Transcript From behaviour to genes…and back again

From behaviour to
genes…and back again
Dr Dougal Julian Hare
School of Psychological Sciences
University of Manchester
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Psychology is a science (don’t laugh, it really is supposed to
be a science)
Basis of science is classification
With a classification system, can determine both membership
and relationships:
 Is Xn a member of class X ?
 What is the relationship of Xn to X¹ or to Y¹ ?
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With an adequate classificatory system, can begin to examine
mechanisms i.e. move to explanation:
 Why does Xn have features a,b & c ?
Scientific explanations can be holistic and reductionist
Reductionist explanations can be parsimonious and satisfy
Occam’s razor
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Science aims to produce predictive general laws and models
Failure to predict is important as breakdowns in models and
laws leads to new developments and in some case paradigms
(Kuhn 1962)
Therefore, should we focus on when cognition and
development goes wrong ?
Two fields in clinical psychology are concerned with evident
neurocognitive dysfunction:
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Acquired brain injury (inc. progressive disorders)
Intellectual disabilities
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In the case of neuropsychology, almost all advances in
knowledge and theory have come from the study of acquired
brain injury, both structural and functional.
Most ABI is idiopathic
People with ABI can be compared to non-ABI population
Some examples of genetic aetiology in both seizure disorders
such as juvenile myoclonic epilepsy (Iqbal et al 2009) and
progressive disorders such as Parkinson’s and Huntington’s
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Very different with regard to disordered developmental
processes and development of psychological knowledge
Very distinct split between intellectually disabled [mental
retardation/mental handicap/learning disabled] and nonintellectually disabled populations with developmental
disorders
Emphasis in research on non-ID populations e.g. autism
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Major problem with psychiatric theorising is failure to develop
either valid descriptive [diagnostic] or reliable predictive
[prognostic] models (Bentall 2004)
Clinical psychology as a whole has been successful in
developing idiosyncratic predictive models having moved
away from psychiatric diagnostic systems
Clinical psychology and intellectual
disabilities
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Clinical psychology practice and research with people with ID
has developed in a unique manner due to:
 Different classificatory system based on g / IQ [IQ testing]
 Explicit emphasis on observable behaviour based on
Skinnerian operant conditioning
Obsolete technologies that are used primarily with people with
ID…
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In clinical practice, this has worked – up to point:
 Crude identification of ID
 Function of behaviour and immediate contingencies
identifiable for and intervention effective ~ 75% of cases
(Symons & Thompson 1997).
As both g/IQ and behaviourism are base level explanations
(i.e. no lower level explanation is possible/permitted), focus
has been on higher-level supra-individual explanation
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In effect, psychological research and practice with regard to
people with ID has been driven by 1930s technology (IQ
testing and operant conditioning) rather than current science.
Most non-behaviourist psychological research in ID has
necessarily focussed on systemic and social level explanation
– social constructionism
Led to social level interventions (normalisation, personcentred planning) and also theories of social aetiology of ID
being dominant
WHO impairment-disability-handicap
model
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Impairment - physiological disorder or injury
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Disability - inability to execute some class of movements, or
pick up sensory information of some sort, or perform some
cognitive function, that typical unimpaired humans are able to
execute or pick up or perform
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Handicap - an inability to accomplish something one might
want to do, that most others around one are able to accomplish
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In effect, psychology has focused on describing Disability and
ameliorating Handicap
Ironically, the obsolete term ‘mental handicap’ is possibly
more descriptive of how psychologists view people with
ID…[NB I’m being ironic here]
The focus of psychological research has thus been essentially
reactive, aiming to reduce the handicapping effects of
disability
Not very interested in the nature and aetiology of ID ?
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The one exception to this has been autism
Recognition in the 1960s that autism was an organic and
probably highly inheritable disorder
Autism is not reducible to or explicable in terms of low g/IQ
Autism always regarded as not just a discrete syndrome but as
qualitatively different
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Moreover, this sense of difference manifested not just in terms
of presentation but also in terms of their needs for education,
support and care
Led to ground-breaking research of the 1980s (Baron-Cohen,
Leslie, Frith etc) into the psychological and
neuropsychological basis of autism i.e. moving beyond merely
describing the behavioural manifestations of the disorder.
Initial notion that people with autism have specific needs best
met by specific service provision proved to be correct (e.g.
Bennett, Wood & Hare 2004)
Autism as a discrete disorder
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Research into mentalisation and subsequent work on
executive dysfunction, innate emotional recognition, episodic
memory etc in autism carried out, disseminated and utilised
outside of ‘mainstream’ ID
Autism research has explicitly worked on identifying the links
between the biological, psychological & behavioural domains
Developed framework for more recent work into other
syndromes and their behavioural phenotypes.
