Defining the Brain Phenotype of Children With Williams Syndrome

Background: \- Little is known about how the brain changes during childhood and adolescence, how genes affect this process, or how the brains of people with 7q11.23 genetic variation change during this period. Researchers are interested in using magnetic resonance imaging to study how the brain changes in healthy children and children with 7q11.23 genetic variation, including Williams syndrome and 7q11.23 duplication syndrome. Objectives: \- To study developmental changes in the brains of healthy children and children who have been diagnosed with Williams syndrome,7q11.23 duplication syndrome, or other 7q11.23 genetic variation. Eligibility: * 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, 7q11.23 duplication syndrome, or have other 7q11.23 genetic variation. Design: * 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.

Williams syndrome 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 Williams syndrome resulted in a clear delineation of the Williams syndrome 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 Williams syndrome. The findings in adult Williams syndrome 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 Williams syndrome 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 Williams syndrome 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 will allow 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 c trial.show_full_description

* INCLUSION 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 Williams syndrome critical region of chromosome 7q11.23, and control participants must have normal intelligence. EXCLUSION CRITERIA: 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 data. 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.