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
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 syndromespecific profiles in late childhood and
early adulthood
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
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)
What has changed?
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
(a) Fragile X syndrome which results from the
silencing of a single gene
(b) Williams syndrome which results from a
hemizygous microdeletion of 28 genes on
chromosome 7q11.23
(c) Down syndrome caused by a trisomy on
chromosome 21
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
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
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 child’s syndrome-specific
strengths and challenges
5. 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’
By its very nature this research
needs to be interdisciplinary
Neuro-anatomic
Neurochemical
Genetic
origins
Developmental
disability
Environmental
factors
Cognitive &
Behaviour
Core Question:
How do we identify syndrome specific signatures?
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
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?
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
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
Fragile X Mental Retardation Gene
(fMR1) identified in 1991
FMR1
X
Premutation
Full mutation
Prevalence of the FMR1 gene forms
Common
Intermediate
1/25
1/16
1/813
1/250
1/4000
1/8000
Premutation
Full mutation—Fragile X syndrome
FRAGILE X: genetic & brain levels
FMR-1 gene silenced
FMRP not expressed
synaptic plasticity
FRAGILE X: Phenotype
• PREMUTATION (“carrier”)
• 50-200 CGG repeats
• Subtle phenotypic
• FULL MUTATION (fullyaffected)
• greater than CGG 200
repeats (>200)
• males: affected with mental
retardation
• females: 50-70%
borderline I.Q
• 30-50% normal I.Q.
Physical features of Fragile X
•Elongated face
•Large prominent ears
and forehead
•High-arched palate
•Hyperextensible
finger joints
Recent research advances
The development of
finer-tuned,
experimental
paradigms have
enabled researchers to
elucidate the cognitive
‘signatures’ in fragile X
from toddlerhood
through to adulthood
e.g. visual search task
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 childhood
• Toddlers
e.g. Cornish, Scerif & Karmiloff-Smith, 2007; Wilding, Cornish & Munir, 2002
Toddler selective attention
Multiple measures:
• Speed and path with
displays varying in
number and type of
distractors
• Error Types:
• Distractor Touches
• Perseverations
Toddler selective attention
• 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
0.9
0.8
0.7
0.6
0.5
0.4
repetitions per hit
0.3
0.2
0.1
0
Toddlers with Toddlers with Toddlers with
WS
FXS
DS
"Typical"
toddlers
Toddler selective attention
7
6
5
4
Confusions per run (dissimilar)
3
Confusions per run (similar)
2
1
0
Toddlers
with DS
Toddlers
with FXS
Toddlers
with WS
"Typical"
toddlers
Childhood selective attention
100
90
80
70
60
50
40
30
20
10
0
Total errors (FAs)
% repeats
% shape confusions
FX
DS
Poor Good att.
att. control
Control
Childhood selective attention
8
7
6
5
4
3
2
1
0
Perseverations per hit
Mean number of
repetitions on nontargets
FX
DS Poor att. Good
Control att.
Control
Remaining questions
• 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
Academic and Cognitive Signature in
FXS Boys and Girls
•Vocabulary
•Long and short-term
memory for
meaningful
information
•Face and emotion
recognition
•Good visual memory
•Good imitators
The attention deficit remains
constant from infancy through
to adulthood and differentiates
FXS from other developmental
disorders (Cornish et al 2007,
Cortex)
•Repetitive speech
•Short and long-term
memory for abstract
information
•Sequential processing
•Math and number
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
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)
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)
Autism: triad of challenges
• a 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 IQ’s below
70 have more severe
characteristics than
student with IQ’s
approaching the typical
range (around 100)
• substantial number (up to
80%) display ADHD
characteristics
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)
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)
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 relationships
• Theory of mind
• Speech and language
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
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
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)
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
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
Speech and language Fragile X and
autism
Delays 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)
Speech and conversational language
FXS 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)
Speech and conversational language
In 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
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
Autism and FXS: Similar classroom
management techniques
• Provide opportunities for your student to
release their excessive energy during
class time
• Use word processors and assistive
technology because this does not require
direct eye contact
• Tape-recorders, multimedia
• Provide information in chunk size pieces and
not with too many sequential steps
Autism and FXS: Different classroom
management techniques
• Autism – 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)
Strategies that focus on a child’s
strengths are crucial
In 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
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 child’s routine
Early speech and language intervention can
significantly improve outcome in later childhood
and adolescence
Fragile X and autism
More information on differences
between autism and FXS go to:
www.fragilex.org/html/autism.htm
Many thanks
• Canada Research Chairs Program
• Canadian Institutes of Health Research
• Canada Foundation for Innovation
• Wellcome Trust, UK