Some clinical psychologists, (applied behaviour analysts ?) do
not ‘believe’ in autism –which begs the response of what is not
being believed in ?
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Case of autism illustrates another issue with using g/IQ to
define a research or clinical population - the curious case of
Asperger syndrome.
Can be contrasted with the other forms of developmental
disorder such as Klinefelter’s syndrome, Turners syndrome
and the other readily identifiable conditions with mean IQ ≥ 70
Recognised as having specific difficulties resulting from
developmental disorder that are not the result of impaired
general intelligence.
Categorical models of ID
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Effectively started by John Langdon Down (1866) with
descriptions of Downs, Prader Willi and West Syndromes
Wrote first ID textbook (1876) advocating a psychoeducational approach to ID
Correctly identified that there exist real entities, in the form of
distinct intellectual and developmental disorders:
Several hundred forms of IDD now identified:
 40-50% known genotype
 40-45% known ante- or peri-natal damage
 10-15% unknown aetiology
Downs syndrome as a discrete
disorder
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Phenotype of Downs syndrome identified in 1866
Genotype of Downs syndrome identified in 1959
Most common form of discrete ID (40% of ID population)
Physical features of DS make it hard to ignore (not that some
ID services haven’t tried…)
DS as ‘prototype’ form of intellectual disability ?
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Modern genetic technology has identified new syndromes (e.g.
X linked syndromes Muir, 2010) as well as accounting for
known disorders:
 Prader-Willi syndrome - micro-deletion on chromosome
15q11-q13 was determined by a new high-resolution
banding; fluorescent in situ hybridisation (FISH)
 related aetiology of Prader-Willi and Angelman
syndromes - genomic imprinting, (Muir, 2000) where one
inherited gene from either parent in a gene pair is repressed
or inactive through an epigenetic mechanism.
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Percentage of cases of ID of unknown aetiology is steadily
reducing
Recent work on de novo mutations (Vissers et al., 2010),
where neither parent possesses or transmits the mutation, has
identified that these now account for many cases of mild moderate IDD, previously regarded as environmentally caused
(Ellison et al., 2013; Veltman & Brunner, 2012)
Science of behavioural phenotyping has developed alongside
advances in genetic technology (Oliver & Hagerman, 2007)
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Genotype
 Genetic constitution of an individual; the particular set of
genes carried.
 Inherited influences that facilitate development of particular
traits
Phenotype
 Manifest structure, function or behaviour
Behavioural phenotypes
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Concept of behavioural phenotype initially used by Nyhan
(1972) in description of stereotypic hand wringing in people
with Lesch-Nyhan syndrome
Broadened to describe distinctive physical, behavioural and
cognitive profiles of genetic syndromes (O'Brien, Barnard,
Pearson & Rippon, 2002).
Probabilistic definition of BP - behaviour reliably occurring in
most cases of a syndrome and/or genotype can be considered
part of the phenotype (Dykens 1995)
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Can conceptualise the specificity of the aetiology-behavioural
phenotype linkage as:
 No specificity i.e. no link between outcome and disorder
 Partial specificity i.e. specific outcome(s) may result from
several disorders (e.g. repetitive behaviour is associated
with several disorders)
 Total specificity i.e. unique outcome for given disorder
Substantive empirical support (Basile, Villa, Selicorni &
Molteni; Levy & Ebstein, 2009; Lewis et al., 2006; Sinnema et
al., 2011; Varela, Kok, Otto & Koiffmann, 2004).
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Behavioural phenotypes can be regarded as information-giving
devices that explain:
 why a given syndrome has occurred,
 how it will affect development
 a proportion of the variance in problematic behaviours.
Tunnicliffe & Oliver (2011) note that phenotypic behaviour
can be subject to change via operant reinforcement by
environmental and internal contingencies
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Early intervention with known BPs, including provision of
information to services regarding the phenotype, improves
quality of life and challenges deterministic views of diagnoses.
Understanding BPs facilitates the development of tailored
interventions (Courtenay et al 2009):
 self-injurious behaviour in various syndromes (Oliver &
Richards, 2010;Arron et al 2011)
 early-onset dementia in people with Down syndrome
(Kozma, 2008)
 impact on carer well-being (Adams 2013)
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People with IDDs and their families have welcomed genetic
and BP research in ID (Costain et al 2012; Trottier et al 2013).
Participating in genetic research gives opportunities to
determine a diagnosis and/or to obtain understanding of an
existing diagnosis (Statham et al. 2010)
Parent support groups are a key driving force in behavioural
phenotyping research (Harris 2010)
Genetic diagnoses result in greater understanding and control
by providing prognosis and facilitating access to services and
care (Costain et al 2012).
