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

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 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

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 interdisciplinary

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 1991XFMR1No gene productFull mutation

IntermediatePremutationFull mutationFragile X syndromeCommon1/25 1/161/813 1/2501/4000 1/8000Prevalence of the FMR1 gene forms

FRAGILE X: genetic & brain levels

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.

Physical features of Fragile X Elongated face

Large prominent ears and forehead

High-arched palate

Hyperextensible finger joints

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

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

Toddler selective attentionMultiple measures: Speed and path with displays varying in number and type of distractors Error Types: Distractor Touches Perseverations

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

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



Sheet3

repetitions per hit

Toddler selective attention

Chart4

1.312.88

0.863.59

36.63

0.981.1



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



Sheet2



Sheet3

repetitions per hit

Childhood selective attention

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

Childhood selective attention

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

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)

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 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

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 relationshipsTheory of mindSpeech 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 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)

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)

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

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 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

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)

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

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:

www.fragilex.org/html/autism.htm

Many thanks Canada Research Chairs Program

Canadian Institutes of Health Research

Canada Foundation for Innovation

Wellcome Trust, UK

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