Early Biomarkers of Autism 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 3-12 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
development.

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- 12 months of age at time of enrollment. For study purposes, 3
months is defined as ≥ 9 weeks, 1 day and 12 months is defined as ≤ 13.5 months.

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 at the
time of study enrollment

5. History of epilepsy surgery at the time of study enrollment

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