Owing to the increased informativeness of recently developed markers, recent estimates suggest that up to 75 percent of individuals coming for testing will be found to have genetically informative families. Prenatal Diagnosis. Two types of prenatal diagnostic tests are available: 1) a non-disclosing prenatal or "exclusion test," and 2) a fully disclosing diagnostic test. In a non-disclosing prenatal test, the risk status of the at-risk parent is not altered, only the risk of the fetus. DNA from the fetus is checked for the presence of the grandparental chromosome from the affected or from the unaffected grandparent. In the first instance, the fetus would have a 50 percent risk, the same as the at-risk parent who carries the same chromosome. In the second instance, the fetus would have only a negligible risk (approximately 2 percent, due to the possibility of recombination). The option of a non-disclosing prenatal test can be offered to those at risk who do not wish to know their genetic status or who do not have sufficient family members to make a full disclosing test possible. A non-disclosing prenatal test can be carried out with DNA from only the expectant parents, the fetus, and a single parent, either healthy or affected with the disease, of the at-risk individual. If a family is genetically informative, and the couple wishes to have the information, the fetus can be tested, with full disclosure of its genotype. Some parents may choose to proceed with full disclosure after a previous non-disclosing test has revealed a fetus with a 50 percent risk. If the fetus proves to have a negligible risk, the genetic identity of the at-risk parent is still protected. If the fetus is found most likely to carry the allele of Huntingtons disease, parent and child are diagnosed simultaneously in a double tragedy. One problem that arises during prenatal testing is that the analysis of samples is time-consuming. Couples who embark on full testing of a fetus, even after chorion-villus sampling at eight to twelve weeks, may endure very late and often psychologically traumatic terminations. Presymptomatic Testing. Presymptomatic and prenatal testing is now being offered in twenty-two centers in the United States, as well as several centers in the United Kingdom and Canada. Canada has formed the Canadian Collaborative Study of Predictive Testing for Huntingtons Disease and has created fourteen testing centers across Canada. France is just embarking on a program in Paris, and other countries, such as Germany and Scandinavia, may be beginning their own. I have directed a small pilot project providing testing at the College of Physicians and Surgeons of Columbia University since 1987 under the auspices of the Robert Wood Johnson Foundation. The following observations reflect our experiences, together with those from other centers. Attitudinal Surveys Prior to Test Availability. Following the announcement of the discovery of the marker, attitudinal surveys were conducted of families with Huntingtons disease. Some surveys were aimed only at those at risk, while others solicited opinions from the entire family. There was a wide range of outcomes, from as low as 40 percent of the at-risk population interested in testing to as high as 100 percent. A few investigators found that some people, once positive about testing, had changed their minds with the pending availability of the test. A Dutch survey concluded that those more knowledgeable about the test itself were less eager to be tested. In all studies, level of. education or income, occupation, or marital status made no difference. Who Comes for Testing? There are four outcomes from presymptomatic-linkage testing for the allele of Huntingtons disease. A person can have a high probability of being positive or negative for carrying the gene. The test can also prove genetically uninformative. Occasionally, non-paternity is revealed, which indicates that the testee is not actually at risk. Every at-risk person who seeks testing has a unique story, but there are some generalizations that one can make about characteristics and motivations. Individuals requesting testing can be grouped into four general categories: young adults, older at-risk parents, the offspring of people newly diagnosed, and clinically symptomatic individuals who do not recognize their affected status. Young Adults. one group is comprised of young adults in their twenties and thirties who are planning or have recently entered into new careers or who plan to be married and have children. It was initially thought that this group would be the largest, but experience has yet to determine whether this will be the case. These people are perhaps most affected by whether or not they are gene carriers, for the test may greatly influence their decision making. Many are enthusiastic, resilient, and full of youthful energy. This group also has the highest genetic risk, since most of them are young and still have a 50 percent probability (which declines with age) of having inherited the disease. They have the most to gain and the most to lose. Many of them are also filled with the adolescents sense of invulnerability--"It cant happen to me." They feel so healthy, well coordinated, functional, and fine that the prospect of having the illness is more or less an intellectual proposition. At the same time, they scan themselves incessantly for initial signs. A sense of invulnerability and adolescent bravado may push them to take the test without adequate psychological preparation for the possibility that the gene will be found to be present. They are often full of plans for what they will do if the gene is not there but are vague and unsettled about a life waiting for the disease itself to