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Disorders of Known Genetic Origin (Paterson et al., (2006) (Results (WS…
Disorders of Known Genetic Origin
Down Syndrome
Overview
John Langdon Down - first described cluster of symptoms, intellectual impairments (1866)
Currently affects ~ 1 in 700/1000 live births
Leading genetic cause of intellectual impairment
Life expectancy ~ 60
Causal Model
Gene - chromosome 21: n/300 genes
Enviro - maternal age, school/family influences
Bio - reduced plasticity, aberrant synaptic, structures, hippocampal abnormalities, small cerebellum
Cog - cog impairment and early decline, reduced processing speed, impaired memory+learning, uneven lang profile
Beh - distinct physical characteristics, associated health/behavioural risks
Physical characteristics
Features
Eyes that slant upwards
Small ears
Protruding tongue
White spots on iris (blush field spots)
Short fingers & loose joints
Shorter stature
Increased risk of
Congenital heart disease - 80%
Leukaemia
Gastrointestinal abnormalities
Hearing impairments
Screening
Detection of DS
From amniocentesis
1966
Risk of miscarriage = 1%
2nd Trimester
92% of prenatal diagnosis result in termination
1st Trimester Screening
Maternal age
Nuchal translucency
Maternal pregnancy hormones
Genes
Genes + Environment
Although genetic disorder, not usually hereditary (97%)
Maternal age = environmental risk factor
Older = much more likely
Known genetic cause: presence of extra copy of genetic material on chromosome 21, whole or part
Not all cells copy but most
Effects of extra copy varies
~ 300 genes on chromosome 21; unclear which contribute to phenotype
Not specific to know outcomes
Cog Phenotype
Learning disability/intellectual impairment
Moderate to severe
IQ range: standard scores of 40-70 (normal = 85-115)
Unusual trajectory
Plateau of cog abilities after first few years of life (ability to improve)
Decline in IQ scores - not actual decline, staying the same but seen as worse compared to age
Variability within individuals - IDs, methodological issues
Heterogeneity between individuals
Relatively simple genetic cause > such variability (within and across)
Lang Impairment
More impaired than nonverbal functioning
Problems with speech intelligibility - difficultly producing sounds + therefore subsequent lang/communication
Delays acquisition of first words/phrases
Comprehension generally better than lang expression
Very high risk for hearing impairment
Uneven profiles across lang domains - nature/degree depends on what is being measured (phonology, vocab/semantics, grammar)
Naess et al (2011)
- differences in different aspects of lang
Vocab better than aspects of grammar
Comprehension related to chronological rather than mental age
Expressive predicted by chronological and mental age
Narrative predicted more by mental age and/or grammar comprehension
Overall profile resembles developmental lang disorder - SLI
Reading = relative strength - variable and still below typical expectations
Slower speed of processing - both orientation to, processing of, and response to environmental inputs
EF deficits
Memory (
Lee et al., 2010
)
Relative weakness in verbal WM
Relative in visuo-spatial memory
Particular problems with phonological loop
Neural Phenotype
In utero, DS brains - cerebellar hypoplasia + relatively short frontal lobe
Reduced brain stem + cerebellum size, Global differences = reduced myelination
By 35, neuropathological characteristics similar to Alzheimer's
Mouse Model
O'Doherty et al (2005)
Abnormalities in synaptic structure +transmission, esp hippocampus (memory) and cortio-striatal circuits (EF - inhibition, delayed gratification)
Reduced plasticity - ability to learn new skills
Smaller cerebellum
Long way of knowing implications/interactions
Enviro -
Esbensen et al (2013)
Parental characteristics = sig predictors of health, functional abilities, behaviour problems
Lower levels of behaviour problems predicted by improvements in maternal depressive symptoms
Higher levels of functional abilities predicted by prior measures of/improvements in maternal depressive symptoms
Better health = predicted by prior measures (maternal depressive symptoms, paternal positive psychological wellbeing, relationship quality between fathers + their adult children, improvements in maternal positive psychological wellbeing)
