Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations

• ClinicalTrials.gov Identifier: NCT02461446
• Recruitment Status: Recruiting
• First Posted: June 3, 2015
• Last Update Posted: September 26, 2022
• Sponsor: Boston Children's Hospital
• Collaborators: National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS); Office of Rare Diseases (ORD); National Center for Advancing Translational Sciences (NCATS); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Mustafa Sahin, Boston Children's Hospital

Tracking Information

• First Submitted Date: May 11, 2015
• First Posted Date: June 3, 2015
• Last Update Posted Date: September 26, 2022
• Study Start Date: May 2015
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 14, 2018)

• Change in verbal abilities at 12 months [ Time Frame: 12 months ]
  Verbal and non-verbal ability will be evaluated using Stanford Binet -5 or Mullen Scales of Early Learning (MSEL) at 12 months
• Change in communication ability at 12 months [ Time Frame: 12 months ]
  Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4).
• Change in communication ability at 12 months [ Time Frame: 12 months ]
  Communication ability will be evaluated using composite score of the Expressive Vocabulary Test (EVT-2) at 12 months.
• Change in verbal abilities at 24 months [ Time Frame: 24 months ]
  Verbal and non-verbal ability will be evaluated using Stanford Binet 5 or Mullen Scales of Early Learning (MSEL) at 24 months
• Change in visual perception at 12 months [ Time Frame: 12 months ]
  Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 12 months
• Change in working memory at 12 months [ Time Frame: 12 months ]
  Working memory will be evaluated using the Stanford Binet 5 at 12 months
• Change in processing speed at 12 months [ Time Frame: 12 months ]
  Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 12 months
• Change in working memory at 24 months [ Time Frame: 24 months ]
  Working memory will be evaluated using the Stanford Binet 5 at 24 months
• Change in processing speed at 24 months [ Time Frame: 24 months ]
  Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 24 months
• Change in visual perception at 24 months [ Time Frame: 24 months ]
  Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 24 months
• Change in communication ability at 24 months [ Time Frame: 24 months ]
  Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4) at 24 months
• Change in communication ability at 24 months [ Time Frame: 24 months ]
  Communication ability will be evaluated using composite score of the Expressive Vocabulary Test (EVT-2) at 24 months.

Original Primary Outcome Measures (submitted: June 1, 2015)

• Change in verbal abilities at 12 months [ Time Frame: 12 months ]
  Verbal and non-verbal ability will be evaluated using Stanford Binet -5 or Mullen Scales of Early Learning (MSEL) at 12 months
• Change in communication ability at 12 months [ Time Frame: 12 months ]
  Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4), Expressive Vocabulary Test (EVT-2), and the Children's Communication Checklist (CCC-2) at 12 months
• Change in verbal abilities at 24 months [ Time Frame: 24 months ]
  Verbal and non-verbal ability will be evaluated using Stanford Binet 5 or Mullen Scales of Early Learning (MSEL) at 24 months
• Change in working memory at 12 months [ Time Frame: 12 months ]
  Working memory will be evaluated using the Stanford Binet 5 at 12 months
• Change in processing speed at 12 months [ Time Frame: 12 months ]
  Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 12 months
• Change in visual perception at 12 months [ Time Frame: 12 months ]
  Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 12 months
• Change in motor functioning at 12 months [ Time Frame: 12 months ]
  Motor functioning will be evaluated using the Purdue Pegboard (Pegs) at 12 months
• Change in working memory at 24 months [ Time Frame: 24 months ]
  Working memory will be evaluated using the Stanford Binet 5 at 24 months
• Change in processing speed at 24 months [ Time Frame: 24 months ]
  Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 24 months
• Change in visual perception at 24 months [ Time Frame: 24 months ]
  Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 24 months
• Change in motor functioning at 24 months [ Time Frame: 24 months ]
  Motor functioning will be evaluated using the Purdue Pegboard (Pegs) at 24 months
• Change in communication ability at 24 months [ Time Frame: 24 months ]
  Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4), Expressive Vocabulary Test (EVT-2), and the Children's Communication Checklist (CCC-2) at 24 months

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations
• Official Title: Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations
• Brief Summary: The purpose of this study is to determine cross-sectional and longitudinal medical, behavioral, and cognitive differences between PTEN ASD and other groups, as well as to identify cognitive, neural systems, and molecular biomarkers specific to PTEN ASD. In addition, this study will be creating and maintaining a biorepository and linked phenotypic database for PTEN ASD.

