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Presymptomatic Testing For Huntington's Disease
Harbinger Of The New Genetics


Department of Neurology and Psychiatry,
College of Physicians and Surgeons,
Columbia University, New York, NY 10032, USA

From: Genetics, Ethics And Human Values
Human Genome Mapping, Genetic Screening And Gene Therapy
Proceedings of the XXIVth CIOMS Round Table Conference
Edited by Z. Bankowski and A.M. Capron
Tokyo and Inuyama City, Japan
22-27 July 1990

There is an allure to trying new technologies. We flex our laboratory muscles and prepare to test our latest diversions. And there is something particularly aesthetic about genetic diagnosis, with those clean, impersonal bars stretching across the lanes at their appointed positions. Without words, they can reveal past couplings or confess extramarital transgressions. And they are clairvoyant, unpeeling shrouds from the future as well as the past.

When a DNA marker was discovered in 1983 closely linked to the Huntington's disease gene, a world was opened up, not only for families suffering from Huntington's disease, but for all those with genetic illness.1-4 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.

Huntington's 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 20 years toward an inevitably fatal outcome and therapy is palliative at best.5

Families, scientists and clinicians involved with research on, or treatment of, Huntington's disease have been aware that their development of a 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 while 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% to 96% or higher of being positive or negative for the Huntington's disease gene.6-10 Even though there has been some uncertainty as to the exact location of the Huntington's disease gene within 4p16.3, the most telomeric band on chromosome 4, there are sufficient markers to alter a person's risk significantly if a family is genetically informative.11-12 Initially, less than half of all families listed on the National Huntington's Disease Roster at Indiana University had such an appropriate structure.13 Owing to the increased informativeness of recently developed markers, recent estimates suggest that up to 75% of individuals coming for testing will have genetically informative families.14 Prenatal diagnosis

Two types of prenatal diagnosis tests are available: 1) a nondisclosing prenatal or "exclusion test," and 2) a fully disclosing diagnostic test.15-17 In a nondisclosing 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% risk, or the same risk as the at-risk parent who carries the same chromosome. In the second instance, the fetus would have only a negligible risk (approximately 2%, due to the possibility of recombination). The option of a nondisclosing 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 nondisclosing 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 know 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 nondisclosing test has revealed a fetus with a 50% 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 HD allele, parent and child are diagnosed simultaneously in a double tragedy.

One problem which 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 8- 12 weeks, may endure very late and often psychologically traumatic terminations. Presymptomatic testing

Presymptomatic and prenatal testing is now being offered in 22 centers in the United States, as well as several centers in the United Kingdom and Canada.18-25 Canada has formed the Canadian Collaborative Study of Predictive Testing for Huntington's Disease and has created 14 testing centers across Canada. France is just embarking on a program in Paris, and other countries, such as Germany and Scandinavia, may be beginning. 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. Guidelines for testing

There are variations among countries and centers but the following represents some key elements of the basic protocol which is followed, at least in the United States and Canada:

1) There must be a minimum of three to six separate counseling sessions before diagnostic information is delivered. Each session should be several hours long. Intensive counseling regarding motivations and preparation for testing is the most essential element of the entire protocol. Post-test counseling must be part of any protocol but clients sometimes prefer to seek counseling closer to home.

2) Potential clients should be evaluated neurologically, neuropsychologically and psychiatrically.

3) Relatives at risk or symptomatic who are donating a DNA sample for a client to be tested should be evaluated neurologically as well. A diagnosis should not be accepted on the basis of hearsay evidence, even from a family member. Corroboration should be sought from the diagnosing physician and a re-evaluation should be arranged if there is any doubt. If persons at risk cannot or will not be examined, their risk should be assigned very conservatively in the linkage analysis. The disease should be confirmed in at least one relative by autopsy diagnosis or by very reliable neurological examination.

4) Clients found to have significant psychiatric disorders, particularly a history of suicide or severe depression, or those undergoing stressful life circumstances causing emotional upheaval, such as divorce or a death in the family, are not suitable testing candidates.

5) Diagnostic information must always be given in a face- to-face session, never over the telephone. Even if the outcome is genetically uninformative, clients need an opportunity to discuss what this information may mean.

6) Most programs require or strongly urge that clients be accompanied by a companion to at least one counseling session and at the disclosure session.

7) Long-term follow-up is essential, particularly for those who test positive for the gene. As the time draws near when symptoms are likely to appear, clients need to know that they have a relationship with a supportive therapeutic individual or group.

8) Some programs require that a client contact a psychotherapist prior to receiving diagnostic information. Other programs provide the therapists. These therapists can continue to see clients, particularly after a positive diagnosis.

