Journal of the American Academy of Child and Adolescent
Psychiatry
May, 2001
Genetics of Childhood Disorders: XXVI. Williams Syndrome
and Brain--Behavior Relationships.
Author/s: Robert T. Schultz
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 indep endence 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, LIMKI, 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 uniq ue 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 sele ct
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 LIMKI and deficits in
visuospatial abilities was reported in the mid-1990s in a
family with a smaller than typical deletion involving only
LIMKI 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 LIMKI 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 maybe disproportionately reduced in WS
(Reiss et al., 2000). This could have relevance to the
duality in fun ctioning 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 per ception.
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.
ADDITIONAL READINGS
Bellugi U, Lichtenberger L, Mills D, Galaburda A,
Korenberg JR (1999), Bridging cognition, the brain and
molecular genetics: evidence from Williams syndrome.
Trends Neurosci 22:197-207
Howlin P, Davies M, Udwin O (1998), Cognitive
functioning in adults with Williams syndrome. J Child
Psychol Psychiatry 39:183-189
Karmiloff-Smith A, Tyler LK, Voice K et al. (1998),
Linguistic dissociations in Williams syndrome: evaluating
receptive syntax in on-line and off-line tasks.
Neuropsychologia 36:343-351
Pober BR, Dykens EM (1996), Williams syndrome: an
overview of medical, cognitive, and behavioral features.
Child Adolesc Psychiatr Clin N Am 5:929-943
Reiss AL, Eliez S, Schmitt JE et al. (2000),
Neuroanatomy of Williams syndrome: a high-resolution MRI
study. J Cogn Neurosci 12(suppl 1):65-73
Schultz RT, Gauthier I, Klin A et al. (2000), Abnormal
ventral temporal cortical activity among individuals with
autism and Asperger syndrome during face discrimination.
Arch Gen Psychiatry 57:331-340 |
| Tager-Flusberg H, Sullivan
K (2000), A componential view of theory of mind: evidence
from Williams syndrome. Cognition 76:59-90 Tassabehji
M, Metcalfe K, Karmiloff-Smith A et al. (1999), Williams
syndrome: use of chromosomal microdeletions as a tool to
dissect cognitive and physical phenotypes. J Hum Genet
64:118-125
Accepted November 22, 2000.
Dr. Schultz is Associate Professor and Mr. Grelotti is
a Research Associate, Child Study Center; Dr. Pober is
Associate Professor, Department of Genetics, Yale
University School of Medicine. New Haven, CT.
Correspondence to Dr. Lombraso, Child Study Center,
Yale University School of Medicine, 2.30 South Frontage
Road, New Haven, CT 06520; e-mail: Paul.Lambroso@Yale.edu.
To read all the articles in this series, visit the Web
site at
http://info.med.yale.edu/chldstdy/plomdevelop/
0890-8567/01/4005-0606[C]2001 by the American Academy
of Child and Adolescent Psychiatry.
Changes in the Incidence of Childhood Autism and Other
Autistic Spectrum Disorders in Preschool Children From Two
Areas of the West Midlands, UK. JE Powell, MA, PhD, A.
Edwards, MRCGP, DCCH, M. Edwards, MD, B.S. Pandit, MD,
DGO, S.R. Sungum-Paliwal, MD, MRCPsych, W. Whitehouse,
BSc, FRCP
The incidence of childhood autism and other autistic
spectrum disorders (ASDs) in preschool children was
determined for two areas of the West Midlands between 1991
and 1996. Children diagnosed before the age of 5 years and
residing within the study areas at diagnosis were detected
from the records of four child development centres. The
incidence rate per 10000 children per year for the
combined areas was 8.3 for all children with ASDs, 3.5 for
classical childhood autism (CA), and 4.8 for other ASDs.
Rates were similar in both areas, despite differences in
social deprivation and proportions of ethnic minorities.
While rates for classical CA increased by 18% per year, a
much larger increase (55% per year) was seen for 'other
ASDs', suggesting that clinicians are becoming
increasingly able and/or willing to diagnose ASDs in
preschool children. Dev Med Child Neurol 2000;42:624-628.
Maternal Expressed Emotion and Treatment Compliance of
Children With Epilepsy. Soraya Otero, MD, PhD, Matthew
Hodes, BSc, MSc, MRCPsych
This study investigated the association between family
relationships and compliance in the treatment of childhood
epilepsy. It was a prospective study of 21 families with a
child who had epilepsy attending Central Middlesex
Hospital, London. There were 13 boys and eight girls, with
a mean age of 12.0 years (SD 2.9) at initial assessment.
Mothers were interviewed for assessment of expressed
emotion ass measure of parent-child relationships.
Assessment of the mothers' adjustment using the General
Health Questionnaire (Goldberg 1978), and psychological
adjustment of the children using the Rutter Scales (Rutter
et al. 1970a), were completed by mothers and teachers.
Reassessment was 3 to 4 years after initial contact,
including a paediatric case-note review to assess clinic
attendance and overall treatment compliance. Significantly
more of the group who had a good level of compliance had
recovered from epilepsy at follow-up. Good treatment
compliance was found to be associated with less maternal
hostility and crit icism. Children and mothers in the good
compliance group had fewer psychiatric symptoms. Poor
treatment compliance and the associated psychological
disturbances suggest that assertive paediatric and
psychosocial intervention may be needed for some children
with epilepsy. Dev Med Child Neurol 2000;42:604-608. |
| The Alcohol Warning and
Adolescents: 5-Year Effects. David P. MacKinnon, PhD, Liva
Nohre, MA, Mary Ann Pentz, PhD, Alan W. Stacy, PhD
Objectives: This study, a follow-up to the authors'
earlier report examined the effects of the alcohol warning
label on adolescents during the first 5 years that the
warning was required. Methods: Surveys were administered
to 10th-grade (n = 16661) and 12th grade (n = 15856)
students from the 1989-1990 school year through 1994-1995
school year. The measures were awareness of, exposure to,
and recognition memory of the alcohol warning label;
beliefs about the risks listed on the warning, and
open-ended statements about consequences of alcohol use,
alcohol consumption, and self-reported driving after
drinking. Results: There were increases in warning
awareness, exposure, and recognition memory. These effects
leveled off approximately 3.5 years after the inclusion of
the warning on alcohol beverage containers. There was no
beneficial change attributable to the warning in beliefs,
alcohol consumption, or driving after drinking.
Conclusions: The initial positive effects of the alcohol
warning label on adolescents have leveled off, consistent
with theories of repeated exposure to persuasive
information. The alcohol warning has not affected
adolescents' beliefs about alcohol or alcohol-related
behaviors. Am J Public Health 2000;90:1589-1594. Copyright
2000 by the American Public Health Association. |
-------------------------------------------------------------------------------
COPYRIGHT 2001 Lippincott/Williams & Wilkins
in association with The Gale Group and LookSmart.
COPYRIGHT 2001 Gale Group |
-------------------------------------------------------------------------------
|
View
Our Guestbook
