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 enrol 550 people who have had the predictive test (250 enrolled so 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 foetal 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.

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 the possibility of 'living wills’ 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, and 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.

 Study of Juvenile HD 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 clusters. 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.

 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. Patients 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.

 Patients 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 exciting 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 acids (HUFA) which play an important role in the structure and function of brain tissue. Highly unsaturated acids have been implicated in 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 shows 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 will 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 Children’s Hospital Westmead;

WCHD Congress Program Book