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Tony Holland Cambridge Intellectual and Developmental Disabilities Research Group

Delve into the complex interplay of eating behavior, obesity risks, mental health challenges in Prader-Willi Syndrome. Explore genetic factors, physical health implications, and service needs.

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Tony Holland Cambridge Intellectual and Developmental Disabilities Research Group

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  1. Understanding the eating disorder and mental health needs of people with PWSBehaviour and mental health in PWSBewleys Hotel, DublinTuesday 19th April 2013 Tony Holland Cambridge Intellectual and Developmental Disabilities Research Group Department of Psychiatry www.ciddrg.org.uk

  2. Outline • Introduction to PWS • Characteristics over the lifespan (phenotype) • Genetics (genotype) • Eating behaviour and risk of obesity • Physical ill-health • Obesity related co-morbidities • Other physical illnesses • Mental ill-health and problem behaviours • Implications for services and support • Importance of the environment

  3. PWS over the lifespan Gender specific genomic imprinting C/D box snoRNA SNORD 116 (HBII-85) Intra-uterine (placental) • Poor growth • Limited foetal movement • High rates atypical births Infancy • Extreme hypotonia • Failure to thrive Childhood • Developmental delay – intellectual disabilities • Short statute – relative growth hormone deficiency • Sexual immaturity – sex hormone deficiencies • Over-eating - risk of severe obesity and its complications • Scoliosis, respiratory disorders, maladaptive behaviours Adulthood • Increased risk of obesity (with greater independence) • Age-related physical and psychiatric morbidity McAllister et al, International Journal of Obesity 2011

  4. Display of normal human chromosome complement Pairs 1 to 23 Chr 15 pair Y chromosome X chromosome

  5. Schematic of chromosome abnormalities resulting in PWS Chromosome 15 70% 25% <5%

  6. Cambridge PWS Study Assuming no age-specific ascertainment bias Estimated birth incidence 1:29,000 Estimated population prevalence 1:52,000 Estimated mortality rate: 3% across the age-range or 7% per year over age 30 Whittington et al, 2001

  7. Eating disorder in PWS • Initial presentation • Failure to thrive • Development of over-eating • Mechanisms • Abnormality of satiety • Increased reward value of food • Implications • Childhood • Adult life

  8. Intra-uterine and peri-natal problems • Abnormal foetal growth (small for dates at gestation) (imprinted genes and placental function) • Reduced foetal movement • Increased rates of caesarean section • Polyhydramnios (excess intra-uterine fluid) Dudley et al 2007 Early Human Development 83: 471 Whittington et al (2008). Early Human Development, 84: 331-336.

  9. Characteristics that predicts +genetics • Hypotonia at birth and failure to thrive • Developmental delay and learning disabilities • Undescended testes at birth • Over-eating behaviour Whittington et al 2003 J Med Genet, 39, 926

  10. Weight and height in infancyDeletions only

  11. Weight and height in infancyNon-deletions only (UPD)

  12. Weight chart of young adult with PWS

  13. Holland et al. (1993). Measurement of excessive appetite and metabolic changes in Prader-Willi Syndrome. International Journal of Obesity: 17:527-532.

  14. PWS

  15. PET functional brain imaging study Post meal condition Hunger condition Controls The high calorie meal (in comparison to fasting) did not result in the same pattern of brain activation that was found following food intake in those without PWS No activations survived the analysis once the correction for multiple comparisons was applied PWS Hinton et al (2006). Neural Representations of hunger and satiety in Prader-Willi syndrome. International Journal of Obesity 30:313-321

  16. Satiety Cascade Blundell, 1991

  17. Brain control of food intake Regulation of food intake is controlled by a combination of signals to and from the brain. People with PWS have delayed and impaired satiety and may be lacking or insensitive to peripheral signals to the brain. Signals from fat cells Farooqi, Oxford Textbook of Medicine Signals from the gut

  18. Why the eating disorder? The Paradox of PWS: a genetic model of starvation Holland et al, Lancet, 2003, 362, 989-991 Disruption of the hypothalamic feeding pathways or high threshold set for satiety (Barker hypothesis) McAllister et al, International Journal of Obesity, 2011

  19. Eating disorder Feeding support after birth and in infancy At transition biological abnormality of satiety and/or reward mechanisms associated with food becomes apparent; No specific treatment as yet for the eating disorder; Supervised access to food prevents obesity (and associated morbidity) and may help wellbeing; Strategies to help manage the tension between choice and the need to control access to food