Classification by aetiology and
psychological research
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Understanding the genetics & aetiology of ID permits a finegrain classification of the previously homogenous ID
population (i.e. IQ≤70)
Behavioural phenotyping facilitates a rational programme of
research based on this classification
Down syndrome is the most common chromosomal cause of
ID
Fragile X is most common inheritable cause of ID
Chromosomal aetiologies of ID
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Other important forms of ID/DD with known genetic
aetiology include:
 Velocardiofacial (VCFS)[c22q-del]
 Rubinstein-Taybi [c16p 13.3 ?]
 Prader-Willi (PWS) / Angelman (AS)[both c15 q11-13 del.
– paternal/maternal]
 Williams (WS) [c7 continuous gene deletion]
 Smith-Magenis (SMS) [c17p11.2]
 cri-du-chat (CDC) [5p del]
(1) Possibility of identifying specific behaviours uniquely associated
with specific behavioural phenotypes:
 Prader-Willi [hyperphagia]
 Lesch-Nyan [extreme SIB]
 Smith-Magenis [bodily self-hugging & insertion of objects
into bodily orifices]
 Rett [stereotyped hand movements]
 Cri-du-chat [“cat cry” in infancy & distinctive
vocalisation/screaming]
 Williams [very poor visuo-spatial skills]
(2) Quantifiable proportion of the variance in a person’s behaviour :
 Hyper-sociability [‘attention seeking’] in WS and SMGS
 Abnormal sleep in San Filippo syndrome
 Self-injurious behaviours in Lesch-Nyan and Retts
(3) Prognosis:
 Early on-set dementia in DS
 Early mortality in RS and SFS
 Psychosis in VCFS
Inter-syndrome variations in challenging
behaviour
Syndromic variation in topologies of SIB (Arron et al 2011):
Syndrome-specific topology:
FgX – self-biting
PWS – scratching
Lowe syndrome – eye poking [90% visual impairment]
Multiple topologies:
CDC – self-pulling, rubbing or scratching
CdLS – self-hitting and pulling
SMS- multiple topologies
Inter-syndrome variations in challenging
behaviour
Correlates of SIB (Arron et al 2011):
Low
ability (CdLS)
Repetitive behaviour, over-activity & impulsivity (CdLS, FX/ LS/ PWS)
Over-activity & impulsivity (SMS)
Correlates of physical aggression:
Over-activity
&impulsivity (AS/CDC/CdLS/FX/PWS/LS/SMS)
Genes to behaviour to families
 Genes-enzymes-neural architecture-cognitive- emotional
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functioning-behaviour- social & familial
Pathways already mapped for Prader Willi Syndrome and
Fragile X Syndrome
Recent work from the Manchester ClinPsyD programme on
Muccoplysaccharidosis type III [Sanfilippo syndrome]
MPS III/Sanfilippo Syndrome
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Rare genetic disorder causing progressive mental and
physical degeneration, resulting in premature death
usually in 2nd or 3rd decade of life
1 in 89,000 live births in the UK
Lysosomal storage disorder - deficiency in one of four
enzymes involved in the break down of the
glycosaminoglycan heparan sulphate
Based on the enzyme deficiency, four main subtypes
found - MPS III A - D
Progressive degeneration in MPS III
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Currently no cure but disease-modifying therapies under
development [ Genestein trial utilising stem cell
transplantation ongoing utilising research to be described]
Clinical input mainly supportive care to manage child
symptoms – no psychological support for children or
parents
Rarity of disorder and normal initial development - families
may have 2-3 children with MPS III prior to diagnosis
Evidence base
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Extreme heterogeneity, even among siblings (Valstar et
al 2008) makes prognosis difficult
UK-wide survey of life-limiting diseases (Malcolm et al
2011) highlighted MPS III as priority area for research
Specific difficulties of behavioural problems,financial
and emotional impact of progressive decline and social
isolation of families
Methodological limitations in previous research
Limited research on MPS III behavioural phenotype
(Ulcar et al 2010; Malcolm et al 2012)
Sleep & circadian functioning [Mahon et al
2014; Mumford et al submitted]
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Sleep problems prevalent associated with MPS III (Fraser et
al 2005):
 Settling difficulties, nocturnal waking, disruptive/dangerous
behaviours during the night, and early morning waking.
 Most studies use questionnaire
 Mariotti et al. (2003) – PSG and reported reduced nighttime sleep/ increased daytime sleep compared to age- and
sex-matched controls.
Hendriksz et al. (2012) - aggressive behaviour, hyperactivity,
and severe sleep disorders due to abnormal circadian rhythm ?
