|
 Neurodevelopmental
syndromes, especially those with a clear genetic basis, present unique
opportunities for understanding brain–behavior and gene–behavior
relationships. Distinct aspects of cognitive and social-emotional phenotypes
can be associated with their genotypic and neurofunctional foundations.
Among the genetically defined neurodevelopmental disorders, perhaps none
presents as compelling a case for the functional independence of select
abilities as does Williams syndrome (WS). The neuropsychological profile
in WS is remarkable because of the magnitude of the disparity between
cognitive strengths and weaknesses, a disparity that is thought to be
rooted in the functional integrity of different neural networks. In addition,
WS has a striking social-emotional phenotype that includes unusually high
sociability and empathy, as well as a strong attraction to music because
of emotional factors. Large differences among abilities and the presence
of splinter skills argue for a high degree of functional independence
in underlying neural systems, and elucidation of these systems can help
characterize more precisely the modular organization of large-scale networks
in the brain. Thus, WS is often held as a model disorder that can teach
us about the nature of parallel functional networks within the brain and
the manner by which these are instantiated by genetic processes during
neurodevelopment.
WS
is a genetic disorder caused by a hemizygous “microdeletion”
on the long arm of chromosome 7 (7q.11.23) affecting multiple organ systems
(Pober and Dykens, 1996). The syndrome was first characterized in the
early 1960s by cardiologists who noted a particular constellation of abnormalities.
These included supravalvular aortic stenosis, distinctive facial features,
and cognitive impairment. Over the subsequent decades, the full clinical
manifestations of the disorder were well described, but it was not until
the early 1990s that the genetic deletion responsible for WS was discovered.
Current research shows that the WS deletion spans a 1.5 megabase chromosomal
segment, and codes for an estimated 17 genes, including elastin (ELN)
and four genes that are highly expressed in the brain (FZD9, STXIA,
LIMK1, CYLN2). WS occurs at a rate of about 1 in 20,000, and the mechanism
thought to cause the deletion is unequal recombination during meiosis.
WS
is associated with distinctive physical characteristics, including unique
facial features that may include a stellate iris, periorbital fullness,
full nasal tip and flattened nasal bridge, wide mouth with full lips,
long philtrum, full cheeks, and a small jaw. Facial appearance can change
dramatically with age. Other physical manifestations of the disorder include
short stature, dental malocclusion, hypercalcemia, hyperacusis, lower-extremity
hyperreflexia, a premature and abbreviated pubertal growth spurt, and
cardiovascular abnormalities, especially supravalvular aortic stenosis.
The deletion of the ELN gene is believed to cause the cardiac abnormalities
and possibly some of the connective tissue problems, such as lax joints,
premature aging of the skin, joint contractures, a hoarse voice, and hernias.
One
of the more intriguing features of WS is its distinct social-affective
profile. WS is associated with an engaging personality and excessive sociability
with strangers, an increased frequency of affective prosody, strengths
in face perception and face recognition memory, and an increased interest
in music, especially the rhythm and emotional flavor of music. Most individuals
with WS function in the mild range of mental retardation, with IQs averaging
about 60. A modest percentage of cases have IQs greater than 70, with
an upper limit of perhaps 100. Against this backdrop of mild mental retardation,
persons with WS have a distinctive neuropsychological profile that includes
strengths in face perception, affective attunement, short-term auditory
memory and select aspects of language, along with weaknesses in visuospatial,
motor, visuomotor integration, and arithmetic skills. The differences
between peak and trough in the WS neuropsychological profile can be extreme,
and, therefore, this syndrome offers unique leverage for understanding
better the modular nature of neurocognitive and neuroaffective systems
within the brain.
Persons
with WS show a strong dissociation between relatively preserved language
abilities and profound deficits in visuospatial functions. Whereas most
people without WS might show some pattern of strengths and weaknesses,
the difference between abilities for the average person is typically modest.
Persons with WS, on the other hand, show differences between verbal and
nonverbal abilities that can exceed two or three standard deviations on
standardized measures. Upon meeting a person with WS for the first time,
one might not immediately guess that the person has developmental cognitive
delays. They frequently show “cocktail party” verbal abilities—language
abilities that are superficially quite intact, coupled with good adherence
to social conventions and mores and a rather intense social interest.
Formal assessment of language abilities, however, yields a somewhat mixed
picture (Karmiloff-Smith et al., 1998). There are strengths in the areas
of phonological processing, verbal fluency, vocabulary, and select aspects
of morphosyntax, but overall language abilities are delayed for chronological
age. Thus, while some language skills might venture into the normal range
despite a mean IQ in the mildly retarded range, other language skills
are only slightly elevated compared to overall IQ.
Recent
magnetic resonance imaging (MRI) morphometric evidence provides a possible
physiological basis for strengths in language and also for the heightened
interest in music and, in some cases, savant-like musical skill. Despite
whole brain volumes that are about 15% smaller than normal, the superior
temporal gyrus, an area that encompasses primary auditory cortex and association
regions important for the elaboration of auditory inputs necessary for
both language and music processing, is of approximately normal volume
in people with WS (Reiss et al., 2000). To date there have been no published
functional neuroimaging studies in WS, although a small study using auditory
event-related potentials found increased amplitude of early endogenous
components suggesting hyperexcitability of the primary auditory cortex.
