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that immediate response, while providing detailed mformatlon to statutory
and sctenttfic authorities throughout the world. Separate but interrelated mea-
sures have been taken to protect public health against any rrsk that BSE may
pose, to prevent infectton being spread to other animal species, and to eradr-
cate BSE from UK cattle. The costs of doing so-more than &160 mtlhon
(approx $256 million) on compensation and drsposal costs alone at the time of
wrmng-have been enormous, and rt should be noted that almost all of these
costs have been incurred by the public health protection measures. Animal
health IS protected m other, less expensrve, ways, although the cost of destroy-
mg SBOs has been srgmficant. The hypothesis developed after studying the
first 200 or so cases, that BSE was basically a food-borne common source
epidemtc that could be controlled by preventing the use of infected feed, has
been vindicated by events. The effect of the feed ban 1sshown clearly m the
eptdemic curve (see Fig. 2) and m the dramatically reduced number of casesm
animals born after its mtroductton (see Fig. 3, prevzouspuge). Such progress IS
pleasing, but only partially relevant to public health, which IS protected by
separate measures designed to be effective whether BSE is controlled and eradr-
cated or not.
References
1 Report of the Working Party on Bovine Spongiform Encephalopathy (The
Southwood Report) (1989) DoH, MAFF, HMSO, London.
2 Consultative Committee on Research mto Sponglform Encephalopathles Interim
Report (“The Tyrrell Report”) (1989) MAFF, DoH, HMSO, London
3 Spongiform Encephalopathy Advisory Committee (1992) Interim Report on
Research. DoH, MAFF; HMSO, London.
4. Sponglform Encephalopathy Adwsory Committee. (1995) Transmissible Spon-
glform Encephalopathies. A Summary of Present Knowledge and Research.
HMSQ, London.
Tyrt-e/l and Taylor
198
5 Ammal Health, 1988-1993 mcluslve (Reports of the Chief Vetermary Officer)
HMSO, London.
6 Transmlsslble Sponglform Encephalopathles of Ammals OIE Sclentlfic and
Techmcal Review (1992) vol 11
7 Bovme Sponglform Encephalopathy m Great Britain (1994) A Progress Report
MAFF; HMSO, London.
8. Taylor, K C (1991) The control of bovine sponglform encephalopathy m Great
Britain. Vet Ret 129, 522-526
9 Taylor, K C (1994) Bovine sponglform encephalopathy control m Great Britain
Lwestock Prod Scl 38, 17-21
Special Problems
of Genetic Counseling in Adult-Onset Diseases
Huntington™s Disease as a Model

Jonathon FL Gray, Jo R. Soldan, and Peter S. Harper


1. Introduction
Neurological disorders impose a severe burden on affected mdividuals
Inherited neurological disorders of late onset present their own specific difficul-
ties m terms of genetic counselmg, management, and patients™ psychological
adaptation. Huntington™s disease (HD) is the archetypal late-onset neurogenetic
disorder. It is an autosomal-dominant disorder usually of adult onset m which
progressive degeneration of the cerebral cortex and basal ganglia result m
choreiform movements and progressive mental deterioration. Closely linked
genetic markers have been available smce 1983 so that presymptomatic testmg
protocols have been m development longer for this disorder than for any other
similar disorder (for further mformatron on HD specifically see ref. I). In this
chapter we highlight the major issues we consider relevant to achieving opti-
mal diagnostic, predictive, and prenatal testing and to the family management
of indrvtduals from HD famlhes. We put forward the protocols we have devel-
oped to help chmcians and other allied workers approach these difficult areas.
One of the mam issues in late-onset disorders relates to diagnostic and
presymptomatic testing. It IS important to recognize from the outset that these
are separate problems and must be treated as such. Clear distinction is implicit
m the term “diagnostrc” test, in which the patient is referred for specific muta-
tion analysis because of suspicious clinical features of that disorder. Presymp-
tomatic testing, on the other hand, is performed on healthy mdtviduals in the
absence of any clinical features of the disorder.