make its appearance if the gene does turn out to be there. News of a positive result can be shocking and traumatic, even with adequate psychological rehearsal and preparation. Young adults have the longest to wait in the "presymptomatic state," before the disease becomes manifest. For most, this seems to be a boon--the disease is a long way off. But for others, the interval may be years of anxiety, dread, and ambiguity, of hypochondriacal concern and hypervigilance for symptoms. Because of the newness of the testing programs, very few individuals have had to live even three years with the knowledge of a possibly positive test outcome. Some may deny the appearance of symptoms when those symptoms do begin, and others may shut down early on a healthy life, ending the ambiguity and the waiting by becoming patients prematurely. For some young people, the knowledge that they are destined to develop Huntingtons disease arrives before a career is chosen or a marriage bond sealed. A gene carrier may pull back on wishes to become a physician, an astronaut, or a Wall Street financier or to enter any profession requiring a great deal of training, coordination, and judgment. And some would argue that this is all for the best in that they will not pose a hazard for themselves and others. Yet many with Huntingtons disease have enjoyed great success and satisfaction in a variety of careers prior to becoming incapacitated. Some presymptomatic carriers may constrict their lives unnecessarily, while others may be galvanized into leading a fuller life, knowing that time is limited. Marital planning is an important impetus for testing. Often at-risk individuals are more eager to clarify their risk status than are the prospective spouses. Persons at risk want their prospective spouses to know what is in store for them. But some prospective spouses explicitly do not want to know. They feel bound to honor the engagement even more if the probable outcome of the test is positive; so they prefer to get married in hope that will not be the case. Many at risk feel guilty about imposing their uncertain and possibly difficult future on their spouses. A positive diagnosis may make single presymptomatic individuals retreat even further from marriage and intimacy. The timing of Huntingtons disease, with its late onset and prolonged course, can cause problems in adjusting to diagnostic testing. Many young adults who are eager for testing have parents who have just died or are in the terminal phases of the illness. It can be traumatic to nurse a dying parent after learning that this is to be ones own fate. At-risk individuals are frequently the primary careers of their parents with Huntingtons disease. Knowing that they themselves have inherited the same gene may make this task doubly painful and cause role readjustments for all family members. Older At-Risk Parents: The Altruistic Testee. The second group interested in presymptomatic testing consists of at-risk individuals in their fourth through sixth decades who are parents of children approaching young adulthood. Often these older people at risk do not want predictive information for themselves. Left to their own devices, they would not get tested. They have led full lives, made decisions as best they could, and gained a certain feeling of confidence as the disease has not yet appeared. They know, however, that if they are tested and found free of the gene, their children are relieved of any risk. Many parents are willing to subject themselves to the testing as a gift to their children. Given their age, their genetic risk is already reduced, a fact that augurs well for a good outcome. However, to a person who has achieved some sense of freedom from the threat of Huntingtons disease, the information that the gene is most probably present may be all the more devastating. Also, the disease may be more likely to appear soon, depending on their age. On the other hand, the fact that they have lived without symptoms for so many years and have accomplished so much may bring some solace and diminish the impact of bad news. We must learn whether taking the test for altruistic motivations produces different needs and stresses, both pre- and post-testing. Bibliography Adams, Jean. (1990). Confidentiality and Huntingtons chorea. Journal of Medical Ethics. 16(4): 196-199 Bloch, M. ; Hayden, M.R. (1990). Opinion: predictive testing for Huntington disease in childhood: challenges and implications. American Journal of Human Genetics. 1990 Jan; 46(1): 1-4 Clarke, G.; Collins, R. A.; Leavitt, B. R.; Andrews, D. F.; Hayden, M. R.; Lumsden, C. J.; McInnes, R. R. (2000): A one-hit model of cell death in inherited neuronal degenerations. Nature 406: 195-199. Connor, Steve. (1983). Gene probes find Huntingtons disease. [News]. New Scientist. 100(1383): 399 Dyer, R. B.; McMurray, C. T. (2001): Mutant protein in Huntington disease is resistant to proteolysis in affected brain. Nature Genet. 29: 270-278. Falck, Arthur. (1973). Issues and ethics in genetic counseling with Huntingtons Disease families. Psychiatric Forum 4(1): 51-60 Hemphill, Michael. (1973). Pretesting for Huntingtons disease: an overview. Hastings Center Report 3(3): 12-13 Hoogeveen, A. T.; Willemsen, R.; Meyer, N.; de Rooij, K. E.; Roos, R. A. C.; van Ommen, G.-J. B.; Galjaard, H. (1993): Characterization and localization of the Huntington disease gene product. Hum. Molec. Genet. 2: 2069-2073. MacDonald, M. E.; Novelletto, A.; Lin, C.; Tagle, D.; Barnes, G.; Bates, G.; Taylor, S.; Allitto, B.; Altherr, M.; Myers, R.; Lehrach, H.; Collins, F. S.; Wasmuth, J. J.; Frontali, M.; Gusella, J. F. (1992): The Huntingtons disease candidate region exhibits many different haplotypes. Nature Genet. 1: 99-103. Read More