9) All DNA determinations must be carried out independently at least twice. If contradictions appear, new DNA samples are collected. Some centers collect two independent blood samples. If blood has been donated from relatives for research purposes these samples must be re-collected unless explicit permission is given for them to be used in diagnostic testing. Even then it is best to collect new samples on crucial individuals.

10) A genetic linkage computer analysis of haplotypes generated must always be conducted. Diagnostic information must never be given on the basis of a visual analysis of the gels alone.

11) If siblings of a client need to be analyzed to determine phase or to reconstruct the haplotype of a deceased parent, the identities of these siblings should be confidential and data analyzed anonymously. This prevents those providing counseling from inadvertently receiving unwanted and inappropriate information.

12) Testing should be available only to persons aged 18 years or older who can give informed consent. One potential complication of this guideline may occur if parents have a nondisclosing prenatal test and choose to maintain a pregnancy in which the fetus is found to have a 50% risk. If the at-risk parent develops Huntington's disease, the child is de facto diagnosed. Another ethical quandary may occur when couples who wish to adopt a child at risk insist on testing as a condition of adoption.

13) All testing must be totally voluntary and the results remain totally confidential, even to other family members.

Attitudinal surveys prior to test availability

Following the announcement of the discovery of the marker, attitudinal surveys were conducted of families with Huntington's 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% of the at-risk population interested in testing to as high as 100%.26-32 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.33 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 Huntington's disease allele. A person can have a high probability of being positive or negative for carrying the gene. The test can also prove genetically uninformative. Occasionally, nonpaternity 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 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 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, as the test will greatly influence their decision-making. Many are enthusiastic, resilient and full of youthful energy. This group also has the highest genetic risk as most of them are young and still have a 50% 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 adolescent's sense of invulnerability -- "It can't happen to me." They feel so healthy, well coordinated, functional and perfectly 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 is 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 to make its appearance. 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, these 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 positive test outcome. Some may deny the appearance of symptoms when they do begin and others may shut down early on a healthy life, ending the ambiguity and the waiting by becoming a patient prematurely.

For some young people, the knowledge that they are destined to develop Huntington's disease arrives before a career is chosen or a marriage bond sealed. Gene carriers may pull back on wishes to become a physician, an astronaut, a Wall Street financier, any profession requiring a great deal of training, coordination and judgement. 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 Huntington's 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 outcome is a probable gene-positive test, so they prefer to get married in hope. 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 Huntington's 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 one's own fate. At-risk individuals are frequently the primary carers of their parents with Huntington's disease. Knowing that they 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. These older people at risk often 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, which augurs well for a good outcome. However, to a person who has achieved some sense of freedom from the threat of Huntington's disease, the information that the gene is most probably present may be all the more devastating. Also, the disease would be more likely to appear soon, depending on their age. On the other hand, the fact that they have lived without symptoms for many years and accomplished 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.

The newly at-risk

The third category is comprised of individuals who have just learned that they are at risk, regardless of their age. A fairly universal reaction of people learning for the first time of their genetic risk is to want to resolve their doubt immediately. This novel situation of risk is so ambiguous and so uncomfortable that it is intolerable. This group is perhaps the most vulnerable, for they have not yet had time to realize the implications of the disease and the test. Many have never seen the illness in its terminal stages. It can be disastrous if they get this preview of their own end after they find out that they themselves are positive for the gene. It takes many years to adjust to being at risk; most of the newly at risk are still reeling from this shock. They must be helped to adjust to the risk situation and learn more about the disease before proceeding to presymptomatic testing.

The clinically affected

A small but significant number of people coming for testing are already clinically affected. Some may have an inkling that they are affected and they come for confirmation; others are surprised. Some genuinely do not want to know that they are affected, only whether they will be affected in the future; it is best to recommend that they postpone testing.

The family as a testing partner

Testing does not occur in a vacuum. Samples must be collected from critical relatives, whose permission is required for testing, and each family member has his or her own stake in the information delivered.

Parents must provide a sample for the test to be successful. Most times the healthy parent has spent years caring for an ill spouse and may be looking forward to a respite before children begin the same fatal trajectory. It is also horrifying for them to face the prospect that they may die and be unable to care for sick children. Parents affected by Huntington's disease may feel especially guilty, knowing that they have transmitted the fatal gene to their children.

