PRENATAL DIAGNOSIS, VOL.
16: 1237-1 245 (1996)
HUNTINGTON’S DISEASE
DAVID CRAUFURD
Department of Clinical Genetics, St. Mary’s Hospital, Manchester, U.K
SUMMARY
Huntington’s disease (HD) is a late-onset degenerative disorder of the central nervous system, caused by a
dominantly inherited mutation in a gene on chromosome 4p. The identification of the trinucleotide repeat mutation
responsible for this disorder has been an important step towards understanding the molecular pathology of HD, but
in the meantime has also made it possible to offer predictive testing and prenatal diagnosis to individuals at high
genetic risk. Predictive testing offers obvious benefits for those who receive a favourable result, but also runs the
risk of significant psychological and social problems for the families involved. Uptake of testing to date has been
limited. Prenatal testing where the pregnancy is at 25% risk carries the same disadvantages as adult predictive
testing, because an unfavourable result would also establish that the at-risk parent is a gene carrier; prenatal
exclusion testing offers an alternative method of detecting and terminating at-risk pregnancies without revealing
the genetic status of the at-risk parent.
KEY WORDS:
Huntington’s disease; genetic testing; prenatal diagnosis
to a wheelchair. Although HD is usually thought
of as a neurological disorder, the motor symptoms
Huntington’s disease (HD) is a chronic, are often preceded by behavioural abnormalities
degenerative disorder of the central nervous including depression, anxiety, imtability and
system which is inherited as an autosomal changes of personality (Folstein et al., 1983a,b)
dominant trait. The characteristic clinical features which in many cases cause much more disability
were first described by George Huntington in 1872 than the neurological problems. Suicide is
(Huntington, 1872) and include motor, cognitive substantially more common than in the general
and behavioural abnormalities; onset occurs most population, especially during the early stages
commonly between the ages of 30 and 50 years, (Schoenfeld et al., 1984; Farrer, 1986). As the
and the disease follows a progressive course with a disease progresses patients invariably develop a
mean interval from diagnosis to death of 17 years form of dementia with poor concentration,
(Quarrel1 and Harper, 1991). Motor abnormalities difficulty in switching attention between different
usually start with involuntary choreiform move- tasks, inefficient use of memory, impairment of
ments (hence the earlier name of Huntington’s executive functions and marked slowing of mental
chorea), which increase in severity for the first few activity.
years but eventually fade away again to be
replaced by bradykinesia and hypokinesia or
rigidity, which is the real cause of the motor
GENETICS
disability in this disorder. Increasingly, the patient
develops dysarthria, dysphagia and impairment of
The disorder is inherited as an autosomal
balance, gait and coordination. The underlying dominant trait with complete penetrance. Children
hypokinetic state gradually comes to dominate the of affected individuals have a 5050 risk of
clinical picture so that by the later stages the developing the disorder in their turn. HD is
patient may be completely bedbound or confined unusual among human genetic disorders in that it
INTRODUCTION
CCC 0 197-385 1/96/13 1237-9
0 1996 by John Wiley & Sons, Ltd.
1238
D. CRAUFURD
displays a true dominant pattern of inheritance,
affected homozygotes being indistinguishable
clinically from heterozygotes (Wexler et al., 1987;
Myers et al., 1989). This finding suggests that the
mutation responsible confers a gain of function in
some way, rather than disrupting the action of the
normal gene. Although penetrance is complete if
the individual carrying the mutation lives long
enough, the age at onset can vary from early
childhood-about 4% of heterozygotes have an
onset before the age of 20 (Walker et al., 1981)to the late 70s or beyond. The resulting uncertainty
causes great problems for the offspring of affected
individuals, who have to cope with the possibility
that they are carrying the HD gene and the
difficulty this creates for making decisions about
career, marriage and reproductive options (Wexler,
1979). For every individual affected with HD at
any given time, there are aproximately another 10
at high genetic risk (50% or 25%) who cannot be
sure that they have escaped the disease until long
after their own families are complete.
