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Defining the syndrome specific profiles and trajectories of
children with differing developmental disabilities: the case of
fragile X syndrome & autism
Professor & Director, McGill's Child Laboratory for Research
and Education in Developmental Disorders
Kim Cornish Ph.D
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Two Core Objectives:
To understand why syndrome-specific signatures are so important
in helping to target early interventions and resources
To understand the critical role of development in defining
syndrome-specific profiles in late childhood and early
adulthood
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The identification of cognitive impairments that distinguish
children with differing neurodevelopmental disorders from each
other and from typically developing children is a potentially
powerful tool for early identification and treatment of syndrome
specific proficiencies and deficiencies
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Until recently, few researchers or practitioners considered
important the causal roots of intellectual or behavioural
impairments
So, in both research and practice, individuals were merely
classified according to their degree of impairment (e.g., mild,
moderate, severe, and profound)
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What has changed?
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Staggering advances in our understanding of the genetics and
neuroscience of developmental disorders
1. it is now possible to provide very early diagnosis for many
developmental disabilities including disorders for which genetic
aetiology, although not in doubt, is still not determined, such as
Autism, as well as those disorders for which the genetic origins
are known, such as Fragile X syndrome which results from the
silencing of a single geneWilliams syndrome which results from a
hemizygous microdeletion of 28 genes on chromosome 7q11.23Down
syndrome caused by a trisomy on chromosome 21
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2. With such early diagnosis there is a critical need for
thorough investigations into the impact of a condition across the
full lifespan, beginning in infancy when, because of the plasticity
of the developing cortex, interventions are most likely to have
their most significant impact
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3. Our previous work has shown that it is crucial not to assume
that the effects of genetic dysfunctions through development are
replicas of outcomes in adulthood: starting states in early
childhood may be different and thus need to be empirically
tested
Cornish, Scerif & Karmiloff-Smith 2007; Scerif, Cornish et
al 2004, 2007
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4. Using an interdisciplinary model to chart developmental
trajectories will also help to prevent misdiagnosis that can give
rise to inappropriate remediation (clinical and academic) that
fails to target an affected childs syndrome-specific strengths and
challenges
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This is especially relevant for disorders that appear to share
common behavioural characteristics at least by mid-childhood (for
example, Fragile X and Autism) However, a closer inspection may
reveal very different developmental pathways that necessitate
tailor-made interventions that recognize syndrome-specific
signatures
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By its very nature this research needs to be
interdisciplinary
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Core Question:
How do we identify syndrome -specific signatures?
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Addressing any questions that relate to syndrome-specific
signatures requires cross-syndrome research - comparing and
contrasting the behaviours and performance of two or more differing
developmental disabilities
Fragile X, Down syndrome and William syndrome Fragile X and
autism
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Fragile X syndrome and autism To what extent does common
clinical or behavioural characteristics across syndromes by late
childhood imply common developmental pathways or aetiologies?
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Fragile X syndrome and autism
Fragile X and Autism are two specific disabilities that at first
glance appear to share overlapping behavioural features and
academic skills
There are currently very few single gene studies for which there
is a certainty of the involvement of Autism; Fragile X is one of
those disorders
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What is fragile X syndrome?FXS is a genetic inherited
condition
It was originally named because of an unusual appearance at the
end of the X chromosome in those with the condition
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Fragile X Mental Retardation Gene (fMR1) identified in
1991XFMR1No gene productFull mutation
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IntermediatePremutationFull mutationFragile X syndromeCommon1/25
1/161/813 1/2501/4000 1/8000Prevalence of the FMR1 gene forms
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FRAGILE X: genetic & brain levels
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FRAGILE X: PhenotypePREMUTATION (carrier)50-200 CGG
repeatsSubtle phenotypic
FULL MUTATION (fully-affected)greater than CGG 200 repeats
(>200)males: affected with mental retardationfemales: 50-70%
borderline I.Q30-50% normal I.Q.
