The Huntington's Scene In New Zealand |
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| Articles sent by the International Huntingtons Association |
Highlights
from Toronto
Overview of HD Research and the
Huntington Study Group
Dr Ira Shoulson, Rochester USA
The Huntington Study Group was
formed in 1987. There are now 60 active sites in USA, Europe and Australia with 250
clinical investigators and scientists. The HSG is supported by Huntington Disease Society
of America, the Huntington Society of Canada, the Hereditary Disease Foundation and the
High Q Foundation.
Entering coded clinical data about
HD patients assessed by the Unified HD Rating Scale into central database provides the
basis for clinical trials. .
A new approach is to collect
information on potential 'biomarkers' that may affect disease onset and progression. This
may be the key to developing new treatments.
Clinical trials are based on the
outcomes of mouse studies.
Phase 1 -tested on non-HD controls.
Phase 2 -safety , tolerability and
dosage trial with people with HD.
Phase 3 -large scale, long term
trial.
CARE-HD was conducted in the USA.
Co-enzymeQ and Remacemide were
tested in a double blind placebo study with 450 patients with early stage HD.
It was found that Remacemide
decreased chorea and was safe but did not slow progression.
Coenzyme Q at 600 mg/day showed a
15% slowing of the rate of progression, but this is not enough to prove effective. However
a trial with Parkinson's disease on 1200mg/day has found a 40% slowing of rate of
progression.
It is planned to run a Phase 2 trial
to test the safety of a higher dose in people with HD.
If found to be safe, a large scale
trial (2-CARE) will begin in 2004 with over 1,000 early stage HD patients.
Trials of riluzole, minocyline and
creatine are also being undertaken.
Two studies with pre-symptomatic
people at risk are being conducted.
PHAROS will run from 1999 to 2007 in
the USA & Canada with 960 at risk people aged from 30 to 55 who have not been DNA
tested.
Participants undergo physical and
psychosocial assessment for HD-related features every 9 months. Their DNA is analysed but
the results not revealed.
PREDICT -HD will be conducted from
2002 to 2008. The aim is to enroll 550 people who have had the predictive test (250
enrolled 50 far) with sites in USA and Australia.
Same assessments as for PHAROS
study, once a year for 4 years, however the main difference is that those participating
know their results.
Neurosurgical Approaches to Therapy
for HD
Dr Marc Peschanski, Creteil, France
Seven to ten week fetal brain cells
will form new connections if the brain is damaged and if cells specific for damaged area
are used.
Originally started with trials in
animals and these showed promise.
The first human transplants were
undertaken from 1996 to 1997 after presurgery assessment over 2 years.
Of the five early stage HD patients
who underwent surgery, one did not improve. Of the four who showed improvement, one did so
significantly but then lost
everything. The three others showed
sustained improvement after 12 months, both physically and cognitively.
The trial is to be expanded to 50
patients across 7 centres in UK and Europe and it is hoped the trial will be completed by
2007.
Gene therapy trials, that is
inserting neuroprotective agents into brain cells, have also commenced
Cell Dysfunction Rather than Cell
Death
Dr Patrik Brundin and Dr Asa
Petersen, Lund,
Sweden
Transgenic mice studies have shown
that the cause of HD symptoms may not just be due to cell death but also to cell
dysfunction.
HD cells are unable to release
neuro-transmitters at normal rate and they also don't respond to toxins in normal way but
are resistant.
Therapy needs to be found to prevent
cell dysfunction.
European HD Research Network
Dr Bernhard Landwehrmeyer, Germany
Formation of a European HD Research
Network with funding from US High Q Foundation. The network will cover Italy, UK, Germany,
The Netherlands, France and Sweden and it will establish the same clinical database as the
HSG.
It is planned to run Phase 2
(tolerability) trials of 3 compounds, with one commencing in 2004.
There is a plan to look for
biomarkers and a PREDICT type study which will include PET scans, will also commence.
The stakeholders' committee for the
European network will include consumer representatives.
Website:
www.nesu.mphy.lu.se
Counselling issues in predictive
Testing
Ms Roslyn Tassicker, Melbourne,
Australia
Non-consensual predictive testing,
that is, where requests for predictive or prenatal testing may reveal a result for another
person who does not want to know, has complex counselling and legal issues. Does the
clinician have a legal or clinical responsibility to a person who has not contacted the
genetics service?