There is no cure for HD at present, and no
known treatment capable of delaying the onset of
the disorder. However, the outlook for affected
families has improved greatly during the last 15
years with the advent of modem molecular genetic
techniques. The discovery of genetic markers linked
to the disease on the short arm of chromosome 4
(Gusella et al., 1983) and subsequent identification
of the mutation which causes the disease
(Huntington’s Disease Collaborative Research
Group, 1993) have opened up the possibility of new
treatments based on a clear understanding of the
molecular pathology of the disorder. The mutation
responsible for the disease has turned out to be a
(CAG), trinucleotide repeat sequence close to the 5‘
end of the gene, which is expanded and unstable on
affected chromosomes. Most unaffected individuals
in the general population have alleles with 11-31
copies of the (CAG) repeat, while affected
individuals usually have in excess of 38 repeats
(Huntingdon’s Disease Collaborative Research
Group, 1993; Andrew et al., 1993; Duyao et al.,
1993; Snell et al., 1993). The situation is not
completely clear for the intermediate range between
32 and 38 repeats; recent research suggests there
may well be a small region of overlap between the
normal and abnormal ranges, with at least one
affected case reported to have 36 repeats but several
individuals who remain clinically unaffected at an
advanced age with up to 39 repeats (Rubinszstein et
al., 1966). This mutational mechanism has recently
been identified as the basis for a number of
inherited disorders including Myotonic Dystrophy,
Fragile X Mental Retardation, Spino-Bulbar
Muscular Atrophy (SBMA), Dentato-Rubral
Pallido-Luysian Atrophy (DRPLA), SpinoCerebellar Atrophy types I and In (SCA-I and
SCA-111) and most recently, Friedreich’s Ataxia.
Although these disorders are caused by various
trinucleotide repeat mutations at different
chromosomal locations, those caused by (CAG)
repeats are all neurodegenerative diseases with a
similar range of normal and abnormal allele sizes,
and they are all characterised by onset in middle
age followed by a progressive course (Table I).
The disorders caused by unstable (CAG),
mutations also resemble one another in that most
demonstrate the phenomenon of anticipation
(earlier age at onset or increasing clinical severity in
successive generations) when the gene is
transmitted by the father, but not when it is
transmitted by the mother. Age at onset of HD in
the offspring is quite strongly correlated with age at
onset in the affected parent (Farrer et al., 1984;
Myers et al., 1985) but it has been known for many
years that juvenile-onset cases are almost always
associated with paternal transmission of the gene
(Memtt et al., 1969; Stevens, 1976; Newcombe et
al., 1981) and that paternal transmission is
associated with a slightly earlier onset in the child
than in the father across the whole range of ages at
onset (Myers et al., 1983; Farrer and Conneally
1985; Ridley et al., 1988). The explanation for this
has become clear with the discovery that age at
onset is correlated with the number of (CAG)
repeats, larger expansions being associated with
earlier onset (Huntington’s Disease Collaborative
Research Group, 1993) although it is clear that
other factors must also be involved as repeat
number only explains about 50% of the variance in
age at onset and even less in older patients
(Andrew et al., 1993). When the gene is
transmitted by the mother, and in most cases
where transmission is from an affected father, the
child inherits a gene with aproximately the same
number of repeats and has a similar age at onset;
however, in about a third of cases with paternal
transmission the offspring inherits a larger number
of repeats than in the affected parent and has an
earlier onset (Table 11). This may be a matter of
particular concern to males at risk for HD, who
run a small but not insignificant risk of passing on
the disorder to their children in its juvenile-onset
form.
1239
HUNTINGDON’S DISEASE
Table I-Disorders caused by trinucleotide repeat mutations
Disease
Repeat
Normal range
Full mutation
FMRl (Fragile X)
SBMA
HD
CGG
CAG
CAG
CAG
CAG
5-52
11-33
10-39
7-23
&-44
13-40
5-37
7-22
230->1000
4062
36-100
49-75
40-82
68-79
DRPLA
SCA I
SCA III (Machado-Joseph)
DM
Friedreich ataxia
CAG
CTG
GAA
1004000
200->900
Predictive testing offers the prospect of freedom
Table 11-Anticipation with paternal transmissionin
Huntington’s disease: number of CAG repeats in fathers from the psychological burdens associated with
transmitting the disorder and their affected offspring
being at risk, if the individual is shown not to be a
carrier of the disease mutation. It also means that
all the descendants of someone receiving a
Number of CAG
Number of CAG
favourable test result will no longer be at risk.