From Methods m Molecular Medrcrne Prron Diseases
E&ted by H Baker and R M Rtdley Humana Press Inc , Totowa, NJ

199
Gray, Soldan, and Harper
200

Although the experience and procedures discussed here have been based on
HD, they have wide relevance and applicabthty to other late-onset neurologr-
cal drsorders. In recogmtion that many issues relating to late-onset disorders
are not resolved but still open to debate, we conclude with a consideratton of
some of the outstanding problems.
2. Diagnostic Testing
2.1. Special issues
Diagnostic testmg m HD alms not only to confirm a diagnosis, but also to
rule out other possrble underlying causesof the same clmical features, some of
which may be treatable. Given the multiple problems presented by HD and the
importance of specificity of dtagnosis, dtagnostrc protocols must address
problems associated with differential dtagnosts, the various referral routes, and
associated halsons with other spectaltsts, for example neurologtsts and
psychtatrtsts.
Genetic testing for the specific HD mutation now forms an Important part of
the diagnostic process but should be used m conJunctton wtth other clmical
and mvestigatlve approaches and not as a substitute for them. Particular care
must be taken when mvestigatmg relatives of a known case of HD where pres-
ence of the mutation may not necessarily be related to the cause of the symp-
toms. A full diagnostic workup allows the rulmg out of the varied alternative
dragnoses and rf necessary provides the space for full counselmg if the tests do
suggest HD.
In the majority of cases,prevtous rusk of HD IS known, and therefore dtag-
nests mvolves a transition from hvmg at risk to having the disease. Often quite
subtle changes m symptoms signify a significant change m self-perceptton,
against which a number of defenses may have already developed (2). Thts tran-
sttton, therefore, requires careful management. Diagnostic protocols must
include an assessmentof the ttmmg of diagnosis, which must be carefully con-
sidered from the patient™s pomt of view, the result not bemg given until It IS
wanted by the patient (3).
2.2. Procedures
2.2.1. Neurological Examination
2 2.1.1. GENERAL INTERVIEW
Be aware of potential dragnostrc clues, e.g., minor mvoluntary movements,
altered mental state, abnormal gait or posture.
2.2 1.2. GENERAL EXAMINATION
This IS not expected to be abnormal.
201
Genetic Counseling
2.2 1 3. CRANIALNERVES
FundI* normal.
Eye movements Saccades are a sensitive early sign
Hearing. normal
Facial muscles* Early evidence of chorelform movements may be visible
Tongue. chorea, dyspraxla.
Speech rarely affected m early disease, but may be severe later
2 2.1 4 LlME3S

General chorelc movements early m hands and feet. No early wasting
Power. normal, but may seem to tluctuate because of chorea
Tone* usually mmally normal, increased early m rigid cases.
Reflexes: usually normal, except m juvenile form Often increased late rn
some cases, with upgomg plantars Reflexes impaired or absent m neuro-
acanthocytosls
Coordmatlon Rarely there may be cerebellar signs
Sensation. normal.
Gait. normal early but may be bizarre later and affected by chorea/dystoma
2 2.2 Neuropsychological Assessment
A range of global memory and frontal lobe assessments can ascertam the
mdlvidual™s cognitive performance in HD and hence give an mdlcatlon of any
global or specific problems. In addition to being helpful m the diagnostic pro-
file, the results of objective, standardized tests can be helpful for the patient
and family. Ascertaining objective problems can facilitate the understanding
and acceptance of what are often bewildering, gradual changes.
2.2.3. Radiological Assessment
1, Computerized tomography (CT) Caudate or generalized cortical atrophy are use-
ful but not dlagnostlc indicators
2. Magnetic resonance imaging (MRI) provides similar information but wrth some
Improved defimtlon. Its value hes in excluding differential diagnoses, such as
tumors and infarcts. Practical limitations include normal scan often seen early in
disease and the possibility ofpoorpatlent cooperation with scanmng m later disease.
2 2.4. Laboratory Investigations
A number of laboratory mvestlgatlons (many of which will exclude other
condltlons) may be useful in suspectedcasesof HD. These are shown in Table 1.
2.3. Outstanding Problems
Diagnostic procedures are normally only instituted with the express consent
of the person being tested. This, of course, may not always be possible ma
202 Gray, Soldan, and Harper
Table 1
Laboratory Investigations in Suspected Cases of Huntington™s Disease
Changes m HD
Investlgatlon Usefulness
Blood film (fresh Normal May suggest neuroacanthocytosls
thrck wet film) or alcohohc encephalopathy
Creattne kmase Raised m neuroacanthocytosls
Normal
Red cell Indices Exclude polycythemta
Normal
Copper studtes Exclude Wilson™s dtsease
Norma1
Sht lamp Norma1 Exclude Wtlson™s dtsease
Thyroid functton test Normal Exclude thyrotoxtcosrs
Antmuclear factor Normal Exclude systemtc lupus
erythematosts
Exclude syphilis
Syphihs serology Normal
Usually charactertsttc
Postmortem Distmguishes from other neuro-
neuropathology but may appear degeneratrve dtsorders
normal m early stages
DNA analysts Expanded trtplet repeats Dtagnostic for genettc status, but
may not be explanatton for
current status


