Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)

The purpose of this study is to characterize the developmental phenotype of ASD and ID and to identify biomarkers using advanced MRI methodology and electrophysiological biomarkers of synaptic function and connectivity predictive of ASD and ID presence and severity in patients with TSC. In addition, this study will be establishing infrastructure for the collection and storage of human bio-specimens, including genetic material, from TSC patients and their family members with ASD.

Study Overview

• Status: Recruiting
• Conditions: Intellectual Disability; Tuberous Sclerosis; Autism Disorder

Detailed Description

Tuberous Sclerosis Complex (TSC) is a multi-system disease that usually exhibits a high variability in clinical findings both among and within families. About 50% of individuals with TSC develop intellectual disability (ID) and/or autism spectrum disorder (ASD). The purpose of this research study is to learn more information about ASD/ID in individuals with TSC through neurobehavioral assessments, electroencephalogram (EEG) data, and magnetic resonance imaging so that ultimately effective treatments and interventions for ASD/ID can be realized.

Individuals with TSC will be asked to participate in this study if they are 18 months or older at the time of enrollment and have been diagnosed with suspected or confirmed autism spectrum disorder and/or intellectual disability, as well as healthy controls. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals' primary communicative language must be English. The participant and at least one biological parent will be asked to provide biological specimens including DNA and RNA for inclusion in the TSC RDCRN Biorepository.

The study involves 3 on site visits over the course of two years. Study visits will vary in length from about 4 hours to 6 hours. Study visits involve a physical exam, medical history questions, and neuropsychological assessments. A subset of participants between the ages of 2 and 11 years old will take part in the EEG portion of the study. At one point during the study, a blood draw will be done for future research studies. Individuals who have a clinically indicated MRI will have an option to provide routine clinical scans for analysis.

• Study Type: Observational
• Enrollment (Anticipated): 195

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • University of Alabama at Birmingham
      • Contact: Jessica Krefting, RN; Phone Number: 205-975-2890; Email: JessicaKrefting@uab.edu
      • Contact: Phone Number: 256-533-0833
      • Principal Investigator: Martina Bebin, MD
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California at Los Angeles
      • Contact: Chloe Schwartz; Phone Number: 310-825-3478; Email: ChloeSchwartz@mednet.ucla.edu
      • Principal Investigator: Shafali Jeste, MD
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford University
      • Contact: Jennifer Winterbottom; Phone Number: 650-498-9732; Email: jwinter2@stanford.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas at Houston
      • Principal Investigator: Hope Northrup, MD
      • Contact: Saba Usmani; Phone Number: 713-500-5766; Email: Saba.Usmani@uth.tmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

A total of 195 participants over the age of 18 months old with TSC and suspected or diagnosed ASD, ID, or combined ASD/ID will be enrolled into the study. Diagnosis of TSC will be based on established clinical or genetic criteria. Subjects will be enrolled from current and new TSC patients at each of the 6 centers.

Description

Inclusion Criteria:

• Meets genetic or clinical diagnostic criteria for TSC (Tuberous Sclerosis), the latter based on current recommendations for diagnostic evaluation, such as physical exam, neuroimaging, and echocardiogram.
• Age criteria: over 18 months of age at time of enrollment.
• Is diagnosed or suspected to have ASD and/or ID.
• Primary communicative language is English

Exclusion Criteria:

• Has taken an investigational drug as part of another research study, within 30 days prior to study enrollment.
• For subjects involved in imaging biomarker assessment: contraindications to 3T MRI scanning, such as metal implants/non-compatible medical devices or medical conditions, including vagus nerve stimulator.
• For subjects involved in EEG/ERP biomarker assessment: contraindications to EEG/ERP, such as uncooperative or destructive behaviors preventing lead placement or capture by ERP/VEP equipment. Under age 2 or above age 11 at the time of enrollment.
• Unwilling or unable to comply with study procedures and assessments.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Tuberous Sclerosis Complex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ADOS-2 scores at end of study	Using standardized composite score for ADOS-2 performed yearly to determine ASD	24 months
Change in SBIS-5 scores or Mullen Scales of Early Learning (MSEL) at end of study	Using standardized IQ score from the Stanford-Binet Intelligence Scales Fifth Edition (SBIS-5) or Mullen Scales of Early Learning (MSEL) performed yearly to determine ID	24 months
Change in Fractional anisotropy (FA) at 12 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be fractional anisotropy (FA) determined by MRI diffusion tensor imaging (DTI) with tractography at 12 months radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) of cerebellar fascicles corresponding to the neuroanatomically-defined excitatory and inhibitory projections cerebellar Purkinje neurons,	12 months
Change in fractional anisotropy (FA) at 24 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be fractional anisotropy (FA) determined by MRI diffusion tensor imaging (DTI) with tractography at 24 months	24 months
Change in radial diffusivity (RD) at 12 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be radial diffusivity (RD) determined by MRI diffusion tensor imaging (DTI) with tractography at 12 months	12 months
Change in radial diffusivity (RD) at 24 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be radial diffusivity (RD) determined by MRI diffusion tensor imaging (DTI) with tractography at 24 months	24 months
Change in mean diffusivity (MD) of cerebellar fascicles at 12 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be mean diffusivity (MD) of cerebellar fascicles determined by MRI diffusion tensor imaging (DTI) with tractography at 12 months	12 months
Change in mean diffusivity (MD) of cerebellar fascicles at 24 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be mean diffusivity (MD) of cerebellar fascicles determined by MRI diffusion tensor imaging (DTI) with tractography at 24 months	24 months
Change in axial diffusivity (AD) at 12 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be axial diffusivity (AD) determined by MRI diffusion tensor imaging (DTI) with tractography at 12 months	12 months
Change in axial diffusivity (AD) at 24 months	To determine cerebellum white matter structural integrity, the primary outcome measures will be axial diffusivity (AD) determined by MRI diffusion tensor imaging (DTI) with tractography at 24 months	24 months

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH); National Center for Advancing Translational Sciences (NCATS); Office of Rare Diseases (ORD); Tuberous Sclerosis Alliance
• Investigators: Study Chair: Darcy Krueger, MD, PhD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (ANTICIPATED): December 1, 2024
• Study Completion (ANTICIPATED): December 1, 2025

Study Registration Dates

• First Submitted: May 11, 2015
• First Submitted That Met QC Criteria: June 1, 2015
• First Posted (ESTIMATE): June 3, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 27, 2022
• Last Update Submitted That Met QC Criteria: September 23, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: MRI; Tuberous Sclerosis Complex; ASD; Autism; EEG; Intellectual Disability; TSC; ID
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Neoplasms; Neurologic Manifestations; Neurobehavioral Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Sclerosis; Autistic Disorder; Autism Spectrum Disorder; Intellectual Disability; Tuberous Sclerosis
• Other Study ID Numbers: IRB-P00013585; 1U54NS092090 (NIH)