Alterations of function in this brain region may subserve the high rate
of hyperacusis in WS and could also be related to language and music perceptual
processes. In addition, preliminary structural MRI evidence suggests an
exaggerated leftward asymmetry of the planum temporale, a cortical region
buried in the depth of the sylvian fissure along the posterior aspect
of the superior temporal gyrus. A leftward asymmetry of planum temporale
has been linked to normal hemispheric dominance for language, and in musicians
with perfect pitch there appears to be even more pronounced leftward asymmetry
of this region than is typical. The associations between language, music,
and superior aspects of the temporal lobe may be just one of many examples
of this nature in the brains of people with WS. A more general hypothesis
is that variations in the integrity of diverse brain regions, each with
discrete functions within larger networks, provide the physiological bases
for the specific strengths and weaknesses in WS.
In
addition to areas of preserved skill, WS is associated with profound visuospatial
weaknesses. Scores on tasks requiring judgments of positional relationships
between lines or objects are frequently several standard deviations below
IQ. Most individuals with WS have profound difficulties visualizing the
spatial relationships between objects, their distances and overall configuration,
skills critical for movement in a three-dimensional world. Moreover, some
evidence has linked the spatial deficits in WS to one of the four brain-expressed
genes in the deleted region. An association between the deletion of LIMK1
and deficits in visuospatial abilities was reported in the mid-1990s in
a family with a smaller than typical deletion involving only LIMK1
and ELN. Affected members were noted to be of average IQ but with
select deficits in spatial abilities. More recently, this association
has been challenged by several cases with similar small deletions involving
LIMK1 but intact spatial abilities (Tassabehji et al., 1999). It
may be that no one gene acts alone to influence spatial functions, but
rather specific combinations are important. While more work is needed
to clarify this problem, these case studies highlight the potential power
that rare deletions in the WS critical region have for elucidating specific
gene–behavior associations.
Much
is known about functional segregation of visual processes in the brain.
Processing is split by visual domain (visuospatial versus visuofeature)
into a dorsal stream that connects the occipital cortices and the parietal
lobe (the “where pathway”), and a ventral stream of information
flow from the occipital to the temporal cortices (the “what pathway”).
The large skill difference in the perception of faces and spatial material
seen in WS suggests that these two pathways are quite dissimilar in their
functionality, and perhaps also in their neuroanatomical integrity. However,
there have been no direct neuroimaging assessments of this functional
discontinuity. A group of investigators at the Salk Institute led by Ursula
Bellugi have reported in a small sample of patients that the posterior
width of the brain is reduced in WS, and more recently that the total
gray matter volume in the occipital cortex may be disproportionately reduced
in WS (Reiss et al., 2000). This could have relevance to the duality in
functioning in “face and space” in WS.
The
processing of objects and faces has been extensively studied with functional
imaging methodologies in typically developing individuals. Indeed, one
region on the underside of the temporal lobes, the fusiform gyrus (FG),
has a specific role in face perception. It is likely that face perception
and related functions such as understanding the emotional states of others
through facial cues are closely tied to social-cognitive skills and the
ability to form and maintain social relationships. The presence of anatomical
connections between the FG and limbic areas of the brain that are responsible
for many emotional processes supports this conjecture. Thus workers in
this field have been eager to relate the perceptual expertise for faces
seen in WS to their hypersociability and prosocial orientation.
A
similar comparison is frequently made in the study of an unrelated disorder:
autism. In many ways, autism is the polar opposite of WS. Whereas autism
is defined by low sociability, lessened empathy, and deficits in face
recognition and nonverbal aspects of communication (prosody and pragmatic
aspects of language), these are all areas of strength in WS. Studies by
our group have shown that persons with autism spectrum conditions fail
to engage the FG during face perception tasks (Schultz et al., 2000),
perhaps because of their unique developmental history marked by the lack
of interest in social relationships. We have now extended this work to
a sample of persons with WS. Figure
1 shows the similarity in FG activation to faces in a person with
WS and a matched control. It includes a comparison to a typical person
with autism for whom there is no activation of this region at this threshold
level. Preliminary results such as these suggest that individuals with
WS are normal in their use of the FG for face perception. Moreover, we
believe that levels of FG activation can be related to levels of social
relatedness. Thus, similar to the connection between language and intact
superior temporal gyrus morphology, our initial results are showing intact
face recognition representation in the temporal cortex in the context
of intact social relatedness.
There
is converging evidence to suggest that the WS brain is a mosaic of spared
and affected systems and that the pattern of spared and affected brain
networks will correlate and predict the WS cognitive and social-affective
profile. This not only serves as a model for understanding the functional
and structural independence of discrete brain systems, but as more is
learned about the functions of genes in the WS critical region, there
is the promise of being able to delineate the ontological progression
of genes to brain organization to phenotypic function.
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