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Analysis of Cerebral Shape in Williams Syndrome
J. Eric Schmitt, AB;
Stephan Eliez, MD;
Ursula Bellugi, EdD;
Allan L. Reiss, MD
Arch Neurol. 2001;58:283-287.
ABSTRACT
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Background As a neurobehavioral disorder with a specific neurocognitive profile
and a well-defined genetic etiology, Williams syndrome (WMS) provides an exceptional
opportunity to examine associations among measures of behavior, neuroanatomy,
and genetics. This study was designed to determine how cerebral shape differs
between the brains of subjects with WMS and those of normal controls.
Subjects Twenty adults with clinically and genetically diagnosed WMS (mean ±
SD age, 28.5 ± 8.3 years) and 20 healthy, age- and sex-matched controls
(mean ± SD age, 28.5 ± 8.2 years).
Design High-resolution structural magnetic resonance imaging data were used
for shape-based morphological analysis of the right and left cerebral hemispheres
and the corpus callosum. Statistical analyses were performed to examine group
differences.
Results Both right and left cerebral hemispheres of subjects with WMS bend to
a lesser degree in the sagittal plane than normal controls (P<.001). The corpus callosum also bends less in subjects with WMS
(P = .05). In addition, subjects with WMS have decreased
cerebral (P<.001) and corpus callosum (P<.001) midline lengths.
Conclusions Subjects with WMS have significantly different cerebral shape from normal
controls, perhaps due to decreased parieto-occipital lobe volumes relative
to frontal regions. The similar observation in the corpus callosum may be
associated with a decreased size of the splenium in WMS. These findings may
provide important clues to the effect of genes in the WMS-deleted region on
brain development.
INTRODUCTION
WILLIAMS syndrome (WMS) is a rare genetic disorder caused by a hemizygous
deletion on the long arm of chromosome 7.1, 2, 3, 4, 5
It is characterized by a variety of physical manifestations, including infantile
hypercalcemia, supravalvular aortic stenosis, other cardiac and vascular problems,
as well as delayed motor and cognitive development.6, 7, 8
Adolescent and adult individuals with WMS also characteristically manifest
an unusual profile of neurocognitive strengths and weaknesses. In the context
of general cognitive impairment and difficulties in problem solving, language
is relatively spared in WMS. Visuospatial abilities are dramatically impaired,
however, with drawings and block design exhibiting fractionated attention
to detail; in contrast, face processing is remarkably spared, remaining at
the level of normal controls.9, 10, 11, 12, 13, 14
This cognitive profile of peaks and valleys of abilities suggests that the
deleted genes associated with WMS may lead to uneven effects on brain development
and function.10
Previous neuroimaging studies suggest that subjects with WMS have whole-brain
volumes that are reduced by approximately 13% when compared with normal controls,
though cerebellar volume is typically preserved.15, 16, 17
Recent findings using higher resolution scans show that the reduction in cerebral
volume is not uniform throughout the brain, but instead follows a topographic
pattern that suggests a neuroanatomical substrate for some neurobehavioral
features occurring in this condition. For example, compared with normal controls,
the occipital lobe is disproportionately reduced in WMS, particularly on the
right, while there is a proportional increase in the volume of the superior
temporal gyrus (STG), cerebellum, and the frontal lobe.17
The pattern from these data indicates that subjects with WMS may have gross
differences in brain morphology compared with individuals with normal brain
development.
The initial study of brain shape described here represents a follow-up
to our most recent description of the WMS brain.17
In particular, the analyses are based on the consistent observation that the
occipital lobe and cerebellum of individuals with WMS fail to conform to a
standard sterotaxic grid used in our neuroimaging laboratory as well as others.17, 18, 19 This is the first
study designed to quantify these previous qualitative observations in WMS
(Figure 1) by directly measuring
cerebral shape differences in WMS, as well as differences in the shape of
the cerebrum's most prominent white matter structure, the corpus callosum.
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Figure 1. Midsagittal magnetic resonance
imaging slice of a subject with Williams syndrome (WMS) and an age- and sex-matched
control, demonstrating the qualitative cerebral shape differences in WMS.
Note the significantly decreased bend of the cerebrum and the decreased size
of the posterior cerebral regions in the WMS brain.
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SUBJECTS AND METHODS
SUBJECTS
Twenty subjects with WMS (13 women and 7 men; mean age, 28.5 ±
8.3 years; age range 19-44 years) and 20 normal controls individually matched
for age and sex (13 women and 7 men; mean age, 28.5 ± 8.2 years; age
range 19-48 years) were studied. Each subject gave informed consent for their
participation in the study. All subjects underwent a battery of cognitive
probes, neurophysiological studies, magnetic resonance imaging (MRI), and
molecular genetics studies that were provided within the context of a multisite
research program based at the Salk Institute for Biological Studies, La Jolla,
Calif.