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Physical features of Fragile X Elongated face
Large prominent ears and forehead
High-arched palate
Hyperextensible finger joints
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Recent research advancesThe development of finer-tuned,
experimental paradigms have enabled researchers to elucidate the
cognitive signatures in fragile X from toddlerhood through to
adulthoode.g. visual search task
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Teasing apart the attention signature at the cognitive level By
investigating attention across its varying sub-domains (selective,
sustained and attentional control) we have been able to distinguish
syndrome-specific profiles
Mid/late childhoodToddlerse.g. Cornish, Scerif &
Karmiloff-Smith, 2007; Wilding, Cornish & Munir, 2002
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Toddler selective attentionMultiple measures: Speed and path
with displays varying in number and type of distractors Error
Types: Distractor Touches Perseverations
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40 typically developing toddlers [24 - 48 months]8 toddlers with
Down syndrome [56 - 72 months]8 toddlers with fragile X syndrome
[34 - 50 months]8 toddlers with Williams syndrome [37 - 50
months]Toddler selective attention
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Toddler selective attention
Chart2
0.25
0.89
0.33
0.13
repetitions per hit
Sheet1
repetitions per hitConfusions per run (dissimilar)Confusions per
run (similar)
Toddlers with DS0.25Toddlers with DS1.31Toddlers with DS2.88
Toddlers with FXS0.89Toddlers with FXS0.86Toddlers with
FXS3.59
Toddlers with WS0.33Toddlers with WS3Toddlers with WS6.63
"Typical" toddlers0.13"Typical" toddlers0.98"Typical"
toddlers1.1
Confusions per run (dissimilar)Confusions per run (similar)
Toddlers with DS1.312.88
Toddlers with FXS0.863.59
Toddlers with WS36.63
"Typical" toddlers0.981.1
Sheet1
Confusions per run (dissimilar)
Confusions per run (similar)
Sheet2
Confusions per run (dissimilar)
Confusions per run (similar)
Sheet3
repetitions per hit
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Toddler selective attention
Chart4
1.312.88
0.863.59
36.63
0.981.1
Confusions per run (dissimilar)
Confusions per run (similar)
Sheet1
repetitions per hitConfusions per run (dissimilar)Confusions per
run (similar)
Toddlers with DS0.25Toddlers with DS1.31Toddlers with DS2.88
Toddlers with FXS0.89Toddlers with FXS0.86Toddlers with
FXS3.59
Toddlers with WS0.33Toddlers with WS3Toddlers with WS6.63
"Typical" toddlers0.13"Typical" toddlers0.98"Typical"
toddlers1.1
Confusions per run (dissimilar)Confusions per run (similar)
Toddlers with DS1.312.88
Toddlers with FXS0.863.59
Toddlers with WS36.63
"Typical" toddlers0.981.1
Sheet1
Confusions per run (dissimilar)
Confusions per run (similar)
Sheet2
Confusions per run (dissimilar)
Confusions per run (similar)
Sheet3
repetitions per hit
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Childhood selective attention
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This shows the total number of errors (false alarms to
non-targets) which increased from about 4 in the Good attention
group to the poor attention group to DS to about 36 in FX.
This figure also shows that the nature of these errors differed
between the LD groups and controls.
1. Repetitions on targets predominate the LD groups
2. In contrast, the normal main errors are shape
confusions-characterised by responses to targets of the same colour
but different shape from the target
Interestingly, the LD groups made only repetition errors not
shape confusions
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Childhood selective attention
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To what extent do starting states in early childhood differ from
the phenotypic outcomes in adults?