Detailed Description

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by social communication/interaction impairments and restricted/repetitive behaviors. ASD associated with germline heterozygous PTEN mutations (PTEN ASD) is a genetically defined sub-group that, may be one of the more prevalent genetic disorders contributing to ASD (0.5-2%). The purpose of this research study is to carefully track the phenotypic and molecular characteristics of PTEN ASD and identify biomarkers for intervention studies.

Individuals with PTEN ASD, with macrocephalic ASD without a PTEN mutation (macro-ASD), healthy controls, and individuals with PTEN mutations without ASD (PTEN no-ASD) will be asked to participate in this study if they are 18 months and older. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals' primary communicative language must be English.

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, neuropsychological assessments, and a blood draw done for laboratory studies. A subset of participants between the ages of 2 and 11 years old will take part in the EEG portion of the study. Individuals who have a clinically indicated MRI will have an option to provide routine clinical scans for analysis.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Blood draw for future correlative studies in the PTEN Biorepository of the Developmental Synaptopathies Consortium.

170 subjects; 100 existing subjects, 70 newly enrolled participants; 50 controls

• Sampling Method: Non-Probability Sample
• Study Population: 170 patients will be enrolled for this study, over the age of 18 month old.

Condition

• PTEN
• ASD
• Autism
• Macrocephaly
• PTEN Hamartoma Tumor Syndrome

• Intervention: Not Provided

Study Groups/Cohorts

• PTEN ASD
  PTEN participants with Autism Spectrum Disorder group
• PTEN no ASD
  PTEN participants without Autism Spectrum Disorder group
• Controls
  Healthy control group

• Publications *: Frazier TW, Jaini R, Busch RM, Wolf M, Sadler T, Klaas P, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C; Developmental Synaptopathies Consortium. Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism. Mol Autism. 2021 Jan 28;12(1):5. doi: 10.1186/s13229-020-00406-6.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 3, 2020): 170
• Original Estimated Enrollment (submitted: June 1, 2015): 120
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

• Individuals above the age of 18 months old at the time of consent who have documentation of a clinical diagnosis of autism spectrum disorder and/or a verified PTEN mutation from a medical or mental health professional for inclusion in the PTEN ASD, PTEN no-ASD or ASD macrocephaly groups.
• Macrocephaly (head circumference greater than or equal to 98th percentile) for inclusion in the ASD macrocephaly group.
• For youths, consent from parents or legal guardian. For adults, consent from self or legal guardian.
• Youths who are able (some young or severely impaired participants may not be able to provide assent) will be asked to provide assent as per IRB guidelines.
• Families with multiple children who meet the above inclusion criteria will be permitted to have as many children participate as they wish. A separate consent form will be filled out for each child enrolled in the study.
• Primary communicative language must be English

Exclusion Criteria

• Unwilling or unable to comply with study procedures and assessments
• Clinically significant medical disease that would prohibit participation in the study procedures.
• For subjects ELIGIBLE FOR OPTIONAL 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 ELIGIBLE FOR 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 over 11 at the time of enrollment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Rajna Filip-Dhima, MS; 617-919-7068; Rajna.Filip-Dhima@childrens.harvard.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02461446
• Other Study ID Numbers: P00013150; 1U54NS092090-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Mustafa Sahin, Boston Children's Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Boston Children's Hospital
• Original Study Sponsor: Same as current

Collaborators

• National Institutes of Health (NIH)
• National Institute of Neurological Disorders and Stroke (NINDS)
• Office of Rare Diseases (ORD)
• National Center for Advancing Translational Sciences (NCATS)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Study Chair: Charis Eng, MD, PhD; The Cleveland Clinic

• PRS Account: Boston Children's Hospital
• Verification Date: September 2022