Understanding the eating disorder and mental health needs of people with PWS Behaviour and mental health in PWS Bewleys Hotel, Dublin Tuesday 19 th April 2013 Tony Holland Cambridge Intellectual and Developmental Disabilities Research Group Department of Psychiatry www.ciddrg.org.uk

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

PWS over the lifespan

Intra-uterine (placental)

• Poor growth • Limited foetal movement • High rates atypical births

Infancy

• Extreme hypotonia • Failure to thrive Gender specific genomic imprinting C/D box snoRNA SNORD 116 (HBII-85)

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

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

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

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

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

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 .

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

Weight and height in infancy Deletions only

Mean difference between wt & ht centiles 6 By age- Deletions (wt-ht) 3 0 -3 N = 9 19 20 16 14 14 13 11 11 9 10 9 9 9 8 6 6 4 4 2 birth 3m 6m 9m 1yr 15m 18m 21m 2y 27m 30m 33m 3y 39m 42m 4y w t 45m 51m 54m 57m

Weight and height in infancy Non-deletions only (UPD)

Mean difference between wt & ht centiles 6 By age - non deletions 3 0 -3 N = 10 birth 20 3m 23 6m 22 9m 21 1y 17 15m 14 18m 14 21m 9 2y 8 27m 8 30m 8 33m 7 3y 7 39m 7 42m 8 45m 6 4y 6 51m 5 54m 4 57m

Weight chart of young adult with PWS

Holland et al. (1993). Measurement of excessive appetite and metabolic changes in Prader-Willi Syndrome.

International Journal of Obesity

: 17:527-532.

PWS

PET functional brain imaging study Hunger condition Controls Post meal condition PWS 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 Hinton et al (2006). Neural Representations of hunger and satiety in Prader-Willi syndrome.

International Journal of Obesity

30:313-321

Satiety Cascade Blundell, 1991

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.

Farooqi, Oxford Textbook of Medicine

Signals from fat cells Signals from the gut

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

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

Morbidity in PWS

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

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/m 2 vs 29.6kg/m 2 (p>0.05)

MENTAL HEALTH

Behaviour in PWS

Population-based study

Prevalence (%) of specific behaviours (n=65)

Definite sometime none Excessive eating 78 21 1 Obsessional Tempers 70 23 67 27 7 6 Skin picking Mood swings 59 38 22 19 19 43 Holland et al 2003, Psychological Medicine

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

Mental illness

• Characteristics • Prevalence • Mechanisms • Implications

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

Population-based Study of PWS Psychotic Illness

(Boer et al, Lancet, 2002)

Number with psychotic illness (7/25 28%)

Age 18-27 age 28+ Del (15q11-13) UPD Other

Total

0/4 0/3 0/3 *Imprinting centre defect 1/9 (11%) 5/5 (100%) 1/1*

0/10 7/15 (49%)

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)

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

Deletion (n=85) 71.8

11.8

16.5

UPD (n=34) 35.3

2.9

61.8

0% 20% 40% 60% 80%

Percentage of participants

100% No psychopathology History of non-psychotic illness History of psychotic symptoms

Psychiatric Diagnosis

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

Deletion (n=24) UPD (n=22) 1 6 10 11 9 0 4 5 Comparison (n=15) 0 3 2 0 5 10 10 15

Count

20 25 30 Non-psychotic depression Depressive psychosis Bipolar illness w ith psychotic symptoms Psychotic illness

90 80 70 60 50 40 30 20 10 0 Graph to show symptoms in participants with psychotic symptoms (n=31) Deletion (n=12) Disomy (n=19)

Symptoms

*Difference between genetic subtypes on scores of “agitation”: Fishers Exact test 2 sided; p<0.05

Symptoms of hypomania in people with psychotic symptoms (n=31) 4 3 2 1 0 9 8 7 6 5 Deletion (n=12) Disomy (n=19)

Symptoms

Frequency of psychotic symptoms

16 14 12 10 8 6 4 2 0 A ud ito ry h V al is lu ci ua na l h Ta tio al lu ct ns ci ile O na h al lfa tio lu to ns ci ry na h tio al lu ns ci Th na ou tio gh ns t d is C A or at ny de at d r el on us ic s io n ym In pt si om gh s t p re se nt

Symptom

Deletion (n=12) Disomy (n=19)

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;

Hypothetical model for the development of psychiatric illness in PWS • “Two-hit” model • Hit 1: having PWS (?5HT

2c R 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?

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

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