Method
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Eight children with MPS III A/B (5 males & 3 females, age range 2-15 years) and
eight age-matched typically developing children (4 males, 4 females, age range 3 –
15 years)
All participants wore a Respironics AW2/Cambridge Neurotechnology AW4 for
7-10 days to collect data on circadian rhythm activity and sleep.
Melatonin prescriptions were ceased two weeks prior to data collection.
Saliva samples were collected at three time points at the start and end of data
collection to permit analysis of endogenous melatonin levels.
Parents completed a one-off sleep questionnaire (Children’s Sleep Habits Rating
Scale) and a daily diary detailing times the child went to bed and got up, lights
on/off times, as well as any night-time events such as seizures.
Actigraphic summary data for MPS III and
Control groups
Sleep parameter
MPS III n = 8
Controls n = 8
p
U
Mean
SD
Mean
SD
Time in bed (min)
559.6
75.4
544.9
53.7
0.23
44.0
Night-time sleep (min)
447.2
111.5
479.0
32.9
1.0
32.0
Daytime sleep (min)
13.8
19.2
1.7
4.9
0.046*
48.5
Sleep onset latency (min)
53.2
55.6
14.2
5.1
0.01**
56.0
Sleep efficiency (%)
68.7
17.7
80.8
8.0
1.4
17.5
WASO (min)
112.5
58.9
75.1
51.1
0.279
43.0
WASO = wake after sleep onset; * p < .05, ** p < .01
Sleep - Questionnaire data
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Data from the Children’s Sleep Habits Rating Scale revealed that parents of
children with MPS III saw their child displaying more sleep problems
compared to controls in the areas of :
 bedtime resistance
 sleep onset delay
 sleep duration
 sleep anxiety
 night waking
 night behaviours
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parasomnias
 sleep disordered breathing
 daytime sleepiness
Melatonin analyses
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88.5% data useable and reliable (SDs < 20% of mean) [1 outlier removed]
No significant effects of day of collection (first day vs. last day) (p > 0.05)
Sig. diff. in melatonin level in control group time points (Time 1: 6-8h,
Time 2: 10h-12h, Time 3: 22-24h) on the first [p = 0.002] and last day [p =
0.006] and between Time 2 & Time 3 (p = 0.016) and Time 1 &Time 3 (p
= 0.031) on both days
No reliable differences across time points for the MPS III group on the first
day χ² (2) = 0.50, p = 0.931, or last day χ² (2) = 2.80, p = 0.367.
Visual inspection suggested that the MPS III group had higher melatonin
concentrations at 6-8h and lower levels at 22-24h, compared to controls
NB Exogenous melatonin stopped two weeks prior to actigraphy
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No reliable differences across time were found in the MPS III group, demonstrating
abnormal circadian rhythm of melatonin concentration - melatonin levels lower at
night / higher early morning in children with MPS III, compared to controls
Disruption in the melatonin CR in MPS III (cf Guerrero et al., 2006) could account
for sleep disturbances:
 Lower levels of melatonin at night = difficulties falling asleep
 Higher levels of melatonin in the morning = increase in daytime napping.
Some MPS III were on hypnotic medications (choral hydrate, zopiclone) -without
these sleep may have been reduced and disrupted to a greater degree.
Hypnotic drugs have little/no effect on sleep disorders with an irregular sleep/wake
cycle (Guilleminault et al1993) and all parents described sleep medication as
having little or no benefit
Oldest child prescribed hypnotic drugs had poorest sleep of the entire group.
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Empirical basis for melatonin prescription
Advice on behavioural modification to be provided to
caregivers with focus on bedtime resistance, sleep onset
difficulties, sleep anxiety, night time waking,
disruptive/dangerous behaviours at night, daytime sleep and
tiredness.
Objective assessment using actigraphy and melatonin assays
both recommended and practical
Future research to focus on efficacy and side-effects of sleep
interventions in MPS III.
Behavioural phenotype [Cross et al
submitted]
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2-9 yrs:
 Gross motor skills differentiate MPS III and ID groups.
 Hyperactivity, orality, body movements, interactions with
objects and inattention
10-15 yrs:
 Impaired daily living skills, communication, coping skills
and understanding & expression.
 level of disability increases / challenging behaviour
decreases with age in in the MPS III group
Family functioning [Grant et al 2013]
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Parents of children with MPS III had significantly lower rates
of future-orientated and goal-directed resilience factors than
parents of children with ID (Grant et al 2013)
Future directions
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A small set of behaviours & functions (Repetitive & restricted
behaviour, executive control, language, social communication,
attachment) are dysfunctional in various combinations in many
ID syndromes:
 Reflects a taxonomy of genetic disorders ?
 Possibility of a taxonomy of behavioural phenotypes ?
 Basic genetically-encoded “tool kit” for developmental
‘bootstrapping ?
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