repeats (child)
repeats (father)
Unfortunately, this has to be balanced against the
potential psychological problems facing those who
48
45
receive an unfavourable result. These individuals
44
46
will know that they are inevitably going to develop
44
47
the family illness if they live long enough, and it
55
86
may be very difficult to maintain a positive
45
48
attitude and avoid despair in these circumstances
49
71
(Wexler
er al., 1985). It has been argued that even
43
39
those who prove to carry the gene will benefit
44
46
from the resolution of uncertainty and may be able
43
42
to use the information to plan their future lives
43
51
more effectively (Bates, 1981; Thomas, 1982).
However, molecular genetic testing does not allow
useful prediction of the likely age at onset
PREDICTIVE TESTING
(Craufurd and Dodge, 1993) and the test may
therefore replace concern about whether the
The practical goal of research into the molecular individual will develop HD with the equally
genetics of HD is to develop new approaches to difficult question of when this will occur. Wexler
treatment of the disorder, and work is in progress to er al. (1985) also pointed out that predictive
elucidate the molecular mechanisms by which the testing may have unforseen effects on other family
mutation produces the characteristic pathology of members, and that even those receiving favourable
HD. In the meantime, the discovery of the gene has results may experience feelings of guilt about
also created the possibility of predictive testing both being more fortunate than their siblings-the sofor at-risk individuals who have not yet developed called ‘survivor syndrome’. In addition to these
symptoms, and for prenatal testing to determine psychological problems, concern has been
whether an at-risk fetus is a camer of the HD expressed about practical problems such as the
mutation. Initially this was done using RFLP possibility of discrimination by insurance
markers known to be linked to the disease locus, but companies or potential employers (Craufurd and
this has now been replaced by a direct test Harris, 1986; Berg and Fletcher, 1986).
In spite of these potential problems, several
measuring the number of repeats at the HD locus
which allows quicker, cheaper and more accurate studies carried out just before the introduction of
prediction of carrier status.
predictive testing reported that between 56%- 80%
1240
D. CRAUFURD
of at-risk individuals would choose to have a
predictive test if this were available (Stem and
Eldridge, 1975; Barette and Marsden, 1979;
Teltscher and Polgar, 1981; Tyler and Harper,
1983; Kessler, 1987). In practice, the uptake of
predictive testing has been much more limited and
suggests a considerable degree of caution among
the at-risk population about the potential
psychological problems involved. A study of 110
previously counselled at-risk individuals in regular
contact with the Manchester Genetic Family
Register service, who were contacted and offered
the test, found that only 8 (7.3%) had actually
gone ahead while 9 were still undecided, giving a
maximum possible uptake of 1 5 5 % (Craufurd et
al., 1989). Analysis of uptake figures for the UK
as a whole shows that almost two thirds of those
who do procede with testing are female (Tyler et
al, 1992); this sex difference may well reflect
concern about passing on the gene to future
generations of the family and the generally greater
role of women in the process of making
reproductive decisions (Bloch er al., 1989),
although it may also be due to different methods
of coping used by men and women.
The data available to date suggest that most
people cope surprisingly well after adverse
predictive test results (Bloch et al., 1992;
Wiggins et al., 1992; Tibben et af., 1993; Codori
and Brandt, 1994) although many of these
authors have drawn attention to the difficulties
sometimes experienced by partners of predictive
test patients and even by those receiving
favourable results (Huggins et al., 1992). Even
so, the decision about whether to have a
predictive test is clearly a difficult one and a
consensus has emerged about the need for
adequate counselling and support to be offered
both before and after such tests are carried out.