Two requests were received for
prenatal testing by women whose partners are at 50% risk but do not want testing. A
positive prenatal result gives an answer for the partner. There is no clear legal advice
regarding this issue.
Request for testing by people at 25%
risk when parent at 50% risk does not want to know is another situation. The guidelines
recommend involving both parties in
counselling but this is not always
possible. There may be conflictual relationship between parent and son/daughter and there
is great potential for harm.
Two cases of identical twins where
one twin wanted the test and the other did not have arisen. In both cases, legal advice
was to go ahead with the tests and to warn the non-tested twins of possible harm and
encourage them to seek support from genetic services/
These are extremely complex and
challenging counselling situations.
Pre-implantation Genetic Diagnosis
Ms Alison Lashwood, London, UK
Preimplantation genetic diagnosis
(PGD) for HD commenced in the UK in May 2002.
Prospective parents undergo
extensive counselling to discuss the process of PGD, including the welfare of children
born into a family where one parent will become symptomatic.
Nine couples have undergone
treatment with four couples becoming pregnant. One miscarried triplets, one had twins, two
couples have ongoing pregnancies and
five couples have not achieved an
ongoing pregnancy. Despite a misdiagnosis risk of 2-5% per embryo, all couples decided
against confirmatory prenatal diagnosis
and under the protocol no
confirmatory testing is possible at birth.
Despite its complexity, PGD offers
an acceptable alternative to routine prenatal diagnosis.
PEG Feeding and End-Stage HD
Dr Sheila Simpson, Aberdeen,
Scotland
Feeding using percutaneous
endoscopic gastrostomy (PEG) has been suggested as a means of providing additional
calories in a safer and more reliable fashion.
PEG feeding raises a number of
ethical issues because it is a form of artificial feeding and it does not remove the risk
of aspiration. It will not cure HD, but it may sustain life. None the less it is often put
into place with little or
no discussion with the parent or his
family. There has been little debate about withholding or withdrawal of such feeding which
some view as treatment and others as basic care, yet the dilemma occurs frequently as the
HD patient deteriorates.
In a survey of members of Scottish
HD families, only 6.9% had discussed PEG feeding with their doctor. Although the patient's
wishes should override doctor's, it is often too late and there have been some bad
situations.
It is recommended that patients and
their families be involved in decision making well ahead of time and that tile possibility
of 'living will’s' and 'power of attorney' be investigated.
There is the need for international
guidelines on these issues.
Sexual Behaviour in HD
Dr David Craufurd, Manchester, UK
Previous reports in the medical
literature, including that of Huntington himself, have suggested that HD is associated
with hypersexuality. However the only study to date which examined the issue
systematically using modern research methods found no evidence to support this (Fedoroff
et al., 1994).
Dr Craufurd and his colleagues
investigated libido and sexual behaviour as part of a broader study of behaviour in
patients with HD.
The study involved 134 HD patients,
representing all stages of HD.
The following changes in sexual
behaviour were reported:
62% loss of libido
6% sexual disinhibition
5% demanding behaviour
There was significant correlation
between loss of libido and progression of disease and significant correlation between
sexual behaviour (that is demanding and/or disinhibited) and behavioural features such as
irritability, aggression, lack of insight, obsessiveness, perseveration.
The conclusions reached are:
hypersexual behaviour is rare in HD and affects a small minority of cases only. Loss of
libido and hyposexuality are much more common and correlate strongly with other measures
of disease progression.
Reduced Penetrance Alleles in HD
Dr Oliver Quarrell, Sheffield, UK
Four types of predictive test
results may be recognised: <26 repeats is unequivocally normal; 27-35 repeats is normal
but in a range which may give rise to abnormal expansions in future generations; 36-39
repeats is abnormal but the individual may or may not develop the condition; 40 or more
repeats is unequivocally abnormal.
There are no empirical risk figures
for individuals with a result in the 36-39 range. A survey of UK laboratories indicated
that there had been at least 170 results in this range from both pre-symptomatic and
diagnostic tests.
Ethical committee approval has been
obtained to allow anonymous collection of data on age of onset or age last known to be
asymptomatic for each case with a result in the reduced penetrance range. As part of the
study, DNA samples will be re-analysed. All 21 UK centres have agreed to participate in
the study.
Information collection started in
Feb 2003; so far, data is available on 41 cases: 26 are affected with ages of onset
ranging between 38-80 years; 15 cases are asymptomatic with ages ranging between 35-71
years; 16 of the 41 cases are or would have been asymptomatic at the age of 60 years. Data
collection will continue for the rest of the year.