The diagnosis of WMS was confirmed genetically in all subjects20 with WMS using fluorescent in situ hybridization
probes for elastin, a gene found in the critical
7q11.23 deletion region.1, 3, 4, 5
In addition, diagnosis of WMS was performed clinically, either by a medical
geneticist or other physician familiar with this condition. All diagnoses
were further confirmed using the WMS diagnostic scoresheet, developed by the
Medical Advisory Board of the Williams Syndrome Association, Clawson, Mich.
Subjects were excluded if they had any other neurological or neuropsychiatric
conditions that were not typically associated with WMS. Fourteen of the subjects
with WMS and their age-matched controls were part of our earlier whole-brain
volumetric study.17
IMAGING
Magnetic resonance images of each subject's brain were acquired using
a 1.5-T GE-Signa Scanner (General Electric Co, Milwaukee, Wis). The images
were acquired in the sagittal plane with a volumetric 3-dimensional radio
frequency spoiled gradient echo protocol. The scan parameters were: time to
repeat, 24 milliseconds; echo time, 5 milliseconds; flip angle, 45°; number
of excitations, 2; matrix size, 256 x 192; field of view, 24 cm; and
slice thickness, 1.2 mm. All but 2 of the 40 scans were acquired at the University
of California, San Diego, Medical Center. The remaining 2 scans, both controls,
were acquired using an identical scanner and pulse sequence at Stanford University
Medical Center, Stanford, Calif. Image processing and analysis were performed
at the Stanford Psychiatry Neuroimaging Laboratory, Stanford.
All scans were imported into the program BrainImage
3.X20 for semiautomated removal of nonbrain
tissue. Subsequent manipulations and measurements were also performed in the BrainImage environment. All raters were blinded to the
group identity of the subjects.
The calculation of bending angle was performed identically for both
cerebral and corpus callosum regions of interest (ROIs) using a semiautomated
computer algorithm based on the "curved line" method21, 22;
this computer implementation has been used in previous studies of corpus callosum
morphology in our laboratory.23 The algorithm
determines the midline of the ROI, defined by the
midpoints of lines drawn perpendicular to the ROI surface (Figure 2). Bending angle is defined as
the angle whose vertex is the midpoint of the ROI midline, and whose nodes
are the most anterior and posterior points on the midline. The length of the
midline, and therefore the length of the structure, is automatically calculated
with this algorithm.
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Figure 2. The curved line method of shape
analysis. Multiple lines are drawn perpendicular to the surfaces of the corpus
callosum or cerebrum (the number of lines drawn by the computer version is
limited only by the resolution of the scan). The midline is defined
as the line bisecting all of these lines. Bending angle is defined
as the angle with a vertex at the point of bisection of the midline and nodes
at the most anterior and posterior points on the midline. When measuring cerebral
bending angle and midline length, the region of interest is not drawn on the
midsagittal slice (as shown here for simplicity) but on a slice one fourth
of a Talairach sector away from the midsagittal plane (adapted from Allen
et al).
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CORPUS CALLOSUM MEASUREMENTS
The drawing of ROIs and measurement of each brain was performed based
on a previously established protocol.23 In
brief, each brain was rotated in a multiplaner viewer in BrainImage until the best midsagittal view was acquired. The determination
of the best midsagittal slice was based on the clarity and distinction of
the corpus callosum, cerebellar vermis, cerebral aqueduct, and spinal cord.
The ROIs were then hand drawn around each corpus callosum, and the bending
angle algorithm was applied. Interrater reliability for midline length and
bending angle in datasets10 was 0.98 and 0.93,
respectively, as determined by the intraclass correlation coefficient.
CEREBRAL MEASUREMENTS
A 3-dimensional Talairach-based stereotaxic grid was applied to each
brain.19, 24, 25 This
grid is proportional, adjusting to the size and shape of each individual brain.
The sagittal slice exactly one fourth of a Talairach sector away from the
midsagittal line (approximately 5 mm) was extracted for both the left and
right hemispheres. Because these slices were chosen in Talairach space, they
were parallel to the midsagittal plane and in proportionally the same neuroanatomical
location in each brain analyzed, just medial to the head of the caudate nucleus.
On each of the selected bilateral sagittal slices, the posterior fossa
was circumscribed using methods based on a previously validated protocol.26 The corpus callosum also was removed from each of
the cerebral slices. The bending angle algorithm was then applied to the cerebral
ROIs as described for the corpus callosum above. The reliability for midline
lengths and bending angles of the right and left cerebral regions was 0.98
or higher as defined from 10 datasets.