Ethical guidelines have been published by a joint
committee of the International Huntington Association and the World Federation of Neurology
Research Group on Huntington’s chorea
(International Huntington Association, 1994) and
there is a detailed protocol which is used by all
centres offering predictive testing in the United
Kingdom (Craufurd and Tyler, 1992). It is
recommended that predictive testing should only
be offered in specialist genetic counselling units
knowledgeable about the issues involved, that
care should be taken to ensure the decision is
solely the choice of the individual concerned
(without pressure from third parties, family or
otherwise) and that testing should not be
available to children under the age of majority of
the country concerned. Testing should only take
place in the context of a suitable protocol for preand post-test counselling and support, which in
the UK protocol involves a minimum of two pretest sessions separated by an interval of a few
weeks, so that the person has an opportunity to
reflect on the issues involved. Those in stable
long-term relationships are advised to involve
their spouse/partner in the decision making
process, and everyone requesting testing is
encouraged to select a companion to accompany
him or her throughout all stages of the testing
process. Results should be given as soon as
reasonably possible after completion of the test,
but laboratories are advised not to disclose the
outcome to the clinician involved until very close
to the time when the result is due to be given to
the patient; this avoids problems if the patient has
second thoughts and contacts the clinician
requesting further counselling.
PRENATAL TESTING
One of the more common reasons mentioned by
those requesting predictive tests is that the result
will help to make reproductive decisions. In a
study of 63 individuals receiving predictive test
results in The Netherlands, this was cited as a
major reason by 60% of subjects (Tibben et al.,
1993). While some at-risk individuals may seek
predictive testing with the intention of limiting
their families, or refraining from having children
altogether if they prove to be carriers of the HD
mutation, there are many others who would decide
to go ahead and have a family if it were possible to
be sure that the children do not inherit the
abnormal gene. Prenatal testing, either by linkage
or direct mutation testing, provides a way to
achieve this. In Tibben’s study (llbben et al.,
1993) there were 17 carriers who had not
previously regarded their families as complete, of
whom 5 had decided to refrain from having more
children when interviewed six months after
receiving the unfavourable result, while 12 still
wished to enlarge their families of whom 7 were
definitely considering prenatal testing with
selective termination of pregnancy in the event of
an affected fetus.
Prenatal testing differs little from adult
presymptomatic testing when one of the parents is
HUNTINGDON’S DISEASE
affected or has been given an unfavourable
predictive test result, and the advent of direct
mutation testing has greatly simplified the process
of prenatal diagnosis. Fetal DNA can be obtained
by chorionic villus biopsy (CVB),and the test can
be carried out directly without the need to culture
cells, allowing the result to be obtained within the
first trimester. However, it is fairly uncommon for
couples to embark on a pregnancy after one of
them has been diagnosed with HD, perhaps
because there are concerns not only about the risk
of passing on the gene to another generation, but
also about the ability of the affected individual to
function adequately as a parent until the child is
old enough for this to be no longer necessary.
Prenatal testing is more frequently requested by
couples where one partner is at 50% risk, but may
perhaps prefer not to know whether he or she is a
carrier of the HD mutation. In this situation a test
which demonstrated that the fetus carries an
expanded HD allele would simultaneously reveal
that the at-risk parent is also a carrier. This creates
a number of problems. One option would be for
the at-risk parent to undergo predictive testing
first, but if preparation for this were not already
under way before the pregnancy it would be
impossible to adhere to the ethical guidelines and
allow an adequate interval for reflection within the
time available; furthermore, the relatively low
uptake of predictive testing among the at-risk
population means that most parents in this
situation would ideally prefer not to be tested
themselves.
An alternative solution for prospective parents
who would prefer not to be tested themselves but
feel strongly that they could not risk passing the
disease on to yet another generation is prenatal
exclusion testing (Hayden et al., 1987; Quarrel1 et
al., 1987), where linked genetic markers are used
to determine whether the HD allele passed to the
fetus by the at-risk parent originated with the
affected or the unaffected grandparent. If the fetus
has inherited the relevant markers from the
affected grandparent it shares the same 50:50 risk
as the intervening parent and the pregnancy is
terminated, whereas the haplotype from the
unaffected grandparent leaves the fetus at very low
risk and the parents can be reassured. The
advantage of prenatal exclusion testing is that it
does not provide any additional information about
the carrier status of the at-risk parent, although
many couples have difficulty grasping this point
(Tyler et al., 1990; Adam et al., 1993). The
1241
disadvantage is that an unfavourable result leaves
the fetus at 50% risk, and the couple are faced
with the prospect of terminating a wanted
pregnancy in the knowledge that this may
eventually prove to have been unnecessary. The
ethical justification for selective abortion in these
circumstances is controversial (Post, 1992) and
although it is clearly a matter for personal choice,
the uncertainty of the result and the possibility that
science may devise an effective cure for HD
before the child is old enough to be affected makes
the decision a very difficult one for many couples.