An ethical and psychological dilemma has arisen in several testing centers (Myers Brandt, personal communication). A parent has consented to give a sample for one offspring but not for another, feeling that the children differed in their ability to handle diagnostic information. Once the parent's sample is used in one test and the genetic haplotype determined, it is not needed for any other offspring's test. So despite the parent's wishes, technically the test could be done for all interested offspring. Clearly an ethical problem exists: should testing continue contrary to the parent's wishes or stop, thereby depriving all offspring of information about genotypes. The question is raised of who "owns" a parent's genetic haplotype? Whose wishes have precedence, the at-risk individual wishing personal testing or the parent, who may be acting out of malignity or compelling concern? The best counseling alternative is to endeavor to bring family members to a resolution satisfactory to everyone before testing any of the offspring.

Testing one sibling has repercussions for all. Bringing the test close to home usually forces siblings to decide more actively whether they wish to be tested. Sometimes their genetic information may be required for their sibling's test, to reconstruct the haplotype of a deceased parent, for example. The optimal timing for one sibling to be tested may conflict with another's. Deciding when to take the test can be almost as crucial as whether to take it.

Family secrets

Siblings may entertain the fantasy that one of them could be tested and the others in the family would not know. In some families, this may be the case. However, most family members in reasonable contact with each other find such momentous news hard to hide. Changes in plans -- for example, a decision to have children or a prolonged absence or period of depression -- are revealing signs. And keeping the news from family members may deprive someone newly presymptomatic of necessary support.

If siblings know the outcome of one sibling's test it can affect them, whether or not they choose to be tested. Even though "chance has no memory," siblings often feel that if one goes free their risk increases, or, conversely, if one is diagnosed their risk diminishes. Although each sibling has an independent risk, siblings often feel that their fates are intertwined. Sometimes all siblings in a family are diagnosed positively or negatively, which can be catastrophic or joyous for all. Disparities in test outcome can exacerbate sibling rivalries and family tensions as well as draw families closer together.

Motivations for diagnostic testing

At-risk individuals can come for testing because they want to know either outcome: Huntington's disease gene positive or negative. Others want to know whether they will be free of the disease and are willing to risk hearing bad news for the joy of hearing good.

People come with a variety of motivations, some concerned with planning and others with ending ambiguity. It remains to be seen how much their stated intentions and feelings prior to testing accord over time with their actions following receipt of diagnostic information.

Do people really want to know the truth? A woman came to our testing clinic, highly functional, intelligent, a working wife and mother, and lamented that her family was not genetically informative enough for her to be tested. She stated that she would definitely like to be tested as this would help her advise her family better. This woman had been symptomatic for about five years but never diagnosed. Her statements about why she wanted the test were cogent and persuasive. She wanted to know the truth. Yet something in her very powerfully did not want to know the facts. The truth was that she functioned better in denial; when the denial was finally cracked by a clinical diagnosis, she and her family were devastated.

Testing programs are too recent to have much experience with long-term follow-up. Certain general trends seem to be appearing in the lives of those undergoing testing, which vary according to the diagnostic outcome.

The "escapee"

This group has been the largest across all testing centers. They also seem to undertake the most active changes in their lives. Some are freed to have children or marry or get divorced. Some change jobs or go back to school. It appears that many people at risk unduly restrict themselves from options which they then feel free to pursue once the specter of the disease is lifted.

Many who test most likely negatively for the gene also forget that some risk remains. Although those who test most likely gene-positive cling to the hope that a genetic recombination is responsible for producing their untoward outcome, "escapees" "forget" that the test is not 100% reliable.

"Escapees" with siblings or other relatives are acutely aware that others in their family may not prove so lucky. Some have expressed classic "survivors' guilt," vowing to devote themselves to caring for relatives should they fall ill.

Those most likely gene-positive

This group is the smallest and is being watched the most carefully. There has been one reported instance of attempted suicide by a person who came for testing and discovered she was symptomatic.34 Another person had to be briefly hospitalized for depression after a test outcome with a high probability of being positive.

Hayden has recently reported on longitudinal follow-up of Beck Depression scores of both Huntington's disease patients and persons mostly likely gene-positive. The gene-positive group had fairly stable Beck Depression scores, while the Huntington's disease patients had quite high scores.35 This should warn us that those with a positive test may be holding depression at bay by thinking that the disease is far in the future, but that as they grow older their risk for depression will increase.

Non-informative test

This group seems to blossom rather like those who receive good news. They get on with their lives and adopt children or change jobs and generally behave as if there has been some resolution of their risk status. It is as if they tried to do all they could to contend with their question of risk and now they can focus on living.

What is an informative test?

Testing centers vary in the information they give to testees. Some centers, such as those at Johns Hopkins, Harvard and Columbia Universities, will consider a test genetically informative if it can change a client's risk to 95% or higher in either direction. Below this level of confidence, the test is too vulnerable to such factors as variation in the ages of onset in the family and other data which tend to be murky. The Canadian Collaborative Study group will provide information on any change in risk levels (M. Hayden, personal communication). My experience with clients in our testing program is that they interpret any change as if it were liberating or ominous, and tend to treat all risk alterations as if they were 100% certainties.

