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Defining the syndrome specific profiles and trajectories of children with differing developmental disabilities: the case of fragile X syndrome


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Title: Defining the syndrome specific profiles and trajectories of children with differing developmental disabilities: the case of fragile X syndrome

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 syndrome-specific 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
  • 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 gene
  • Williams syndrome which results from a hemizygous
    microdeletion of 28 genes on chromosome 7q11.23
  • Down syndrome caused by a trisomy on chromosome

  • 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 childs
    syndrome-specific strengths and challenges

  • 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
  • Core Question
  • How do we identify syndrome -specific

  • 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
  • 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

(No Transcript)
Fragile X Mental Retardation Gene
(fMR1) identified in 1991
Full mutation
No gene product
Prevalence of the FMR1 gene forms
1/25 1/16
1/813 1/250
Full mutationFragile X syndrome
1/4000 1/8000
FRAGILE X genetic brain levels
FRAGILE X Phenotype
  • PREMUTATION (carrier)
  • 50-200 CGG repeats
  • Subtle phenotypic
  • FULL MUTATION (fully-affected)
  • greater than CGG 200 repeats (gt200)
  • 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
Toddler selective attention
Childhood selective attention
Childhood selective attention
Remaining questions
  • To what extent do starting states in early
    childhood differ from the phenotypic outcomes in
  • - 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

The attention
deficit remains

constant from infancy through

to adulthood and differentiates

FXS from
other developmental

disorders (Cornish et al 2007,

Fragile X syndrome behavioral characteristics
  • Hyperactivity, impulsivity, inattentiveness
  • Extreme shyness and mood swings (especially in
  • Increased anxiety when exposed to new routines
    and settings
  • Hyperarousal to sensory stimuli leading to
    irritability, tantrums, hand biting or hand

  • 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
  • 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

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

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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
Strategies that focus on a childs strengths are
  • 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 childs 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
Many thanks
  • Canada Research Chairs Program
  • Canadian Institutes of Health Research
  • Canada Foundation for Innovation
  • Wellcome Trust, UK