Tony Holland Cambridge Intellectual and Developmental Disabilities Research Group
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Transcript of Tony Holland Cambridge Intellectual and Developmental Disabilities Research Group
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Understanding the eating disorder and mental health needs of people with PWS
Behaviour and mental health in PWSBewleys Hotel, Dublin
Tuesday 19th April 2013
Tony HollandCambridge Intellectual and Developmental Disabilities Research Group
Department of Psychiatrywww.ciddrg.org.uk
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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
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PWS over the lifespanIntra-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
Gender specific genomic imprinting
C/D box snoRNA SNORD 116 (HBII-85)
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Display of normal human chromosome complement Pairs 1 to 23
Chr 15 pair
X chromosome
Y chromosome
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Schematic of chromosome abnormalities resulting in PWS
70% 25% <5%
Chromosome 15
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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
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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
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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.
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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
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Weight and height in infancyDeletions only
24466899910911111314141620199N =
Mean difference between wt & ht centiles
By age- Deletions (wt-ht)
57m
54m
51m
4y w t
45m
42m
39m
3y
33m
30m
27m
2y
21m
18m
15m
1yr
9m
6m
3m
birth
Me
an
n
o c
en
tile
s +
- 2
SE
6
3
0
-3
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Weight and height in infancyNon-deletions only (UPD)
4566877788891414172122232010N =
Mean difference between wt & ht centiles
By age - non deletions
57m
54m
51m
4y
45m
42m
39m
3y
33m
30m
27m
2y
21m
18m
15m
1y
9m
6m
3m
birth
Me
an
no
ce
ntil
es
+-
2 S
E
6
3
0
-3
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Weight chart of young adult with PWS
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Holland et al. (1993). Measurement of excessive appetite and metabolic changes in Prader-Willi Syndrome. International Journal of Obesity: 17:527-532.
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PWS
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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
Hunger condition Post meal condition
Controls
PWS
PET functional brain imaging study
Hinton et al (2006). Neural Representations of hunger and satiety in Prader-Willi syndrome. International Journal of Obesity 30:313-321
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Satiety Cascade
Blundell, 1991
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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 Signals from the gut
Farooqi, Oxford Textbook of Medicine
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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
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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
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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
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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 1/64Mean BMI of those with diagnosis of sleep disorder 36kg/m2 vs 29.6kg/m2 (p>0.05)
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MENTAL HEALTH
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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
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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
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Mental illness
• Characteristics
• Prevalence
• Mechanisms
• Implications
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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
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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
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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)
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Prevalence of psychiatric illness
Psychotic illness more common in mUPD than deletion p<0.001, effect size 0.45
35.3
71.8
2.9
11.8
61.8
16.5
0% 20% 40% 60% 80% 100%
UPD (n=34)
Deletion(n=85)
Gen
eti
c s
ub
typ
e
Percentage of participants
No psychopathology
History of non-psychoticillness
History of psychotic symptoms
Soni et al 2008, Psychological Medicine, 38, 1505
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Psychiatric Diagnosis
0
1
10
3
6
9
2
11
0
10
4
5
0 5 10 15 20 25 30
Comparison(n=15)
UPD (n=22)
Deletion (n=24)
Gen
etic
su
bty
pe
Count
Non-psychotic depression
Depressive psychosis
Bipolar illness w ith psychoticsymptoms
Psychotic illness
Non-psychotic depressive illness more common in deletion than mUPD p=0.005, effect size 0.43
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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
0102030405060708090
Lo
ss o
fe
ne
rgy
Lo
ss o
fco
nfid
en
ce
Po
or
con
cen
tra
tion
Ag
itatio
n*
Incr
ea
se in
foo
d s
ee
kin
gb
eh
avi
ou
r
De
cre
ase
da
pp
etit
e
Dis
turb
ed
sle
ep
Hyp
ers
om
nia
Symptoms
Pe
rce
nta
ge
of
pe
op
le
Deletion (n=12)
Disomy (n=19)
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Symptoms of hypomania in people with psychotic symptoms (n=31)
0123456789
Exp
ansi
ve m
ood
Pre
ssin
g, r
acin
gth
ough
ts
Ove
rtal
kativ
enes
s
Dis
trac
tibili
ty
Ove
ract
ivity
Exa
gger
ated
sel
fes
teem
Symptoms
Nu
mb
er o
f p
eop
le
Deletion (n=12)
Disomy (n=19)
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Frequency of psychotic symptoms
02468
10121416
Symptom
Nu
mb
er o
f p
eop
le
Deletion (n=12)
Disomy (n=19)
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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;
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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?
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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
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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