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Longitudinal Study to Identify Early Biomarkers of Autism Spectrum Disorder (ASD) in Infants With Tuberous Sclerosis Complex (TSC)

3 Months
9 Months
Open (Enrolling)
Tuberous Sclerosis Complex

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Trial Information

Longitudinal Study to Identify Early Biomarkers of Autism Spectrum Disorder (ASD) in Infants With Tuberous Sclerosis Complex (TSC)

This is a five-year multi-site study using MRI and EEG technologies to identify
developmental precursors of Autism Spectrum Disorder in patients with Tuberous Sclerosis
Complex (TSC). The study will be enrolling infants at five TSC centers throughout the
country, including Boston Children's Hospital, Cincinnati Children's Hospital Medical
Center, University of Alabama at Birmingham, University of Texas at Houston and University
of California Los Angeles. The main goal of this study is to identify early signs of autism
in children with TSC looking at the brain through MRI/diffusion tensor imaging, EEG and
behavioral/neuropsychological methods. Eligible infants between the ages of 3-9 months will
be evaluated longitudinally at regular visit intervals up to 3 years of age.

Study Objectives

1. To characterize the developmental precursors of ASD in a large number of TSC infants
using a prospective multi-center design: Infants with TSC will be evaluated
longitudinally at ages 3, 6, 9, 12, 18, 24 and 36 months. At each age, children will
undergo standardized evaluations, using cognitive and adaptive measures. At age 24 and
36 months, formal assessment for autism will be performed. Clinical data including
medication use, seizure history, EEG activity, genotypic variation, and co-morbidities
will be recorded to determine if specific clinical factors modify the course of

2. To identify biomarkers with advanced diffusion tensor imaging (DTI) that help predict
development of ASD in TSC infants: The investigators hypothesize that decreased white
matter integrity performed annually for each of the first 3 years of life, including
DTI sequences with tractography. Radial, axial, and mean diffusivity and fractional
anisometry will be calculated for each time point and change over time correlated with
development of ASD to determine relative risk. Individual measures at each time point
will be compared between ASD and non-spectrum groups to assess the individual impact of
each measure and timing.

3. To identify biomarkers with quantitative EEG that help predict development of ASD in
TSC infants: The investigators hypothesize that altered functional connectivity, as
measured by qEEG coherence and high frequency oscillations, will correlate with
development of ASD in TSC. Quantitative EEG (qEEG), EEG coherence/gamma frequency
(30-50Hz), and high frequency oscillations encompassing both ripples (80-250H) and fast
ripples (250-500 Hz) will be measured at each time point. Changes over time will be
correlated with development of ASD to determine relative risk, as will comparison of
individual measures between the two groups. EEG findings will also be correlated with
MR results obtained to further couple functional connectivity as measured by EEG with
structural connectivity measured by DTI.

Inclusion Criteria:

1. Meets genetic or clinical diagnostic criteria for TSC (Tuberous Sclerosis), the
latter based on current recommendations for diagnostic evaluation, such as physical
exam, neuroimaging, echocardiogram.

2. Age criteria: 3 months - 9 months (less than 10 months) of age at time of enrollment

Exclusion Criteria:

1. Prematurity, defined as gestational age < 36 weeks at time of delivery

2. Has taken an investigational drug as part of another research study, within 30 days
prior to study enrollment

3. Is taking an mTOR inhibitor such as rapamycin, sirolimus, or everolimus (other than
topical formulations) at the time of study enrollment

4. Subependymal Giant Cell Astrocytoma requiring medical or surgical treatment

5. History of epilepsy surgery

6. Contraindications to MRI scanning, such as metal implants/non-compatible medical
devices or medical conditions

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

ADOS evaluation score at the 36 month visit

Outcome Description:

The primary outcome is the possible clinical diagnosis of autism spectrum disorder per the DSM 5 guidelines (Autistic Disorder, Asperger's and PDD-NOS).

Outcome Time Frame:

36 months

Safety Issue:


Principal Investigator

Mustafa Sahin, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Boston Children's Hospital


United States: Federal Government

Study ID:




Start Date:

January 2013

Completion Date:

December 2017

Related Keywords:

  • Tuberous Sclerosis Complex
  • Tuberous Sclerosis Complex
  • TSC
  • Autism
  • ASD
  • Biomarkers
  • Infants
  • Autistic Disorder
  • Sclerosis
  • Tuberous Sclerosis
  • Child Development Disorders, Pervasive



University of Alabama at BirminghamBirmingham, Alabama  35294-3300
University of California at Los AngelesLos Angeles, California  90095
Cincinnati Children's HospitalCincinnati, Ohio  45229
Boston Children's HospitalBoston, Massachusetts  02115
University of Texas at HoustonHouston, Texas  77030