Research articles and links

If you are interested in taking part in research into PWS, click here for details of current studies.

Kate Woodcock - recent findings from behavioural studies of people with PWS

Kate Woodcock is a Research Fellow at the Cerebra Centre for Neurodevelopmental Disorders, part of the School of Psychology at the University of Birmingham. Her research into behaviour in PWS includes repetitive behaviour, and attention-switching and resistance to change. To read her reports on this research, visit www.katewoodcock.com

Adrenal Insufficiency during Acute Illness in People with PWS: New Research suggests treatment to Minimise the Risks of Sudden Death.

Dr Nicholas Finer, Clinical Director, Wellcome Clinical Research Facility, Addenbrook's Hospital, Cambrdge.

When people with PWS become ill, they may show few signs of illness and in particular often do not develop a fever, don?t vomit and may not report pain or discomfort, and this may explain why they are at risk of sudden death. Important findings from Dutch researchers1 have shed light on a possible explanation for this, and suggest treatment that could reduce these risks.

Normally during illness the adrenal glands (small glands that sit on top of the kidneys) increase the amount of steroid hormones they secrete into the blood stream. These hormones (the main one is cortisol) help the body combat infection and stress. The adrenal glands are controlled by the pituitary gland that lies at the bottom of the skull, and which produces a hormone called ACTH that signals the adrenal glands to produce cortisol; the pituitary gland itself is regulated by a part of the brain called the hypothalamus. It is known that a shortage of cortisol is very dangerous and so people who do not have functioning adrenal glands (a condition known as Addison?s Disease) or who take large doses of steroid medications for asthma or other conditions that results in adrenal suppression must take extra cortisol if they fall ill.  The same is true for people who are on replacement cortisol for pituitary disease.

The Dutch investigators studied 25 children with PWS and looked at the ability of their hypothalamus to stimulate the pituitary to stimulate the adrenals to produce cortisol. The children had normal cortisol levels during the day, but nearly two thirds of them failed to increase their cortisol levels in response to a drug called metyrapone. Metyrapone blocks cortisol synthesis, and so should cause an acute increased demand for ACTH production, a situation mimicking stress. Patients with an insufficient ACTH response during the metyrapone test are therefore considered as having adrenal insufficiency during stressful conditions. A particularly vulnerable time for children with PWS could be during the early morning when cortisol levels are normally at their lowest and any failure to increase levels could be critical

The authors of this research suggest that in illnesses that cause ?moderate stress? (e.g. influenza, upper respiratory tract infection, ear infection) children (and probably adults too) with PWS should take extra cortisol (given in the form of hydrocortisone tablets 50mg four times daily) until they are over the acute illness.  For more serious illnesses hydrocortisone should probably be given by injection and in higher doses; this would mean hospital admission in practice.  This advice accords with the ?Sick Day Rules? given to patients known to have adrenal insufficiency for other reasons and would seem a sensible and safe precaution, although the benefits of this are not proven and are based on these early findings from this study.  Parents or people with PWS may wish to carry this information with them as it is unlikely to be known by non-specialist doctors.

1Roderick F. A. de Lind van Wijngaarden and colleagues. J Clin Endocrinol Metab, May 2008, 93(5):1649?1654

UK based Research on Prader-Willi Syndrome
by Professor Tony Holland, University of Cambridge
September 2005

Research into such a complex disorder as PWS takes place from many different theoretical perspectives that can be roughly categorised under the headings of biological, clinical, psychological, and social. Individual studies may focus only on one aspect of the syndrome, the subsequent task being to bring diverse findings and perspectives from different studies together in order to develop the conceptual understanding of the syndrome and to inform treatment, policy, and practice. For example, biological research may focus on the genetics, clinical and psychological research on brain and cognitive function, on hormonal function (e.g., growth hormone), or on behaviour or mental health, and social research on the different forms of care provision for people with the syndrome. The methods used can be anything from analysis of DNA (obtained from blood samples), examination of post-mortem brain tissue (particular the small area of the brain called the hypothalamus), direct assessments and observation of people with PWS, interviews with family and paid carers, and the use of brain scanning techniques. Also the probable genetics of PWS have been modelled in mice so that the link between the genetic abnormality and brain function can be investigated in a way that is not possible in humans. Much of this type of work is being undertaken in the UK and will also be part of an EU funded project on PWS, starting in October 2005, which brings together 11 academic centres and different PWS Associations across Europe. Some examples of on-going work in the UK are given below.

