Defining the Brain Phenotype of Children With Williams Syndrome

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. 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.

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.

- 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.

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.

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.

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.