Some have choosen to undergo a stepwise
procedure (Fahy, 1989) involving a preliminary
exclusion test, with subsequent definitive testing
for themselves and the fetus only if the exclusion
result is unfavourable; this approach removes the
risk of terminating an unaffected pregnancy, but
has the drawback that an unfavourable result
leaves the at-risk parent having to cope with the
loss of a wanted pregnancy at the same time as
coming to terms with hidher own unfavourable
predictive test result for which neither partner has
been adequately prepared. Although this is clearly
an unsatisfactory situation, it may be more
acceptable to some at-risk individuals than
terminating a possibly unaffected pregnancy, and
does at least offer a better chance of a favourable
result than going straight to predictive testing
because there is a 25% probability that the fetus
will be affected while their own risk is 50%.
Essentially the same result can nowadays be
achieved more simply by testing the fetus directly
for the HD mutation, although this does not
provide the useful pause for reflection offered by
the ‘exclusion-definitive’approach.
Another ethical problem associated with
prenatal testing arises when at-risk parents request
prenatal diagnosis and subsequently change their
minds about the decision to terminate the
pregnancy. Even with exclusion testing, a fetus
which has inherited linked markers from the
affected grandparent will share with the at-risk
parent a 50% risk of HD; if the pregnancy were
allowed to continue and the at-risk parent
subsequently developed symptoms, it would
immediately be apparent that (in the absence of
recombination) the child must also be a carrier of
HD. Not to terminate the pregnancy after an
unfavourable prenatal test result creates a situation
where the child potentially will have to grow up
with the knowledge that he or she will one day
develop HD, and deprives the child of any
1242
D. CRAUFURD
personal say in this decision. While some parents
may believe they are entitled to this information
about their child, nothing can be done at present to
modify or delay the onset of the disease and there
is a widespread consensus among clinical
geneticists that testing children for late-onset
genetic diseases in these circumstances is
unethical (Clinical Genetics Society, 1994). It is
therefore inappropriate to carry out prenatal
testing if the at-risk couple do not intend to
terminate the pregnancy in the event of an
unfavourable result (Quarrel1 et al., 1987)
although there have been reports of couples who
start out with this intention and have a last-minute
change of mind (Tolmie et al., 1995).
It is also important for couples contemplating
prenatal testing to consider the implications for
any pre-existing children, who will have to know
in due course that they are at risk for HD, while
any siblings born after prenatal testing are not.
There is a risk that this will create problems with
family relationships later on. A very similar
problem applies to subsequent pregnancies; having
once terminated a pregnancy because of an
unfavourable prenatal test, it may be very difficult
to adopt a different strategy later on and embark
on a pregnancy without testing. It is possible that a
couple may find the psychological cost of
terminating a much-wanted pregnancy too high to
be able to face the prospect of going through it all
again after another unsuccessful test, but at the
same time feel constrained by a sense of
obligation to the lost child that makes it
impossible to simply take the risk without testing.
The development of a rapid, direct PCR test
for the HD mutation has greatly simplified the
process of prenatal diagnosis from the laboratory
perspective, because it is no longer necessary to
analyse DNA samples from the parents and
grandparents of the fetus to be tested. The
problem of identifying an informative marker for
linkage testing can sometimes be quite timeconsuming and involve a considerable amount of
work, often carried out under pressure, in order
to allow a first-trimester termination of
pregnancy in the event of an unfavourable result.
