Early Detection of Autism: Research Perspectives

1. Jane E. Roberts, Ph.D. University of South Carolina Early Detection of Autism: Research Perspectives

2. Outline • Autism Symptomology: Early Signs • Fragile X Syndrome: High Risk Population • Research Study: Early Detection of Autism • Research Study: Language Development

3. Autism • Core Symptoms • Diverse spectrum • Debilitating effects • Increased prevalence

4. Autism: DSM V Proposed Criteria • ASD will encompass autism, Pervasive Developmental Disorder, and Aspergers. • 2 Core Symptoms

5. Autism Co-Morbidity • Intellectual Disability • Executive Function • Anxiety • Attention Deficits • Health Conditions: Seizures, Sleep, Gut,

6. Neurobiology of Autism • Heritability Index - .90 • Polygenic • Epigenetic mechanisms implied • Increased brain size • “Disorder of Connectivity”

7. Videoclip

8. Early Identification of ASD • Retrospective Study & Parental Report: • 50% of infants <12 months display symptoms • 80% of toddlers <24 months display symptoms • Median age at initial diagnosis is 4.0 years • Median age of diagnosis is 5.7 years despite development of tools to diagnose at 2 years

9. Broad Developmental Indicators Mullen: Early Learning Composite Early Learning Composite 9 months Typical ----- FXS ----- ASIB ----- DD ----- 15 months Age F (3, 357) = 10.41, p = <.0001

10. Early Detection – why difficult? • What are the challenges to early detection of ASD? • ? • ? • ? • ?

11. Early Indicators of ASD: Prospective Studies with High Risk Infant Siblings • Extended visual fixation to objects (Zwaigenbaum et al., 2005) • Prolonged latency to disengage visual attention (Bryson et al., 2004; Ozonoff et al., 2008; Zwaigenbaum et al., 2005) • Marked passivity and decreased activity levels in first year with increased negative affect, lower positive affect, and difficulty controlling attention (Brian et al., 2008; Garon et al., 2009; Zwaigenbaum et al., 2005) • Sensory oriented behaviors including reactivity to visual and auditory stimuli (Simmons et al., 2009; Zwaigenbaum et al., 2005)

12. Early Detection – why important? • Importance to Child? • Importance to Family?

13. Treatment Effects Dawson et al., 2009

14. Fragile X Syndrome: A High Risk Population • CGG triplet disorder at Xq27.3 (FMR1 gene) • Primary known cause of hereditary intellectual disability (1:2500) • Males more severely affected • Behavioral and cognitive characteristics • Epigenetic factors including hypermethylation result in reduced FMRP which has been associated with many clinical features

15. FXS: A Single Gene Disorder The fragile X mental retardation 1, FMR1, gene is located on the X chromosome. It codes for the fragile X mental retardation protein, or FMRP. X chromosome FULL MUTATION: People who actually have fragile X syndrome have more than 200 repeats and have the full mutation. 1:2500 - 3500 PREMUTATION: Some people have an expanded number of repeats and may express a normal amount of protein. These people are considered premutation carriers for fragile X and have 50-200 repeats. 1:257 (~1:110, Bailey 2010). FMR-1 gene

16. Hot off the press… • Prevalence rate of premutation in females may be 1:110 (Bailey, 2010) • Children with the FMR1 premutation at are elevated risk for autism : 30% (Farzin et al., 2008) • Infants with premutation found to exhibit delayed visual orienting to the novel but not the familiar stimulus, relative to TD infants (Farzin & Rivera, 2010)

17. CarrierFather (fragile)X Y Carrier Daughter Premutation (usually normal) X X (fragile) Affected Son (Full Mutation) Affected Daughter (Full Mutation) Y X X X (fragile)

18. Neurobiology of Fragile X Syndrome (Irwin etal. 2000; Kaufmann, 2009)

19. FXS Phenotype • Physical • Cognitive • Behavioral • 90% display > 1 autistic feature • 30% - 50% meet diagnostic criteria FXS • 20% - 70% meet diagnostic criteria Premutation

20. Diagnosis of FXS • Diagnosis by DNA analysis • First concern: 12 months • Diagnosis of Developmental Delay: 20 months • Diagnosis of FXS 36 months • Implications of Delayed Diagnosis of FXS • Delay of EI services • Recurrence Risk (64% of uninformed families have second child with FXS) • Family Support: Maternal stress and depression

21. Child Factors: Visual Attention • Look Behavior • Coded videotaped sessions of the 3-minute “toy play” epoch from the Lab-TAB, an experimental measure designed to assess attention in infants. • Variables • Behavioral: • Total Duration in Gaze Stimulus= % of time looking at toy • Latency to Gaze Away (s) = seconds • Autistic Behavior = Childhood Autism Rating Scale • Developmental Age = Mullen Scales of Early Learning • Physiological: • Heart activity = mean level and variability (standard deviation) during epoch