- More detailed adult studies using the same tasks across
development with detailed analysis of e.g. error patterns, in order
to elucidate age-related changes
Remaining questions
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Academic and Cognitive Signature in FXS Boys and Girls
The attention deficit remains constant from infancy through to
adulthood and differentiates FXS from other developmental disorders
(Cornish et al 2007, Cortex)
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Fragile X syndrome: behavioral characteristics
Hyperactivity, impulsivity, inattentiveness (ADHD)
Extreme shyness and mood swings (especially in girls)
Increased anxiety when exposed to new routines and settings
Hyperarousal to sensory stimuli leading to irritability,
tantrums, hand biting or hand flapping
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Autism is a complex and severe neurodevelopmental disability
that has intrigued clinicians and scientists for decades
Recent epidemiological studies indicate that the incidence of
autism is much higher than previously thought, with approximately
30 to 60 cases per 10,000 (Rutter, 2005)
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A large number of studies confirm that autism has an important
and substantial genetic component (for a review, see Rutter
2000)
For example, there is a predominance in males compared to
females (sex ratio M/F: 3-4 ~ 8 /119), and twin studies show
concordance rates of 36 to 91% for monozygotic twins and 1 to 23%
for dizygotic twins (Manning-Courtney et al 2003)
Siblings of autistic children have a higher than expected rate
of language delay (Bailey et al 1996)
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Autism: triad of challengesa severe disruption of cognitive
ability
impaired social interaction and communicative skills
coupled with unusually restricted and repetitive stereotyped
patterns of behaviors and interests
onset in the first 3 years of life
students with IQs below 70 have more severe characteristics than
student with IQs approaching the typical range (around 100)
substantial number (up to 80%) display ADHD characteristics
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Fragile X and autism Almost all affected FXS children, and
especially boys, will display autistic-like characteristics that
may mimic typical autism such as language delay, echolalia, and
perseverative speech alongside poor eye contact, poor social
interactions and stereotypic movements
e.g. Cornish, Turk & Levitas et al (2007); Cornish et al
(2004); Cornish, Levitas & Sudhalter 2007; Demark et al (2003);
Turk & Graham (1997)
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Fragile X and autism Although still controversial, a plethora of
recent studies using a variety of gold standard diagnostic measures
including the Autism Diagnostic Observation Schedule (ADOS-G), and
the Autism Diagnostic Interview-Revised (ADI-R) indicate a
percentage of between 20-35% of FXS individuals will fulfill
criteria for a clinical diagnosis of autism see Hagerman (2006) for
a review & Rogers et al (2001)
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Fragile X and autism Growing number of studies demonstrate that
children diagnosed with FXS, with and without autism, and children
diagnosed with autism alone differ in subtle but fundamental and
clinically important ways across developmental time and across
behavioral and cognitive domains Eye gaze and social
relationshipsTheory of mindSpeech and language
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Eye gaze and social relationships Autism: atypical eye gaze is
most acute in social interactions and appears to be motivated both
by a lack of understanding of the social situation itself and by
the absence of a desire to communicate Fragile X: although tending
to avoid social interactions, will offer what is now classically
termed the fragile X handshake, whereby an initial wish to
communicate socially, with a handshake, or a socially acceptable
remark is coupled with active and even persistent gaze
avoidance
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Eye gaze and social relationships Thus, at first glance,
although eye gaze avoidant behavior appears to unite FXS and
autism, at a deeper level it serves very different purposes and are
likely due to very different mechanisms underlying the
disorders
In FXS, eye gaze aversion, is more symptomatic of their
hyperarousal and social anxiety rather than from an inherent lack
of understanding of the social situation
e.g. Belser & Sudhalter (1995); Cornish et al (2004)
In Autism, there is deviant eye contact (e.g. Senju et al 2003)
with a unique style of processing gaze
Characterized by a more generalized social deficit that impacts
across all social situations and interactions
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Theory of Mind The ability to understand the intention and
beliefs of others is a critical component of cognitive
development
Theory of Mind deficits are well documented in Autism (e.g.