Huntington's disease and AIDS

Analogies can be drawn between presymptomatic testing for Huntington's disease and testing for HIV positivity. In each instance the information to be conveyed is potentially devastating. We still do not know what portion of people who have an HIV positive test eventually develop AIDS. While a diagnosis of Huntington's disease gene positivity carries with it certain lethality, the disease is often further into the future. Both diagnoses bring uncertainty and fear.

Until recently, the Gay Men's Health Coalition was not actively encouraging HIV testing as long as people took precautions. However, with the advent of zidovudine, there is now an appropriate treatment to begin as soon as possible after HIV infection. Attitudes toward testing have changed. Perhaps this will be the case when a treatment is available for Huntington's disease as well.

Genetic illnesses are also sexually transmitted diseases in the sense that only through intercourse are they passed on. As legislation or policies are developed that pertain to HIV infection, those with, or presymptomatic for, genetic diseases may be enmeshed, for better or worse.

Society and the test

I have been focusing mainly on the individual and family aspects of presymptomatic testing for Huntington's disease. There are also important societal implications. For people to decide whether they want to be tested, they should know the legal, financial and social repercussions. Many of these are unexplored areas. How coercive might employers become, knowing the at-risk status of an employee, in pushing that employee to be tested? Can tests be required as a condition of hiring? Will an employer assess that certain positions -- neurosurgeon, pilot, construction worker -- are too hazardous for someone positive for the gene or even at risk, even though their performance is unchanged? What legal recourse and protections do people have who are presymptomatic? The Americans With Disabilities Act, recently passed by the United States Congress, should provide some protection against discrimination by employers.

Insurance companies have not yet decided what attitude to take to confront the rise in the availability of genetic tests. It is not clear whether they will reimburse for such tests, whether they will require knowing the diagnostic outcome, or whether those found to be positive, for Huntington's disease, for example, will lose their insurance or be required to pay exorbitant premiums. Will those found to be free have a lowering of their premiums? As it is now, many people who are at risk for Huntington's disease and not part of a group health policy are uninsurable.

When the gene is known

Presymptomatic testing for Huntington's disease at present takes from several months to over a year. DNA samples must be collected from relatives, who must be neurologically assessed, the counseling and evaluations are extensive, and time passes. The necessary counseling is often difficult and raises complex psychological, ethical, legal and moral conundrums.36-37 This drawn-out process acts as a brake on precipitous action and allows a client to live for some time experimenting with both positive and negative outcomes. Couples and families have time to think and discuss with each other. Sometimes a relative whose blood sample is being sought will dissuade an at-risk person from being tested. It takes time to delve through all the layers of defenses that people at risk have built over time to enable them to cope and allow them to feel the emotional reality of a negative or positive test result.38

Once the gene is identified, testing will be much more rapid and accurate and less expensive. We do not yet know how many different mutations of the Huntington's disease gene there may be, even though there is no evidence of locus heterogeneity.39 It may still be necessary to obtain some samples from relatives to determine just which mutation is present in a family, but the very time-consuming linkage typing of relatives will be obviated.

Will this rapidity be a boon? Just because the testing process is faster and cheaper, the information for clients is no less long-lasting or momentous. Failure to insist that people take the time to digest the possibility of hearing potentially catastrophic news could result in many more casualties of testing than we have yet seen.

Genes and mores: givens and chosens

As the titer of HIV rises in our international bloodstream and as more genetic tests are being developed, our sense of endangerment, embattlement and self-righteous defensiveness may also rise. We face a critical time in educating the public and in ensuring that good and culturally appropriate genetic services are available to all people without regard to class or race.

A young man from Germany, at risk for Huntington's disease, commented on presymptomatic testing: "We must be exceedingly careful with any system of records. We must remember that World War II was not so long ago -- and that Fascism is with us today." We cannot permit concentration camps, literal or figurative, for the ill or genetically stigmatized. We are embarking upon an experiment in improving health in the midst of a world of fragile peace, a world suffocating with sufficient nuclear weaponry to rob any disease of its target. Technological developments and the Human Genome Project are providing us with unparalleled opportunities to understand hereditary disease, but we must remember the camps and never pretend not to see.


I am grateful for the collaboration and expertise of Graciela Penchaszadeh and to Judith Lorimer and Edith Shackell for editorial assistance. This work was supported by a grant from the Robert Wood Johnson Foundation.


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