Defining the Brain Phenotype of Children With Williams Syndrome

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 collected. One hundred children with classic Williams syndrome 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 Williams syndrome 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 Williams syndrome .

Primary outcome measures include size and integrity of grey and white matter; functional 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 Williams syndrome 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 Williams syndrome and from which to launch translational studies of specific gene effects on brain and behavioral phenotypes.