Williams Syndrome

The Nature of Williams Syndrome

Williams syndrome (WS) is a neurodevelopmental disorder caused by the deletion of some 28 genes on one copy of Chromosome 7. The deletion gives rise to distinctive facial features and affects the developing body, brain, mind, and behavior. WS occurs in roughly 1 in 15,000 live births.

Compared to more common disorders, such as Down syndrome, why would such a rare syndrome be of interest not only to psychologists but also to philosophers, neuroscientists, linguists, computer scientists, molecular biologists, and educationists?

The reason lies in the promise that WS seemed to hold for substantiating a popular view of the mind/brain, namely, that it is composed of innately specified, independently functioning modules. Indeed, initial reports suggested that, despite low IQs and seriously impaired visuo-spatial and numerical cognition, individuals with WS had intact language and face processing.

Was this not proof that language could develop independently of general intelligence? After more in-depth analyses of the phenotype, it became clear that WS was far more complex than researchers originally thought.

In reality, far from illustrating the juxtaposition of intact and impaired modules, WS turned out to be a model of the extreme complexity of genotype/phenotype relations and of how domain-general deficits in infancy could cascade over developmental time to result in seemingly domain-specific outcomes in adulthood.

In the remainder of the discussion, some of the latest genetic, brain, and cognitive findings on this intriguing syndrome are presented, showing how WS continues to offer insights to all those fascinated by the human mind.

Genotype/Phenotype Relations

Early molecular research identified partial deletion patients (PD) with only two genes missing in the WS critical region: elastin (ELN) and LIM-kinase1 (LIMK1).

ELN is important for elasticity of skin, lungs, and blood vessels and seemed to explain the WS arterial problems and facial dysmorphology. The PD patients are also presented with visuospatial deficits implicating LIMK1, which is expressed in the brain, in these cognitive impairments. However, studies of other PD patients revealed neither facial dysmorphology nor spatial impairments despite deletions of ELN and LIMK1.

Current research on PD patients with larger deletions, as well as animal models, indicates that four genes at the end of the deletion are those critical for the full WS cognitive and physical phenotype. Interestingly, these are all “transcription factors”; that is, they regulate numerous other downstream genes, suggesting that any one-to-one mapping between specific genes and specific cognitive outcomes is highly unlikely.

The Williams Syndrome Brain

The WS brain is clearly not a normal brain with parts intact and parts impaired. Its volume is only 80% of typically developing brains, with widespread differences across brain regions: particularly small cerebrum but average cerebellum; abnormal size and shape of the corpus callosum, the central sulcus and the orbitofrontal cortex.

Parietal regions have reduced gray matter with abnormal neuronal layering, orientation, density, and size. Where normal brains become increasingly lateralized (hemispherically specialized) over time, the WS adult brain continues to process stimuli bilaterally, also revealing abnormal connectivity between the orbitofrontal cortex and the amygdala Opens in new window.

Note that our knowledge of the WS brain results from research on adults and not on the developing WS brain, which could be informative regarding how differences compound or are compensated for by other networks over developmental time.

The Williams Syndrome Cognitive Profile

Individuals with WS present with an average full IQ of 56, but usually verbal IQ is higher than performance IQ. It is this uneven cognitive profile that has attracted attention. However, even within the domain of language Opens in new window, relative strengths in vocabulary can coexist with serious impairments in pragmatics and complex grammar. Visuospatial abilities also display peaks and troughs, with particular deficits in constructional strengths in perceptual abilities Opens in new window.

One domain of particular interest is WS face processing, because on standardized tasks scores fall within the normal range. Could this be an example of a preserved function?

In fact, brain imaging and cognitive studies have shown that the apparently normal performance stems from different brain processes.

Again, a developmental approach is critical. For example, when studying spatial frequency biases in face recognition over development, children with WS demonstrate an adultlike bias much earlier than typically developing children, pointing to a less flexibly developing system. WS adults use more featural than configural strategies when processing faces. WS illustrates how, even when scores fall in the normal range, it is vital to probe the underlying brain and cognitive processes.

Conclusion

What, then, can be learned from the study of Williams syndrome? Not that WS will be a model of direct-gene behavior or cognition-brain region mappings. Rather, WS illustrates the complexities of the human mind/brain. While significant advances have been made in the genetic, brain, and cognitive domains, it will be critical to bring these complementary levels of analysis together.

It is also essential to understand how having a syndrome like WS alters the environment in which a child develops and thus to study disorders within the full context of their developmental trajectories.

Cross-syndrome studies will help identify which traits are truly syndrome specific. Williams syndrome provides an ideal model for the developmental study of how gene expression, brain, cognition, and environment are integrated to give rise to both the typical and atypical human mind.