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
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 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
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
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
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.
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
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
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
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.
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.
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.
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
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
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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