Dementia status also predicted by parental characteristics
Importance of family context for healthy ageing
Paterson et al., (2006)
Exact number of abilities rely on lang relevant processes
WS and DS > differ in relative abilities
1 Preferential Looking Paradigm
Infants + toddlers
Measure sensitivity to changes in numerosity
2 Reaction Times
Older children + adults
Numerosity various forms of counting
3 Number Battery
Measured various forms of counting + simple arithmetic
Results
WS infants displayed a level of performance equal to CA controls
DS infants failed to reach level of MA controls
Older DS children + adults outstripped older WS group in numerosity abilities
Differences in infant/adult number phenotypes between two genetic disorders
Processing styles might impact developmental trajectories
Fragile X Syndrome
Overview
Full mutilation affects ~ 1/4000 M; 1/6000 F
FXS = responsible for 2-3% of all forms of intellectual impairment
Most common inherited form of intellectual impairment
Implicated in 2-6% of cases of ASD
Causal Model
Gene - Silencing of single gene on X chromosome, heritable, gender differences
Enviro - Home environment, parental IQ
Bio - Larger than typical caudate nucleus, reduced amygdala volume
Cog - Intellectual impairment, attention, pragmatic lang, social
Beh - Distinct physical characteristics, associated health/behavioural risks
Physical characteristics
Elongated face
Long & prominent ears
High palate/flat feet
Hyperextensible finger joints
Males: macro-orchidism
Physical characteristics become more pronounced with age
Loose connective tissue - heart problems + gastroesophageal reflux
Seizures (~20% males)
Gene
Single gene disorder
Caused by expanded CGG trinucleotide repeat on the long arm of the X chromsome
One aspect of X chromosome that becomes repeated
FXS = Inherited Disorder
Unlike DS and WS, FXS is passed from parents to children
Number of repeats directly related to likelihood of passing disorder on
Boys are more severely affected as the only get an X chromosome form the carrier mother
CGG repeats in FMRI gene
Behavioural + Cog Phenotype
Deficts
Attention
Sig attention difficulties - impulsivity, problems with inhibitory control, distractibility
Inhibition: children with FXS = greater difficulties than children with DS
Selective attention: weaker in DS than FXS
By middle childhood sustained attention is a relative strength in both DS and FXS
Infants with WS have pronounced difficulty with orienting
Social
High rates of autistic behaviours in FXS pop, but reverse not true
30% males met full autism criteria, 30% meet for pervasive developmental disorder
Presence of ASD affects phenotype - lower IQ, worse adaptive behaviour outcomes, sig impairment in receptive/expressive lang
Intellectual impairment
~ 90% males; ~25% females have IQs below 70
Slow rate of growth: age dependent gradual decline in IQ
Impacted by slower learning > sig lower scores on intellectual functioning tests
Widening gap from normative sample
Cog profile develops dramatically from childhood to adolescence
Strength for verbal skills vs visuo-spatial constructive skills > rising in adolescence
Pragmatic lang impairments > tangential speech, perseverative/repetitive, delayed echolalia
Brain
Larger than typical caudate nucleus - associated with IQ, possible relation to attention/executive control
Reduced amygdala volume
Differences in brain structure evidence within first 3 years of life
Key differences between FXS and ASD - amygdala volume, caudate nucleus
Environment
Influences
Protection vs risk
Cog outcomes/behaviours - home environment, parent IQ
Interventions could test but existing studies of limited quality
Genes and Enviro
Correlation: exposure to environments is often partially genetically determined
Interaction: environments can modify the expression of an individual's genetic background, strengthening/weakening effect of genes on phenotypes
William's Syndrome
Overview
First study = 1975
Prevalence ~ 1 in 7,500-20,000
Genetic confirmation since 1990s
Sign intellectual impairment - FSIQ 50-60 but averages can mask IDs
Health Problems: cardiac problems, hypercalcemia, feeding difficulties/slow growth, connective tissue abnormalities