Collaborative studies between the Universities of Birmingham and Cambridge funded by the Wellcome Trust continue. Tessa Webb and Esther Maina are geneticists who undertake both the genetic diagnostic work and more fundamental research, working in collaboration with Joyce Whittington, Sarita Soni and myself in Cambridge, and David Clarke and Harm Boer, both clinicians in Birmingham. They are specifically investigating the genetics of people who have the clinical features of PWS but have unusual or apparently no genetic abnormality on chromosome 15. The hope is that by doing this they can identify the key gene or genes on chromosome 15 whose absence of expression leads to PWS. From clinical and psychological perspectives we continue to investigate the cognitive, behavioural and mental health problems of people with PWS. The work of Sarita Soni is on the psychiatric illness that seems to specifically affect those with PWS due to the presence of a chromosome 15 disomy (UPD).  She has shown that the illness is a disorder of mood that has specific characteristics. These observations will eventually inform treatment for such mental health problems. Joyce Whittington is investigating whether some of the classical behaviour problems associated with PWS change over time, what factors influence the cognitive ability of people with PWS, and, together with Jill Butler, she is part of a new study looking at the very early characteristics of PWS (such as the floppiness) and how that might relate to specific blood hormone levels. Ella Hinton has finished her brain scanning study. This work is now being published. She has shown, that in the case of people with PWS, the brain does not respond to food intake in the normal way. This would seem to account for why feelings of hunger do not change with eating. A further Cambridge based study that takes a more social perspective is that being undertaken by Becca Hawkins. She is observing how people with PWS are supported at the Gretton Group of homes. The aim is to identify what seems to be crucial in the provision of social care to people with PWS. This project very much complements the work of Kerry Allen, based at the University of Leicester, who has been interviewing families and their children with PWS.

Elsewhere others are undertaking research or planning new studies to inform our understanding of different aspects of PWS. Chris Oliver, at the University of Birmingham, has studied skin picking and Bob Whalley in Edinburgh has investigated the ability of people with PWS to undertake, what are referred to as ?executive functions?. These are cognitive abilities that are important when undertaking complex tasks such as planning. He has found that these abilities are very much as you would predict for that person?s intellectual abilities, not worse as he thought they might be.  Malcolm Donaldson, at the University of Glasgow, has established a PWS research network in the UK to facilitate such research.

With respect to future work an application has been made to a consortium of UK research councils under the ?New Dynamics of Ageing? programme for money to fund a three centre study of ageing as it affects people with learning disabilities, including those with PWS. This type of study brings together the investigation of children and adults with different genetic syndromes as such comparative studies can be very informative. With Chris Oliver and colleagues we are also working on planning the next grant application that will enable us to take forward our work on the mental health problems of people with PWS. Tony Goldstone, who previously worked at the Hammersmith and St Bartholomew?s Hospitals in London and with Professor Swaab in the Netherlands, has continued his studies in the USA. He will be returning and will be a very welcome addition to the PWS research community here in the UK. His work has been a combination of hormonal studies and investigations of body metabolism and of the hypothalamus.

The PWSA (UK) is very much at the centre of these endeavours. It facilitates access to people willing to participate in research, seeks to raise money, and has been a main player in the European project. This EU funded project will enable larger studies to take place that are not possible in any one country because of the comparative rarity of PWS. Funding is crucial to all this work. In Cambridge we have been well supported by the Wellcome Trust, the Health Foundation, and for PhD studentships, by individuals and private organisations. We are very grateful for that support and we would encourage others to seek funding to maintain the strong PWS research base in the UK. It is very much a partnership between the Association and its membership and different academic organisations.  Progress is being made and the UK should be proud of its role in contributing to this. I have listed below many of the papers that have been published over the years that illustrate this progress.

REFERENCES

Holland, A.J., Treasure, J. Coskeran, P., Dallow, J. Milton, N. and Hillhouse, E. (1993) Measurement of excessive appetite and metabolic changes in Prader-Willi Syndrome.  International Journal of Obesity: 17:527-532.

Richards, A., Quaghebeur, G., Clift, S., Holland, A., Dahlitz, M and Parkes D. (1994) The upper airway and sleep apnoea in the the Prader-Willi Syndrome.  Clinical Otolaryngology, 19: 193-197. 

Holland, A.J., Treasure, J., Coskeran, P. and Dallow, J. (1995) Characteristics of the eating disorder in the Prader-Willi Syndrome: implications for treatment.  Journal of Intellectual Disability Research, 39(5):373-381.

Holland, A.J.  (1998) Understanding the eating disorder affecting people with Prader-Willi Syndrome.  Journal of Applied Research in Intellectual Disability, 11(3): 192-206.