  20. Morbidity in PWS Rates of reported illness <18years >17years Diabetes (type II) 0 8/32 (25%) Respiratory 18/34 (53%) 12/32 (38%) Scoliosis 9/34 (26%) 10/31 (32%) Fractures 7/34 (21%) 12/32 (38%) Butler et al 2002

  21. Morbidity in PWS Sleep disorders: • Noisy or disturbed sleep 40/63 (64%) • Exc. daytime sleepiness 47/64 (73%) • Diagnosis of sleep apnoea 13/64 (20%) • Diagnosis of narcolepsy 1/64 Mean BMI of those with diagnosis of sleep disorder 36kg/m2 vs 29.6kg/m2 (p>0.05)

  22. MENTAL HEALTH

  23. Behaviour in PWSPopulation-based study Prevalence (%) of specific behaviours (n=65) Definite sometime none Excessive eating 78 21 1 Obsessional 70 23 7 Tempers 67 27 6 Skin picking 59 22 19 Mood swings 38 19 43 Holland et al 2003, Psychological Medicine

  24. The detection of mental ill-health • The prevention and management of problem behaviours depended on your understanding of those behaviours; • The development of a psychiatric illness may present with a change in behaviour • The key to intervention is a good history and mental state examination and formulation • Long standing or of recent onset • Change in nature and severity of existing behavioural difficulties • Evidence of disturbed mood or abnormal mental experiences

  25. Mental illness • Characteristics • Prevalence • Mechanisms • Implications

  26. Psychiatric illness in PWS • Kollrack and Wolff 1966 • Since then, over 20 studies describing the association of PWS with psychiatric illness • Most describe an affective psychosis with characteristic features • However, some methodological problems: • Small sample size • Not genetically confirmed

  27. Population-based Study of PWSPsychotic Illness (Boer et al, Lancet, 2002) Number with psychotic illness (7/25 28%) Age 18-27 age 28+ Del (15q11-13) 0/4 1/9 (11%) UPD 0/3 5/5 (100%) Other 0/3 1/1* Total 0/10 7/15 (49%) *Imprinting centre defect

  28. Method Soni et al 2008 • 46 of 119 (38.7%) adults screened positive for psychopathology • 24 Deletion, 22 mUPD • Further assessment included: • Psychiatric Assessment Schedule for Adults with Developmental Disability (PAS-ADD) • Operational criteria checklist for psychotic and affective illness (OPCRIT) • Family History Questionnaire • modified Life Events Questionnaire • Wechsler Adult Intelligence Scale (WAIS)

  29. Soni et al 2008, Psychological Medicine, 38, 1505 Prevalence of psychiatric illness Psychotic illness more common in mUPD than deletion p<0.001, effect size 0.45

  30. Psychiatric Diagnosis Non-psychotic depressive illness more common in deletion than mUPD p=0.005, effect size 0.43

  31. Graph to show symptoms in participants with psychotic symptoms (n=31) *Difference between genetic subtypes on scores of “agitation”: Fishers Exact test 2 sided; p<0.05

  32. Symptoms of hypomania in people with psychotic symptoms (n=31)

  33. Frequency of psychotic symptoms

  34. Summary of phenomenology • Evidence of mood related psychiatric illness; • Hypomanic symptoms and agitation more pronounced in those with mUPD; • Delusions predominately persecutory in both people with deletion and mUPD; • Auditory and visual hallucinations present in both groups;

  35. Hypothetical model for the development of psychiatric illness in PWS • “Two-hit” model • Hit 1: having PWS (?5HT2cR related) • Hit 2: mUPD paternally imprinted gene on 15 • Act in synergy to lead to development of psychotic illness • What is the normal function of the presumed paternally imprinted gene that predisposes to affective disorder when there is excess expression and how has it become imprinted during evolution? • Might a variant of that gene predispose to affective disorder in the general population?

  36. Prevention, understanding and intervention • The importance of structure, rules, and supportive and informed staff – prevention • The importance of longitudinal knowledge – understanding • Interventions based on a sound understanding - treatment

  37. Finally…. Understand the specific needs of people with PWS Understand the individual with PWS Do not place people with PWS in situations that are intolerable Manage the environment Strategies to compensate for social and cognitive impairments

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