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Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour

Key Points

  • Williams syndrome is a neurodevelopmental disorder with a prevalence of up to 1 in 7,500, caused by a hemizygous deletion of 1.6 megabases, containing 28 genes, on chromosome 7q11.23 through unequal homologous recombination during meiosis. Williams syndrome is characterized by typical facial features, cardiovascular abnormalities, mild to moderate mental retardation or learning difficulties, and unique neuropsychological and behavioural features that have made it a focus of research in neuroscience and genetics.

  • The neuropsychological profile of Williams syndrome shows a severe weakness in visuospatial construction, combined with relative strength in verbal short-term memory and language. However, neither language production nor verbal short-term memory is typically completely normal. Behaviourally, individuals with Williams syndrome show a striking social fearlessness and gregariousness, combined with strongly increased non-social fear.

  • We review recent advances made in defining the neural substrates of the unique neuropsychiatric features of Williams syndrome and define separable neural subsystems in this syndrome, specifying mechanisms for genetic influences on visuospatial cognition, social behaviour and memory. These results are discussed in the context of emerging data that link dissociable genetic contributions to these phenotypes through the study of knockout mouse models and atypical deletions in humans.

  • The brains of individuals with Williams syndrome are smaller and show regions of reduced grey matter volume, and abnormal gyrus and sulcus configuration. A reduction of grey matter volume and depth has been identified in the intraparietal sulcus, a region that is important for visuospatial constructive function. In addition, functional MRI studies show activation deficits in the adjacent parietal lobe as a functional correlate of a circumscribed dorsal visual stream deficit that can be linked to the structural abnormality and may underlie the severe visuospatial constructive impairment seen in Williams syndrome.

  • Convergent imaging evidence shows abnormal resting blood flow and activation of the anterior hippocampal formation together with only subtly abnormal structure. This might be linked to the severe long-term memory and visual-navigational impairments associated with Williams syndrome.

  • In individuals with Williams syndrome, the amygdala is less active to threatening faces, but shows increased activity to threatening non-social stimuli, mirroring the fear profile in behaviour. Interactions between the amygdala and prefrontal regulatory regions, especially the orbitofrontal cortex, are abnormal, which suggests that the neural systems for social and non-social fear are dissociable and underlie different genetic–developmental trajectories.

  • Knockout mouse models for LIM domain kinase 1 (Limk1) and cytoplasmic linker 2 (C yln2) show similar hippocampal abnormalities to those identified in humans, implicating these genes in hippocampal function. The results of studies of human families with small deletions suggest that LIMK1 is a promising candidate gene for involvement in the severe impairment in visuospatial construction seen in individuals with Williams syndrome, and that GTF2I (general transcription factor II i repeat domain-containing 1) hemideletion is necessary for mental retardation in this syndrome.

Abstract

Williams syndrome, a rare disorder caused by hemizygous microdeletion of about 28 genes on chromosome 7q11.23, has long intrigued neuroscientists with its unique combination of striking behavioural abnormalities, such as hypersociability, and characteristic neurocognitive profile. Williams syndrome, therefore, raises fundamental questions about the neural mechanisms of social behaviour, the modularity of mind and brain development, and provides a privileged setting to understand genetic influences on complex brain functions in a 'bottom-up' way. We review recent advances in uncovering the functional and structural neural substrates of Williams syndrome that provide an emerging understanding of how these are related to dissociable genetic contributions characterized both in special participant populations and animal models.

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Figure 1: Genetics of Williams syndrome.
Figure 2: Structural abnormalities in the brains of individuals with Williams syndrome.
Figure 3: Dorsal visual stream functional deficits in Williams syndrome.
Figure 4: Hippocampal abnormalities in Williams syndrome.
Figure 5: Neural mechanisms of hypersociability in Williams syndrome.

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Acknowledgements

This work was supported by the National Institute of Mental Health (NIMH) Intramural Research Program (IRP), a grant from the National Institute of Neurological Disorders and Stroke (C.B.M.) and a grant from the National Institute of Child Health and Human Development (C.B.M.). We thank C. Rainey for help with figure preparation, L. Kempf for preparation of the supplementary table and S. Kippenhan, P. Kohn and C. Morris for their ongoing collaboration on our neuroimaging work.

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DATABASES

OMIM

Down syndrome

Williams syndrome

FURTHER INFORMATION

Meyer-Lindenberg's laboratory

Glossary

Haploinsufficiency

Presence of only a single functional copy of a gene that does not provide sufficient transcript or protein production to assure normal function.

Hypercalcaemia

Abnormally high calcium concentration in the blood.

Hyperreflexia

Exaggerated deep tendon reflexes.

Strabismus

Eye misalignment; also known as 'crossed eyes'.

Nystagmus

Involuntary and often rapid and repetitive oscillatory movements of the eyeballs.

Homologous recombination

Exchange of DNA segments of similar sequence. Occurs by breakage and reunion in paired chromosomes during meiosis.

(Arnold-)Chiari malformations

A group of disorders characterized by protrusion of the cerebellum through the large opening in the base of the skull into the spinal canal.

Differential Ability Scales-School Age

(DAS-School Age). A standardized assessment of general intellectual functioning designed to provide specific information about an individual's strengths and weaknesses across a wide range of intellectual abilities. It is particularly appropriate for assessing individuals with WS because it yields separate standard scores for verbal, nonverbal reasoning and spatial abilities, as well as an overall standard score (general conceptual ability (GCA), which is similar to IQ).

Voxel-based morphometry

(VBM). A widely used method for the analysis of imaging data that enables a statistically principled voxel-wise between-groups comparison of local grey matter volume, unconstrained by anatomical landmarks.

Retinotopic mapping

A functional imaging technique that can be used to delineate the extent of visual brain areas by capitalizing on the fact that they represent retinal information in a consistent spatial map.

Long-term potentiation

(LTP). Enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency stimulation of afferent pathways; LTP has been most studied in the hippocampus.

Theory of mind

The ability to interpret people's behaviour in terms of their mental states. Includes both social–perceptual (capacity to distinguish between people and objects, and to infer mental disposition from facial, prosodic and body expressions) and social–cognitive (explicit representation of and reasoning about others' beliefs and intentions) components.

Endophenotype

A quantitative biological trait associated with a complex genetic disorder that is hoped to more directly index the underlying pathophysiology, facilitating efforts to find or characterize contributing genes.

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Meyer-Lindenberg, A., Mervis, C. & Faith Berman, K. Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci 7, 380–393 (2006). https://doi.org/10.1038/nrn1906

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