Holland, A.J. and Wong, J. (1999) Genetically determined obesity in Prader-Willi Syndrome: The Ethics and Legality of Treatment.  Journal of Medical Ethics, 25: 230-236.

Goldstone, A.P., Thomas, E.L., Brynes, A.E., Bell, J.D., Frost, G., Saeed, N.,Hajnal, J.V., Howard, J.K., Holland, A.J., and Bloom, S.R. (2001)  Visceral adipose tissue and metabolic complications of obesity are reduced in Prader-Willi Syndrome female adults: Evidence for novel influences on body fat distribution.  Journal of Clinical Endocrinology and Metabolism 86 (9): 4330-38.

Whittington, J.E., Holland, A.J., Webb, T., Butler, J., Clarke, D., and Boer. H. (2001) Population prevalence and estimated birth incidence and mortality rate for people with Prader Willi Syndrome in one health district. Journal of Medical Genetics, 38:792-798.

Boer, H., Holland, A.J., Whittington, J., Butler, J., Webb, T. and Clarke, D. (2002)  Psychotic illness in people with Prader Willi Syndrome due to chromosome 15 maternal uniparental disomy The Lancet, 359: 135-136.

Clarke, D.C., Boer, H., Whittington, J.E., Holland, A.J., Butler, J.V. and Webb, T. (2002) Prader-Willi Syndrome, compulsive and ritualistic behaviours: The first population-based survey. British Journal of Psychiatry, 180: 358-362.

Butler, J., Whittington, J.E., Holland, A.J., Webb, T., Clarke, D., and Boer. H. (2002) Medical conditions in Prader Willi Syndrome. Developmental Medicine and Child Neurology 44:248-255.

Goldstone, A.P., Brynes, A.E., Thomas, E.L., Bell, J.D., Frost, G., Holland, A.J., Ghatei, M.A., Bloom, S.R. (2002) Resting metabolic rate, plasma leptin concentrations, leptin receptor expression, and adipose tissue measured by whole-body magnetic resonance imaging in women with Prader-Willi syndrome. American Journal of Clinical Nutrition 75: 468-475.

Whittington, J.E., Holland, A.J., Webb, T., Butler, J.V., Clarke, D.J. and Boer, H. Relationship between clinical and genetic diagnosis of Prader-Willi Syndrome.  (2002) Journal of Medical Genetics.39, 926-932

Webb, T., Whittington, J.E., Clarke, D., Boer, H., Butler, J. and Holland, A.J. (2002) A study of the influence of different genotypes on the physical and behavioural phenotypes of children and adults. Clinical Genetics 62, 273-281.

Goldestone, A.P., Brynes, A.E., Thomas, E.L., Bell, J.D., Frost, G., Holland, A. and Bloom, S. 2003 Body composition using whole body magnetic resonance imaging an resting metabolic rate in Prader-Willi Syndrome adults.  Journal of Clinical Endocrinology and Metabolism.

Holland, A.J., Whittington, J.E. Butler, J., Webb, T., Boer, H and Clarke, D.J. (2003) Behavioural phenotypes associated with specific genetic disorders: evidence from a population-based study of people with Prader-Willi Syndrome.  Psychological Medicine, 33, 141-153

Whittington, J.E., Holland, A.J., Webb, T., Butler, J.V. Clarke, D.J. and Boer, H. (2004) Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome.  Journal of Intellectual Disability Research, 48: 172-187

Whittington, J.E., Holland, A.J., Webb, T., Butler, J.V. Clarke, D.J. and Boer, H. (2004) Underachievement in Prader Willi Syndrome.  Journal of Intellectual Disability Research, 48: 188-200

Goldstone, A.P., Thomas, E.L., Brynes, A.E., Castroman, G., Edwards, R., Ghatei, M.A., Frost, G., Holland, A.J., Grossman, A.B., Korbonits, M., Bloom, S.R., Bell, J.D. (2004) Elevated fasting plasma ghrelin in Prader-Willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance.  Journal of Clinical Endocrinology and Metabolism 89(4):1718-1726

Hinton, E.C, Parkinson, J.A, Holland, A.J., Arana, F.S., Roberts, A.C., Owen, A.M.: Neural contributions to the motivational control of appetite in humans. European Journal of Neurosci, 20(5):1411-8, March 2004

Isles, A., and Holland, A.J.: Imprinted genes and mother-offspring interactions. Elsevier, Early Human Development (2005) 81, 73-77