Defining the Brain Phenotype of Children With Williams Syndrome

Brief Title

Defining the Brain Phenotype of Children With Williams Syndrome

Official Title

Defining the Brain Phenotype of Children With Williams Syndrome

Brief Summary


      - Little is known about how the brain changes during childhood and adolescence, how genes
      affect this process, or how the brains of people with Williams syndrome change during this
      period. Genetic features of Williams syndrome affect the brain s development, but the details
      of this process have not been studied over time. Researchers are interested in using magnetic
      resonance imaging to study how the brain changes in healthy children and children with
      Williams syndrome and related genetic disorders.


      - To study developmental changes in the brains of healthy children and children who have been
      diagnosed with Williams syndrome or a related genetic disorder.


        -  Healthy children and adolescents between 5 and 17 years of age.

        -  Children and adolescents between 5 and 17 years of age who have been diagnosed with
           Williams syndrome or genetic characteristics that overlap with Williams syndrome.


        -  Participants will have a brief physical examination and tests of memory, attention,
           concentration, and thinking. Parents will be asked about their child s personality,
           behavior characteristics, and social interaction and communication skills.

        -  Both participants and their parents may be asked to complete additional questionnaires
           or take various tests as required for the study.

        -  Participants will have approximately 10 hours of magnetic resonance imaging (MRI)
           scanning, usually over 4 to 5 days, within a one month period. Some of these tests will
           require the participants to do specific tasks while inside the MRI scanner.

        -  Participants will be asked to return to the National Institutes of Health clinical
           center to repeat these procedures every 2 years thereafter until age 18.

Detailed Description

      Williams syndrome (WS) is a rare disorder caused by hemizygous microdeletion of approximately
      1.6 megabases on chromosomal band 7q11.23, typically by spontaneous mutation. The disorder is
      characterized by a collection of unique neuropsychiatric manifestations, including marked
      visuospatial construction deficits and hypersociability. Because the genes involved in WS are
      known, the study of neural mechanisms in WS affords a privileged setting for investigating
      genetic influences on complex brain functions in a bottom-up way.

      Previous neuroimaging studies of adults with WS resulted in a clear delineation of the WS
      brain phenotype. Underlying the syndrome s cognitive hallmark, visuospatial construction
      impairment, is a neurostructural anomaly (decreased gray matter volume) and adjacent abnormal
      neural function in the parietal sulcus region of the dorsal visual processing stream. Subtle
      structural hippocampal alterations, along with abnormalities in regional cerebral blood flow,
      neurofunctional activation, and N-acetyl aspartate concentration also contribute to the
      visuospatial phenotype. Underlying the syndrome s social cognition features are structural
      and functional abnormalities in the orbitofrontal cortex, an important affect and social
      regulatory region that participates in a fronto-amygdala regulatory network found to be
      dysfunctional in WS.

      The findings in adult WS patients have created a paradigm for identifying brain phenotypes
      linked to specific genes and for guiding research aimed at understanding the mechanism by
      which gene effects are translated in the brain to clinical phenomena. However, it is clear
      that the cognitive and behavioral disturbances in WS emerge over the course of childhood and
      adolescence from a complex interplay of altered neural systems, which must be studied from a
      developmental and translational perspective. To meet this imperative, we propose a
      cross-sectional and longitudinal neuroimaging study of children with WS to track the
      emergence and modification of the altered neural circuitry observed in the adult population.
      With non-invasive multimodal magnetic resonance imaging including structural MRI, functional
      MRI (fMRI), and diffusion tensor MRI-we propose to target those neural systems associated
      with key clinical features (e.g. visuospatial construction impairment and abnormal social
      cognition). We will employ experimental methods previously successful in assessing cognitive
      and emotional processing in the adult population. For neurofunctional studies, each task
      paradigm is optimized to provide adequate statistical power for single subject mapping, and
      to be amenable for young children. Additionally, structural MRI studies allowing for in depth
      tracking of structural changes, including changes in gray-white matter ratios and the
      integrity of white matter tracts throughout the brain. Blood samples for genetic analysis
      will be collected. One hundred children with classic WS deletions, those with smaller
      deletions, and those with duplications, along with 50 of their unaffected siblings, will be
      studied at the NIH Clinical Center at two-year intervals for repeat neuroimaging studies.
      Additionally, approximately 115 unrelated, healthy children will also be studied. fMRI tasks
      will be piloted on fifteen of the latter. We will continue to study the children enrolled in
      this protocol after they turn 18 in order to determine the developmental trajectory of brain
      structure and function from childhood through adulthood. Additionally, fifty adults with
      classic WS deletions, those with smaller deletions, and those with duplications will be
      studied at the NIH Clinical Center at two-year intervals for repeat neuroimaging studies in
      order to establish good adult end-points for our imaging protocol. Studying adults with WS
      and abnormalities of the WS genetic region with the same tasks and scanner as used for
      children will allow us to establish an adult WS comparison group against which children can
      be directly compared and also allow us to better determine the maturation of neural structure
      and function in WS through adulthood. Typically developing children whom we will continue to
      study after they turn 18 will serve as the control comparison group for adults with WS.

      Primary outcome measures include size and integrity of grey and white matter; afunctional MRI
      BOLD responses during rest, cognitive and emotion information processing; DTI anisotropy
      measures of white matter tracts; tissue perfusion (blood flow) measured with arterial spin
      labeling (ASL); and mcDespot myelin water fraction.

      Secondary outcome measures include relationship of neuropsychological assessments and
      genotyping to the imaging results.

      Our prior success in delineating the brain phenotype in adult WS patients will provide the
      crucial context within which to view the emergence and modification of these neural circuit
      abnormalities from a developmental perspective in children with WS and from which to launch
      translational studies of specific gene effects on brain and behavioral phenotypes.

Study Type


Primary Outcome

fMRI Task Procedures


Williams Syndrome

Study Arms / Comparison Groups

 Adults with WS or genetic abnormalities
Description:  Adults with Williams syndrome or genetic abnormalities in chromosome 7q11.23


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

January 23, 2011

Eligibility Criteria


        For all participants, the following inclusion criteria will apply:

          1. Greater than 5 years old.

          2. Able to provide assent if below the age of 18, or consent if 18 years of age or older.
             Parents will provide consent for participants below the age of 18. For patients who do
             not have the capacity to provide informed consent, consent may be obtained from a
             guardian or the holder of the DPA.

        Additionally, 7q11.23 CNV participants must have a typical 7q11.23 CNV or other genetic
        abnormality in the WS critical region of chromosome 7q11.23, and control participants must
        have normal intelligence.


        For all participants who will participate in MRI scanning, the following exclusion criteria
        will apply:

          1. Any chronic or acute medical condition severe enough to interfere with task
             performance or interpretation of MRI data.

          2. Any medication that might interfere with task performance or interpretation of MRI

          3. Any medical condition that increases risk for MRI (e.g. pacemaker, metallic foreign
             body in eye or other body part, dental braces).

          4. Pregnancy (a urine pregnancy test will be performed prior to all MRI procedures for
             all females of child-bearing potential.

          5. NIMH employees and staff and their immediate family members will be excluded from the
             study per NIMH policy.

        For parents who will undergo blood draws only, they will not be able to participate if they
        have a condition

        that would make collecting blood unsafe.




5 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers


Karen F Berman, M.D., (301) 443-8490, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Institute of Mental Health (NIMH)

Study Sponsor

Karen F Berman, M.D., Principal Investigator, National Institute of Mental Health (NIMH)

Verification Date

August 4, 2022