Reproductive Decision Making Before
and After Predictive Testing
Fiona Richards, Sydney, Australia
This study, an update of an
unpublished 1997 study, retrospectively examines the reproductive decisions of 373 adults
who underwent predictive testing for HD in
Sydney between 1990 and 2002. Data
were collected from genetics records and follow up contact. The total group consisted of
175 males and 198 females. Of these, 222, (59.5%) had one or more pregnancies prior to
predictive testing.
The results of this study support
previous research that reports a low uptake of prenatal testing and other reproductive
options.
The Effect of Huntington's Disease
on the Ability to Respond to Conflicting Spatial Stimuli
Nellie Georgiou-Karistianis,
Melbourne, Australia
The conclusions from this study
support the notion that cognitive deficits in HD may stem from abnormalities of the major
pathways interconnecting the basal ganglia and the frontal lobes.
Study of Juvenile HO Patients of
Italian Origin
Ferdinando Squitieri, Pozzilli,
Italy
This study analysed a population of
juvenile H D subjects of Italian origin (n = 57). The main aim of the study was to analyse
the gender effect of the affected parent on age at onset and clinical presentation of
offspring with juvenile HD. The findings suggest the occurrence of a weaker effect of the
paternal mutation on juvenile age at onset in our population, possibly amplified by other
genetic factors.
Homozygosity in HD
Ferdinando Squitieri, Pozzilli,
Italy
HD patients with two copies of the
HD gene are very rare. As this genetic condition is rare and its implication with the
severity of HD has never been pointed out so far, it has never been contemplated by the
predictive
testing (PT) programs. It would
therefore be of relevance for international guidelines and predictive testing programs to
document the existence of unusual genetic conditions, which may require different
strategies in the genetic counselling approach according to the possible diverse scenarios
occurring within the families.
This study documented the existence
of 14 subjects with two copies of the HD gene. Two of them were unaffected and, therefore,
in a presymptomatic stage of life while some of their relatives had 100% risk to be
mutation carriers. Two patients came from families from small areas/communities of
Northern Italy and Israel, where marriages occurred among relatives potentially
contributing to HD dusters. A patients' tissue bank has been set up and potential
biological differences are being investigated.
Assessment of Change in Cognitive
Function
Dr Julie
Snowden, Manchester, UK
Cognitive impairment is a care
feature of HD. Neuropsychological tests that are sensitive to the presence of HD are well
established. However, longitudinal studies of the natural evolution of cognitive mange
have been relatively limited, so that it is much less clear which tests are most sensitive
to change in cognition over time. We reviewed existing longitudinal studies from the US
and Europe, examined the types of measures that were used and identified those measures
demonstrated to be most sensitive to change. Our own study of asymptomatic people who
carry the HD mutation reveals complementary findings. We argue that simple rather than
sophisticated, cognitively demanding
neuropsychological tests provide the
best tools for measuring change in HD and for use in clinical trials.
Walk and Drink Times.
Dr Elizabeth Howard, Manchester, UK
Reliable measures of motor
progression in Huntington's Disease are essential for the evaluation of new treatments now
being tested. The Unified Huntington's
Disease Rating Scale (UHDRS) is
generally accepted as a sensitive tool for this purpose. In practice, however the utility
of the UHDRS for longitudinal studies may be limited, particularly where frequent
assessments are required. Scores may be affected by variation in chorea from one
appointment to the next due to the impact of emotional state on the severity of
involuntary movements. The gradual decline of involuntary movements in late stage disease
may also cloud the issue. In addition to the UHDRS motor scale we have used two further
measures for evaluation of motor progression of HD. Both are simple quantitative
assessments, which require no special equipment to carry out. They are also easily
reproducible by non-medical personnel. Patients are timed as they walk a fixed
distance (including a 180 degree
turn) as fast as they can. They are also timed drinking
130mls of water as fast as possible. Data were collected from 97 individuals affected by
HD of whom 47 were male and 50 female.
Ages ranged from 22 to 81 years and
duration of illness varied from 1 to 21 years. The shortest walk time was 10 seconds and
the longest 85 seconds. There was even greater variability in drink time from 5 to 330
seconds.
There was a highly significant
correlation between duration of illness and both walk time and drink time as well as
between the two measures themselves. These
new measures can therefore be used
as simple and reliable additions to the UHDRS motor scale when considering longitudinal
outcomes.