disorder such as HD when cognitive function may be impaired. Even m the
absence of stgmficant cognitive impairment, denial can be a major factor m
such patients (2) and although a partner and the clmtcians mvolved may recog-
nize a problem, the mdtvidual at risk may not see tt in the same way. Careful
supportive medical care can be helpful m such situations (3), but often these
are very dtfficult areas to address.
Problems of an unresolved diagnosis are less frequent with the advent of
molecular testing for the HD mutatton, although all pattents embarking on both
dtagnosttc and presymptomatic testmg should be warned of the very small risk
of a result that may not be clearly interpretable. Wrthm our own populatton a
cut-off point of 34 repeats IS usually taken as the upper hmtt of normal,
although as evtdence IS accruing from other centers it is becoming clear that
this IS not universally applicable.
Testing
3. Presymptomatic
3.1. Issues
As already mentioned, presymptomattc testing 1snormally clearly dtstm-
gutshable from diagnostic testing m that there are no clmtcal features of the
disorder at the ttme of the test. One aspect of many presymptomatic testing
programs 1s a neurological exammatron; tf early features of the drsease are
identified then the patient would be offered the opportumty to swatch to a diag-
Genetic Counseling 203

nostic protocol. It is important that candidates be made aware and consent to
such an approach before they embark on presymptomatic testmg (4). An rmpor-
tant feature of most presymptomatic testing evaluattons has been the finding of
abnormal clmical features in a significant proportion of apphcants. If the mdi-
vidual is unaware of these, or if they are equivocal m nature, this may give
special problems in counselmg and may blur the distinction between diagnos-
tic and presymptomatic testing.
The technological simplicity of the laboratory aspectsof the presymptomatic
test contrasts with the complexity of the decision to take the test and potential
psychosocial sequelae of altering one™s status from a 50% risk to no risk or to
presymptomatic gene carrier. Research on other forms of genetic testmg has
shown that how a test is offered has a major effect on uptake (5). Developing
services need to consider how they offer a presymptomatic test, in order to
ensure that individuals know of its availability, without feeling that it is being
medically advised. There are a number of ethical and legal dilemmas associ-
ated with presymptomatrc testing for adult-onset disorders (6-8). The ethical
prmciples of autonomy, beneficience, confidentiality, and justice have been
discussed as playing a major role (9), although the practical decrsions m any
mdrvidual situation can usually be resolved by a sensmve and experienced
approach.
A major issue surrounding presymptomatic testing is the concept of
informed consent (IO). In the case of presymptomatic testing, being “informed”
requires exploration of such information as potential insurance and employ-
ment implications, an understanding of the medical and possible psychiatric
implications related to the disease, and the psychological adaptation necessary
in order to live with a result. Whether normal or abnormal the result will involve
a change in self-perception, and therefore may be perceived as psychologically
threatening until the individual achieves a new homeostasis (2 Z).
The aim of presymptomatic counseling IS to foster insight and understand-
ing that will help the individual in his or her decision-making process concern-
mg taking the test and subsequent adjustment to the result. It IS vital that
particrpation m presymptomatic testing programs is the mdividual™s decision
at each stage of the process, and it is important that participants are aware that
they can withdraw from the program at any stage. In the knowledge of this the
various issues are explored and their possible coping strategies elucidated in
the pretest interviews,
Research evidence is suggesting self-selection for presymptomatic testing
to be the major factor influencing the perception of psychological variables
and perception of ability to cope with the result (12). This may change with
time, different external pressures, and in different disease processes, where
other variables may play a more major role in determining selection of testmg.
Gray, Soldan, and Harper
204

A major issue surrounding the whole concept of presymptomatic testing is
the concept of who should be accepted into such programs It could be argued
that anyone who can give informed consent should be allowed to enter a
presymptomatic testmg program, although such issues as the age of consent,
the testing of children, those showing definite or equivocal signs, or those with
a recent or current psychiatric condition, the testmg of pregnant women, and
the problems associated with testing people at 25% risk (and thereby generat-
ing a result on an intervening parent) all need to be addressed.
An essential part of the HD program is that the counseling about testing and the
potential impact of a result allows Individuals to consider then decision to be tested
and to prepare for the result. This aim is hard to achieve if candidates perceive a
need to convince the clinician that they will cope with a result m order to be allowed
to proceed, a potential confltct that needs to be addressed m service delivery
The impact of a presymptomatic result is the subject of much current
research (13-15). One result that surprised many was the evidence of adverse
reactions to a reduced risk (Z6), highlighting the adaptation demands previ-
ously mentioned contmgent on the change in risk status, m whatever direction.
The result of a presymptomatic test also has implications for the mdividual™s
family, particularly his or her partner, and will have a potential impact on rela-
tionships (13,24). For this reason protocols have advocated the mclusion of the
partner in the testing program.

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