Jane E. Roberts, Ph.D.University of South Carolina

Autism Symptomology: Early Signs

Fragile X Syndrome: High Risk Population

Research Study: Early Detection of Autism

Research Study: Language Development

Core Symptoms

Diverse spectrum

Debilitating effects

Increased prevalence

ASD will encompass autism, Pervasive Developmental Disorder, and Aspergers.

2 Core Symptoms

Intellectual Disability

Executive Function

Anxiety

Attention Deficits

Health Conditions: Seizures, Sleep, Gut,

Heritability Index - .90

Polygenic Epigenetic mechanisms implied

Increased brain size“Disorder of Connectivity”

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 months

15 months

Typical -----FXS ----- ASIB -----DD -----

F (3, 357) = 10.41, p = <.0001 Age

What are the challenges to early detection of ASD? ? ? ? ?

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)

Importance to Child?

Importance to Family?

Dawson et al., 2009

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

FMR-1 gene

X chromosome

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.

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).

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)

Carrier Father

Carrier Daughter

Premutation (usually normal)

Affected Son

(Full Mutation)

Affected Daughter

(Full Mutation)

(fragile) X Y

X X (fragile)

X X (fragile)Y X

(Irwin etal. 2000; Kaufmann, 2009)

Physical

Cognitive

Behavioral 90% display > 1 autistic feature 30% - 50% meet diagnostic criteria FXS 20% - 70% meet diagnostic criteria Premutation

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

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

Table 2. Heart rate measures for FX and TD infants at 12 months

Variable

TD

n=8

FX

n=11 t-test

Mean SD Mean SD t(17) Sig

Mean HR during keys 133.9 12.8 136.8 6.5 -0.63 ns

SD of HR during keys 9.13 3.52 6.27 1.324 2.49 .024

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)

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

Shift from hypo-responsiveness to hyper-responsiveness?? (Baranek et al., 2008; Roberts et al., 2009; Shanahan et al., 2008)

Brain Development

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

300

350

400

450

500

550

0:00:02 0:00:10 0:00:16 0:00:23 0:00:29 0:00:34 0:00:40 0:00:45

Baseline Reactivity Recovery

Typical Infant Response to Arm RestraintIB

I

360

380

400

420

440

460

480

500

0:00:02 0:00:29 0:00:55 0:01:22

Baseline Reactivity Recovery

Fragile X Infant Response to Arm RestraintIB

I

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

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).

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 mutation3. Fragile X Premutation – FMR1 premutation4. Typical Controls NIMH: R01MH090194-01A1

Emergence and Stability of Autism in Fragile X Syndrome, 2011 - 2016 

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.

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.

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

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

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

Infants with Fragile X Syndrome or Siblings of a Child with Autism

Adolescents with Fragile X Syndrome or Autism

www.uscdevlab.comuscdevlab@gmail.comOr come talk to us! (Dr. Jane Roberts-

PI)