Social Cognition in Huntington's
Disease
Dr Jennifer Thompson, Manchester, UK
Altered social conduct and a
breakdown in interpersonal relationships are prominent features of HD. Patient’s are
often described as being self-centred, demanding, mentally inflexible and lacking in
empathy for others. The factors underlying this breakdown in social cognition remain
poorly understood. The aim of this study was to investigate the ability of HD and
frontotemporal dementia patient’s to make social inferences. A novel social cognition
task was developed, which aimed to minimise demands on other cognitive functions. Patient’s
were presented with simple, illustrated vignettes that depicted
everyday social situations and were
required to answer a series of questions tapping their ability to understand the beliefs,
thoughts and feelings of the characters depicted, and to draw inferences about the social
situations, which
necessitated going beyond the
information given. The results demonstrated that although both patient groups were
impaired relative to controls, the pattern of errors differed between the two groups. As
in our previous study, the HD patients were particularly impaired in the ability to draw
appropriate inferences from social situations. The finding that HD patients make faulty
social inferences has implications
for understanding the breakdown in social behaviour in HD.
New Neurons in HD
Maurice Curtis, Auckland, New
Zealand
The recent demonstration of
endogenous stem/progenitor cells in the adult mammalian brain raises the exiting
possibility that these undifferentiated cells may be able to generate new neurons for cell
replacement in neurodegenerative diseases such as HD. This is the first study to map the
pattern of stem/progenitor cell proliferation in an area of the brain adjacent to the
caudate nucleus of the basal ganglia
and provides new evidence of the pattern of neurogenesis in the human brain.
HD in Japan
Dr Kaori Muto, Matsumoto, Japan
The prevalence of HD in Japan is 1
per 100,000 compared with 6 per 100,000 in populations of European origin.
In 2001 there were 604 people with
HD in Japan and the Government covers medical care.
The Japanese HD Network (JHDN) is a
web-based support group for HD families.
A questionnaire survey and
interviews were conducted with some members of JHDN. Most at risk people had not had
predictive testing. The main concern for people
at risk is discrimination in
marriage prospects.
Care giving is a major issue in
Japan.
Efforts to raise awareness of HD in
Japan have included:
Translation of Alice Wexler's book
'Mapping Fate' into Japanese.
TV documentary on HD in September
2003 (first ever shown on Japanese TV).
Translation of UHDRS into Japanese
so Japanese clinicians can contribute to HSG research.
Treatment of H D Using Essential
Fatty Acids
Dr Krishna Vaddadi and Dr Philip
Dingjan,
Melbourne, Australia.
The brain is unique in high
concentration of long chain, highly unsaturated fatty adds (HUFA) which play an important
role in the structure and function of brain tissue. Highly unsaturated fatty adds have
been implicated in a number of neurological conditions from Alzheimer's disease to
Huntington's disease. In one
treatment case example, serial
neuropsychological assessment data over a six year treatment period show limited variation
in scores but not progressive
deterioration in measures of
executive and new verbal learning ability. At the last assessment, all test scores were
within one standard deviation of baseline values.
The lack of deterioration across
such a long time scale, and with a 20 month gap between the last and the penultimate
assessment times, suggests that treatment
with HUFA therapy has been
clinically beneficial.
Innovative Approaches to Improving the Acceptance
of Texture Modified Diets
Karen Keast, Sydney, Australia
We have looked at innovative
approaches to enhance the acceptance of texture modified diets and to reduce the impact of
such diets on people's quality of life. In 1999, a resource package called "Shop to
Swallow" was launched. It provided people with a range of foods available in the
supermarket suitable to each of the soft, minced and puree textured diet categories.
Photographs
provided a visual display of foods
to assist with client awareness and the food lists assisted people with planning and
shopping.
In 2002, a survey of popular fast
food outlets and restaurant chains was conducted. A selection of foods were assessed and
categorised into each of the soft, minced and puree diet textures. This resource wilt be
compiled in a similar format to "Shop to Swallow".
Food moulds alter the appearance of
the pureed food to more closely resemble typically prepared food. A pre and post
implementation study was conducted in June 2003.
Moulded puree meals show promising
preliminary results in enhancing the visual presentation of texture modified food without
compromising taste and ease of swallowing.
Acknowledgements: Robyn Kapp,
AHDA(NSW); Fiona
Richards, the Cildren’s
Hospital Westmead; WCHD
Congress Program Book.