22. Results

23. Results

24. Results • Correlations • CARS: • Trend for Behavioral Gaze at Stimulus (.55; p = .083) • Change Score from 9 to 12 month (.46, p = .09) • No relationship with latency to Gaze Away (p = >.05) • Mullen total AE not correlated with: • Behavioral Gaze at Stimulus (p = >.05) • No relationship with latency to Gaze Away (p = >.05)

25. Summary & Conclusions • FX Infants Compared to TD Controls at 12 months: • Longer time looking at toy • Longer latency to look away (2 – 4 x longer) • Less variability in mean HR when looking at keys • Some of these behaviors appear to be related to indices of autistic behavior

26. Temperament in FXS Shift from hypo-responsiveness to hyper-responsiveness?? (Baranek et al., 2008; Roberts et al., 2009; Shanahan et al., 2008) Brain Development

27. Temperament • May be that relationships emerge between FXS and autism during infancy and early childhood that are reflected in measures of temperament • Predictive of later outcomes, i.e. autism • Important due to high co-morbidity of FXS and autism

28. Typical Infant Response to Arm Restraint IBI Baseline Reactivity Recovery

29. Fragile X Infant Response to Arm Restraint Recovery Reactivity Baseline IBI

30. Age Interaction in IBI Predicting CARS

31. Concluding Points • Autism is a devastating condition • Parsing out heterogeneity important (FX) • Early detection is challenging but crucial • Prospective longitudinal work is essential • Multi-method designs likely most informative • Inclusion of child and parent (family) factors key • Integration of findings from neuroscience critical to identify mechanisms

32. Research at USCNeurodevelopmental LabDr. Jane Roberts

33. Study 1: Early Detection of Autism • Research Program • (1) the co-morbidity of autism and FX by investigating the emergence, predictors and developmental pathways of these two associated conditions • (2) the role of biomarkers to advance our understanding of the underlying mechanisms associated with deleterious outcomes in FX (full and premutation).

34. Early Detection of ASD in High Risk Populations Prospective longitudinal study of early signs of autism in 3 high risk samples at 6,9, 12 and 24 months of age: 1. Idiopathic Autism (infant with diagnosed sibling) 2. Fragile X Syndrome – full mutation 3. Fragile X Premutation – FMR1 premutation 4. Typical Controls NIMH: R01MH090194-01A1 Emergence and Stability of Autism in Fragile X Syndrome, 2011 - 2016

35. Research Aims 1. Identify group differences in biomarkers and behavioral symptoms at 6, 9, 12, and 24 m in infants with FXS and FXpm in comparison to ASIBS and TD infants. • 1a. Examine group differences in heart rate and vagal tone , heart-defined phases of attention, and ERP. • 1b. Examine group differences in autism screening symptoms and visual attention.

36. Research Aims 2. Determine the association between biomarkers and behavioral symptoms at 6, 9, 12, and 24 m to autism severity at 24m in infants with FXS and FXpm in comparison to ASIBS. • 2a. Examine the association between heart rate and vagal tone, heart-defined phases of attention, and ERP to autism severity by group. • 2b.Determine the relationship between FMR1 gene expression (FMRP) and autism severity and potential group differences for infants with FXS and FXpm. • 2c.Examine the association of autism screening symptoms and visual attention to autism severity by group.

37. Participation in Research • Informed Consent • Know what the study is about (benefit/risk/time) • Know what your role is and what you and your child will be asked to do • Be able to commit to the study • Participation • Parent: complete forms, participate in interviews • Child: complete developmental measures, experimental measures • Time – 3 – 5 hours potentially spread across 2 days at USC or in your home

38. Study 2: Language in FXS and ASD Multi-Site Study: Abbeduto, MIND Institute • Describe language in FXS and determine mechanisms of variability: • Stress and anxiety • Genetic markers • Disassociation from Idiopathic Autism • Sample: males, aged 15 – 22 at entry • FXS: 80 (40 usc) • IA: 40 (20 usc) NICHD: Language Development in Fragile X Syndrome

39. Participation • Parent and Child Measures • Parent interview • Child – series of measures to evaluate language, non-verbal reasoning, and autism severity • 3 sessions spread over 2 days at USC

40. Now Recruiting! • Infants with Fragile X Syndrome or Siblings of a Child with Autism • Adolescents with Fragile X Syndrome or Autism www.uscdevlab.com uscdevlab@gmail.com Or come talk to us! (Dr. Jane Roberts-PI)