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Early Biomarkers of Autism in Infants With Tuberous Sclerosis Complex (TSC)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2016 by Children's Hospital Boston
National Institute of Neurological Disorders and Stroke (NINDS)
Tuberous Sclerosis Alliance
Information provided by (Responsible Party):
Mustafa Sahin, Children's Hospital Boston Identifier:
First received: January 28, 2013
Last updated: February 18, 2016
Last verified: February 2016
The investigators are enrolling 3-12 month old infants with a diagnosis of tuberous sclerosis complex (TSC) for a new study on early markers of autism. The study is looking for early signs for autism in a population (TSC) where autism is common. The goal of this project is to use behavioral testing, MRI and EEG techniques to identify children at risk for developing autism starting at 3 months of age and continuing until 36 months of age. Throughout the study, the investigators will recommend Early Intervention services for any child who shows early signs of autism.

Tuberous Sclerosis Complex

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Longitudinal Study to Identify Early Biomarkers of Autism Spectrum Disorder (ASD) in Infants With Tuberous Sclerosis Complex (TSC)

Resource links provided by NLM:

Further study details as provided by Children's Hospital Boston:

Primary Outcome Measures:
  • ADOS evaluation score at the 36 month visit [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    The ADOS performed at 24 and 36 months will be used as a preliminary diagnosis for data analysis. The primary outcome is the possible clinical diagnosis of autism spectrum disorder per the DSM 5 guidelines (Autistic Disorder, Asperger's and PDD-NOS).

  • MRI biomarkers [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    MRI biomarkers obtained at baseline, 12, 24, 36 months will be applied to characterize individual patients in terms of brain tissue, white matter structure and connectivity, functional networks, and pathology. Brain tissue segmentation will be based on structural images derived from T1- and T2-weighted and FLAIR sequences using automated software tools designed for these tasks. White matter integrity and organization will be inferred from DTI imaging sequences. Structural connectivity networks will be delineated by DTI tractography assessment.

  • EEG biomarkers [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    One-hour video-EEG containing both wakefulness and sleep (minimum of 20 minutes of each) will be obtained at baseline, 3, 6, 9, 12, 18, 24 and 36 months. Functional connectivity and pathological activity will be determined by measurement of EEG coherence and gamma frequency/high frequency oscillations.

Biospecimen Retention:   Samples With DNA

Estimated Enrollment: 150
Study Start Date: January 2013
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Tuberous Sclerosis Complex (TSC)
Tuberous Sclerosis Complex

Detailed Description:

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.

Ages Eligible for Study:   3 Months to 12 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
A total of 150 evaluable infants with TSC will be recruited. Diagnosis of TSC will be based on established clinical criteria and will not require genetic testing prior to participation. The target age of entry into study is 3-6 months, but infants up to age 12 months (less than or equal to 13.5 months) will be included.

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01780441

Contact: Rajna Filip-Dhima, MS 617-919-7068
Contact: Central Contact

United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Jessica Krefting, RN    205-934-3866   
Principal Investigator: Martina Bebin, MD         
United States, California
University of California at Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Angela Martinez    310-206-7630   
Principal Investigator: Joyce Wu, MD         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Rachel Gerhardt    617-919-4599   
Principal Investigator: Mustafa Sahin, MD, PhD         
United States, Ohio
Cincinnati Children's Hospital Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Molly Griffith, BA    513-636-9669   
Principal Investigator: Darcy Krueger, MD, PhD         
United States, Texas
University of Texas at Houston Recruiting
Houston, Texas, United States, 77030
Contact: Elida Salazar    713-500-5766   
Contact: Patti Tate    713-500-5659   
Principal Investigator: Hope Northrup, MD         
Sponsors and Collaborators
Children's Hospital Boston
National Institute of Neurological Disorders and Stroke (NINDS)
Tuberous Sclerosis Alliance
Principal Investigator: Mustafa Sahin, MD, PhD Children's Hospital Boston
Principal Investigator: Darcy Krueger, MD, PhD Children's Hospital Medical Center, Cincinnati
  More Information

Additional Information:
Responsible Party: Mustafa Sahin, MD, PhD, Children's Hospital Boston Identifier: NCT01780441     History of Changes
Other Study ID Numbers: IRB-P00005074  1U01NS082320-01 
Study First Received: January 28, 2013
Last Updated: February 18, 2016
Health Authority: United States: Federal Government

Keywords provided by Children's Hospital Boston:
Tuberous Sclerosis Complex

Additional relevant MeSH terms:
Tuberous Sclerosis
Congenital Abnormalities
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Malformations of Cortical Development
Malformations of Cortical Development, Group I
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Nervous System Diseases
Nervous System Malformations
Neurocutaneous Syndromes
Neurodegenerative Diseases
Pathologic Processes processed this record on May 26, 2016