Jane E. Roberts, Ph.D. University of South Carolina.
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Transcript of Jane E. Roberts, Ph.D. University of South Carolina.
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Jane E. Roberts, Ph.D.University of South Carolina
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Autism Symptomology: Early Signs
Fragile X Syndrome: High Risk Population
Research Study: Early Detection of Autism
Research Study: Language Development
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Core Symptoms
Diverse spectrum
Debilitating effects
Increased prevalence
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ASD will encompass autism, Pervasive Developmental Disorder, and Aspergers.
2 Core Symptoms
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Intellectual Disability
Executive Function
Anxiety
Attention Deficits
Health Conditions: Seizures, Sleep, Gut,
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Heritability Index - .90
Polygenic Epigenetic mechanisms implied
Increased brain size“Disorder of Connectivity”
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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
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9 months
15 months
Typical -----FXS ----- ASIB -----DD -----
F (3, 357) = 10.41, p = <.0001 Age
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What are the challenges to early detection of ASD? ? ? ? ?
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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)
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Importance to Child?
Importance to Family?
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Dawson et al., 2009
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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
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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).
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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)
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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
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(Irwin etal. 2000; Kaufmann, 2009)
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Physical
Cognitive
Behavioral 90% display > 1 autistic feature 30% - 50% meet diagnostic criteria FXS 20% - 70% meet diagnostic criteria Premutation
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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
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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
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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
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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)
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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
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Shift from hypo-responsiveness to hyper-responsiveness?? (Baranek et al., 2008; Roberts et al., 2009; Shanahan et al., 2008)
Brain Development
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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
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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
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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
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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
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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).
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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
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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.
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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.
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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
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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
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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
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Infants with Fragile X Syndrome or Siblings of a Child with Autism
Adolescents with Fragile X Syndrome or Autism
[email protected] come talk to us! (Dr. Jane Roberts-
PI)