Causal Model
Gene - delection of ~ 27 genes on long arm of chromosome 7
Enviro - ??? paucity of research
Bio - widespread neuro-involvement, e.g. dorsal visual stream, amydgala
Cog -deficits in visuo-spatial construction, high sociability but poor social competence, lang strengths + weaknesses
Beh - distinct physical characteristics, associated health/behavioural risks, intellectual impairments, vocab strengths, pragmatic weaknesses, friendly
Physical characteristics
Characteristic facial features 'elfin'
Upturned nose
Widely spaced eyes
Wide mouth with full lips
Small chin
Slightly puffy cheeks
Irregular,widely spaced teeth
Genes
Deletion of ~ 26 genes on long arm of chromosome 7
Diagnosing using FISH to detect absence of ELN (key gene)
Cog Phenotype
Visuo-spatial
Worse than predicted from overall IQ
Not due to low level vial processing
Delay profile (~ younger typically developing children) - atypical developmental trajectory
Uneven profile: far worse than verbal abilities and face processing
Drawing = poor while description = rich + intuitive (contrasting)
Lang
Argument: better than predicted from overall IQ
Impaired visual spatial, spared lang skills
Good argument for modules in the brain
Shown picture and asked to give narrative > WS = eloquent, excited, exaggerated (contrasting SLI)
Double Dissociation?
SLI - impair grammar while sparing intelligence; WS - impair intelligence while sparing grammar
Lang abilities in WS need to be truly intact relative to general cog profie
Lang abilities particularly grammar, need to be superior
Other abilities should show opposite
Intact lang?
NO
Delayed lang acquisition
Uneven profile: receptive vocab scores better than other aspects of lang
Pragmatic lang impairments
Narrative difficulties >
Reilly et al (2004)
: WS and SLI did not differ in amount said, number of morphosyntactic errors, grammatical complexity/diversity
Jarrold et al (2001)
- non/verbal abilities develop at different rates, mental age equivalent scores for vocab increase more rapidly than pattern construction test
Hyper-Sociability
Extremely friendly, empathetic, talkative, socially disinhibited
'Intact' face processing skills: high levels of face and emotion recognition
Possibly using difference cog/neurological strategies to succeed on face processing tasks
Drawn to social stimuli, send much longer looking at faces (social cues) than typical controls
Good thing?
Socail disinhibition makes children vulnerable to explotation
Struggle to live independently
Too trusting
Difficulties gaining/maintaining employment
'More' not always 'better'
Riby & Hancock (2008)
WS, ASD, TDC: 13-15 years
Mathced peers for chronological age + general cog ability
Viewed static scenes that included people in natural settings
Eye-tracking
WS spent most time looking at faces, TDC some face, ASD entire scene
Similar findings using cartoons/moving images
Opposite of Autism
Argument: Social
BUT similarities
Difficulties with peers
Impairments in false belief
Poor understanding of social norms/rules
Less able to comment on character intentions/motivations
Pragmatic lang difficulties
High rates of co-morbid ADHD/anxiety disorder
Why atypical?
Executive function deficits - inhibition, planning, monitoring, selective attention
Motor skills - problems with saccadic control, poor visual search, poor joint attention
Need longitudinal studies to see if early difficulties are effecting development
Neural Phenotype
Structual abnormalities adjacent to functional abnormalities in the dorsal visual stream: behavioural deficits in visuo-spatial construction
Ps viewed fearful faces vs fearful scenes, WS = reduced amygdala reactivity to fearful faces but increased to scenes
Overview
Causal Model
Enviro, Bio, Cog, Behavioural
Disorders at all levels of description + interaction
All stages of development
Models to study neurodevelopmental mechanisms of cog/behavioural outcomes
Can use for other genetic/behavioural disorders
Look across timeline
How do genes impact on cognition/behaviour?
Genotype - phenotype relations > one to one mapping vs. more complex
Vary across development
what are the predictors of risk/protective factors and the mechanisms of resilience