In circumstances where couples have decided to
have exclusion testing by linkage analysis, it is
always preferable to obtain DNA from the
prospective parents and grandparents in advance
so that informative markers can be identified
before prenatal testing is carried out. Linkage
analysis is less precise than direct mutation
testing because of the need to allow for genetic
recombination between the marker and the HD
locus. It is also more difficult to detect
inconsistent haplotypes due to laboratory or
clerical errors (or non-paternity) when analysing
marker data from small family groups (King et
al., 1993). However, in the case of exclusion
testing it is not possible to avoid the potential for
this type of error by typing larger numbers of
relatives without the risk of obtaining
information which would be fully predictive for
the at-risk parent (Millan et al., 1989). In spite of
all the advantages of the new direct test there is
still a strong case for retaining the option of
exclusion testing for those who do not want to
know their own carrier status (Rubinsztein et al.,
1994) and direct testing is not without its own
technical problems, notably the difficulty
interpreting the significance of intermediate alleles
and the theoretical possibility of misleading results
due to mitotic instability of the CAG repeat copy
number. Reassuringly, a recent study by Benitez et
al. (1995) of two fetuses aborted after prenatal
diagnosis showed the same number of repeats in
many different fetal tissues as well as the sample
taken at CVB; the authors suggest that previous
reports of somatic instability in tissues from
affected patients may be a secondary consequence
of neuronal degeneration and gliosis.
As with predictive testing, early surveys
suggested a high level of demand for prenatal
testing among the at-risk population. When linkage
markers for the HD gene were first identified, three
studies of at-risk people in the USA indicated that
between 42% and 66% of those surveyed would
consider making use of prenatal testing, although in
each case rather fewer said they would terminate in
the event of a high-risk pregnancy (Kessler et al.,
1987; Markel et al., 1987; Meissen and Berchek,
1987). On the other hand, a very similar study
camed out at exactly the same time in New
England found that only 12% of respondents
thought they were likely to use prenatal testing
(Mastromauro ef al., 1987) and a study looking at
the attitudes of young women in Belgium found
that although 50% of those surveyed found prenatal
testing for late-onset disease acceptable, only 28%
of the group would be prepared to terminate a
pregnancy in these circumstances (Decruyenaere et
al., 1993). Among subjects actually requesting
presymptomatic testing in North West England
(Craufurd, 1989) 81% of those regarding their
families as incomplete said they would consider
1243
HUNTINGDON’S DISEASE
prenatal testing in pregnancy, but only 65% would
consider termination of pregnancy and this fell to
35% when the risk to the fetus was 50% (the
outcome of an unfavourable exclusion test). In the
Canadian predictive test programme, attitudes were
very similar with 29% who would consider prenatal
testing with a view to selective termination of
pregnancy (Bloch et al., 1989). However, the
partners of predictive test patients appear to be
more in favour, with 75% stating that prenatal
testing should be available (Evers-Kiebooms et al.,
1990), while a survey of 308 clinicians in the UK
concerning knowledge and attitudes to prenatal
testing for HD and other serious genetic disorders,
found that 95% thought it was always or often
appropriate to offer the test (Firth and Lindenbaum,
1992).
In practice, the uptake of prenatal testing has
been even less than these figures would suggest. In
the first five years of the predictive test programme
in Canada (Adam et al., 1993), there were 47
pregnancies, of whom 14 (30%) requested prenatal
testing while 24 (51%) did not and 9 (19%)had no
need because they had already received a
favourable predictive test result; 7 subsequently
decided not to go ahead, leaving an overall uptake
rate for prenatal testing of 7/38 (18%). The most
frequently cited reason for not having a prenatal test
was the hope that a cure would be found in time for
their children to benefit from this. World-wide, a
recent international survey identified a total of less
than 250 prenatal tests performed between 1986
and the end of 1994 whereas the number of
predictive tests during the same period amount to
several thousand (Evers-Kiebooms, 1995).
CONCLUSION
especially where it is the male at risk while the
female partner is the one who may have to go
through the trauma of an unwanted termination of
pregnancy. There are no simple solutions to these
problems which can be applied to everyone, and it
is the art (and duty) of the genetic counsellor to
guide our patients through these difficult waters
and help them find their own course in the full
knowledge of the dangers that lie ahead.
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