Syndrome-specific Profiles and Trajectories in Fragile X Syndrome & Autism

1. 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

2. 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

3. 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

4. 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)

5. What has changed?

6. 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 gene • Williams syndrome which results from a hemizygous microdeletion of 28 genes on chromosome 7q11.23 • Down syndrome caused by a trisomy on chromosome 21

7. 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

8. 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

9. 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

10. 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’

11. Genetic origins Neuro-anatomic Neurochemical Developmental disability • Environmental • factors • Cognitive & Behaviour By its very nature this research needs to be interdisciplinary

12. Core Question: How do we identify syndrome -specific signatures?

13. 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

14. 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?

15. Fragile X syndrome and autism • Fragile X and Autismare two specific disabilities that at first glance appear to share overlapping behavioural featuresand 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

16. 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

18. Premutation Fragile X Mental Retardation Gene (fMR1) identified in 1991 FMR1 X Full mutation No gene product

19. Prevalence of the FMR1 gene forms Common Intermediate 1/25 1/16 Premutation 1/813 1/250 Full mutation—Fragile X syndrome 1/4000 1/8000

20. FMR-1 gene silenced FMRP not expressed synaptic plasticity FRAGILE X: genetic & brain levels

21. FRAGILE X: Phenotype • PREMUTATION (“carrier”) • 50-200 CGG repeats • Subtle phenotypic • FULL MUTATION (fully-affected) • greater than CGG 200 repeats (>200) • males: affected with mental retardation • females: 50-70% borderline I.Q • 30-50% normal I.Q.

22. Physicalfeatures of Fragile X • Elongated face • Large prominent ears and forehead • High-arched palate • Hyperextensible finger joints

23. 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

24. 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

25. Toddler selective attention • Multiple measures: • Speed and path with displays varying in number and type of distractors • Error Types: • Distractor Touches • Perseverations

26. 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]

27. Toddler selective attention

28. Toddler selective attention

29. Childhood selective attention

30. Childhood selective attention

31. 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

32. Vocabulary • Long and short-term memory for meaningful information • Face and emotion recognition • Good visual memory • Good imitators • Repetitive speech • Short and long-term memory for abstract information • Sequential processing • Math and number 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)

33. 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

34. 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)

35. 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)

36. 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

37. 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)

38. 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)

39. 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

40. 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

41. 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

42. 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)

43. 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

44. 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 - phenomenisterrors: the perceptual information of an object, overrides allother representations

45. 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)

46. 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)

47. 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

48. 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

49. 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

50. 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)