Baron-Cohen, 1989; Baron-Cohen et al. 1985), and more recently in
FXS (Cornish et al 2005; Grant et al 2007) However, observation of
the error patterns in performance of children with Autism and
children with FXS reveals very different profiles
Sally Ann Task (Baron-Cohen 1985; Frith, 1989)
Appearance/Reality Task (Baron-Cohen 1989)
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Sally-Anne task
This is Sally. Sally has a basket. This is Anne. Anne has a
box.
Sally has a marble. She puts the marble into her basket.
Sally goes out for a walk. Anne takes the marble out of the
basket, and puts it into the box.
Now Sally comes back. She wants to play with her marble. Where
will Sally look for her marble?50% of children with FXS correct
compared to less than a third of children with autism
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Appearance/Reality task
a bottle of milk is shown and the child asked to name the object
and its color an orange filter was then placed in front of the
object and the child is asked:
the appearance question Now what color does the milk look?
the reality question What color is it really?
A correct response is that the milk looked orange but was really
white Although children with fragile X and children with autism
display considerable impairment on this task,their error patterns
are qualitatively different from each other
FXS - realist errors:ignored the appearance of an object and
relied on real knowledge. Autism - phenomenist errors: the
perceptual information of an object, overrides all other
representations
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Speech and language Fragile X and autismDelays in expressive
language development, poor social use of language, and unusual
speech patterns such as echolalia have been well established
in:
Autism (e.g. McCleery et al 2006; Pry et al 2005)
FXS (e.g. Abbeduto et al 2003; Roberts et al 2001)
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Speech and conversational languageFXS specific weaknesses, most
notably in affected males during conversational interactions:
tangential language (errors include off-topic questions, responses
or comments that do not logically follow the preceding
conversational thread)
perseverative language (errors include the reintroduction of
favorite topics over and over)
repetitive speech (errors include repetition of sounds, words or
phrases within an utterance or conversational turn)
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Speech and conversational languageIn all three categories, males
with FXS produced significantly more errors than age matched
children with autism (and children with other forms of mental
retardation)
This suggests that these forms of atypical language production
are not the consequence of cognitive delay or of undiagnosed autism
atypical language profile results from the hyperarousal that social
interactions cause males and females with FXS
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Autism and FXS: Similar classroom management techniques Seating
arrangements (away from distracters and especially corridors where
other children will regularly move around)Noise level of the
classroom (reduced)Use of a visual timetable and photo agenda will
help to reduce the impact of classroom transitions and promote
predictability thus reducing hyperactivity and anxiety levels
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Autism and FXS: Similar classroom management techniques Provide
opportunities for your student to release their excessive energy
during class timeUse word processors and assistive technology
because this does not require direct eye contactTape-recorders,
multimediaProvide information in chunk size pieces and not with too
many sequential steps
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Autism and FXS: Different classroom management techniquesAutism
help maintain eye contact when facilitating strategies to help a
child focus on a task Fragile X Remember that a FXS child although
sociable rarely enjoys eye contact so respect this by using
strategies that minimize eye contact (e.g. sit behind and use
physical prompts, where necessary, to reinforce verbal
instruction)
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Strategies that focus on a childs strengths are crucialIn Math,
make number processing fun!!! Instead of concentrating on learning
abstract numerical concepts use practical everyday examples- e.g.
clocks, playing cards
Avoid too much demand on sequential processing and use visual
representation where possible to make number concepts meaningful- a
visual sequencing board might help
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Given that children with FXS have severe difficulties in speech
and language that include perseveration (self-repetition) rather
than echoing of others as in autism, it is crucial that speech and
language therapy is a daily or weekly part of a childs routine
Early speech and language intervention can significantly improve
outcome in later childhood and adolescence
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Fragile X and autism More information on differences between
autism and FXS go to:
www.fragilex.org/html/autism.htm
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Many thanks Canada Research Chairs Program
Canadian Institutes of Health Research
Canada Foundation for Innovation
Wellcome Trust, UK
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