DATA ANALYSIS
To ensure the validity of using parametric statistics, all data were
first visually inspected for normality. Analyses of variance and covariance
were then performed. Because initial analyses suggested an association between
age and both bending angle and midline length, age was used as a covariate
in all calculations. A 2-tailed P value of .05 or
less was used as the significance level for all analyses.
RESULTS
CORPUS CALLOSUM
As shown in Figure 3A, the
corpus callosum bending angle is significantly larger in subjects with WMS
than in controls (F = 17.45, P<.001). The corpus
callosum midline length, however, tends to be much smaller in subjects with
WMS (F = 22.04, P<.001) (Figure 4A).
Because the midline length
of the corpus callosum could affect the bending angle, an analysis of covariance
was performed using midline length and age as covariates. This analysis suggested
that the WMS corpus callosum bending angle was still larger after covarying
for length and age (F = 4.2, P = .05).
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Figure 3. Bending angle measurements of
the corpus callosum and cerebrum in a group of 18 patients with William syndrome
(WMS) and 18 age- and sex-matched controls. A, Corpus callosum; B, left cerebrum,
and C, right cerebrum.
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Figure 4. Midline length measurements of
the corpus callosum and cerebrum. A, Corpus callosum; B, left cerebrum; and
C, right cerebrum.
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CEREBRAL MEASUREMENTS
In congruence with corpus callosum bending angle measurements, the analyses
showed that subjects with WMS have cerebral bending angles significantly larger
than normal for both the left (analysis of variance, F = 25.7, P<.001) and right (F = 14.1, P<.001)
cerebral hemispheres (Figure 2B-C).
Analyses of covariance covarying for age and midline length also indicated
significant group differences (F  7.5, P = .009).
Paralleling corpus callosum findings, we found cerebral midline length
to be smaller in the WMS group for both left and right hemispheres (F
17.9, P<.001 for both hemispheres). All results
are summarized in Table 1.
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Summary of Experimental Findings*
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COMMENT
Global measures of cerebral shape in persons with WMS differ significantly
from those of normal controls. Specifically, the overall length of both cerebral
hemispheres is significantly smaller in the WMS group. In addition, WMS brains
bend in the sagittal plane less than control brains. This group difference
in bending angle could come from several sources: either the frontal lobe
or the parieto-occipital lobe could be straighter, or brain volume could be
disproportionately reduced in particular regions. Since previous studies have
indicated that the volume of the frontal lobe is relatively spared in WMS,15 we believe that the basis of the shape differences
lies in variation in the parieto-occipital region.
The measurement of corpus callosum shape in WMS parallels the cerebral
findings. The corpora callosa of WMS subjects are shorter and tend to curve
less than those of normal controls, though the group differences are smaller
than that observed in the cerebrum. Though our results of shorter corpora
callosa are in accord with previous findings, an earlier study found no significant
shape differences between the corpora callosa of subjects with WMS and those
of normal controls.27 This discrepancy is most
likely due to different metrics: bending angle in this study vs circularity
in the previous study, the latter representing a ratio of corpus callosum
length over height. Though both measures are sensitive to disproportionate
differences in shape, bending angle is more sensitive to small shape differences
near the anterior and posterior extremes. Since the rostral fifth of the corpus
callosum has been found to be relatively preserved in subjects with WMS,27 it is possible that shape differences are due to
a reduction in the size of the splenium. Our laboratory's preliminary measurements
of corpus callosum size have indicated that both the splenium and the isthmus
(posterior body) are reduced in WMS.28 The
finding of decreased splenium size in WMS supports both the neuroanatomical
evidence of decreased white matter and occipital lobe volume17
as well as the neurobehavioral findings of visuospatial deficits in this condition
because it is the splenium that connects bilateral parieto-occipital lobe
regions.29
Other investigators have used the "mean callosal curvature," a ratio
of the bending angle divided by the midline length, to subtract out a possible
effect of midline length on bending angle.21
However, such a measure may actually amplify differences between 2 groups,
increasing the chances of finding a significant difference. In addition, by
combining bending angle and midline length into 1 ratio, this measure makes
it difficult to determine which of the 2 variables is contributing more to
an observed difference between groups. Nevertheless, to provide data that
can be compared across studies, an analysis of variance of mean callosal curvature
(bending angle over length) was conducted. This analysis indicated a significant
difference between subjects with WMS and normal controls (F = 28.0, P<.001). The difference in mean cerebral curvature also
was significant for both left and right hemispheres (F = 49.6, P<.001; F = 25.01, P<.001, respectively).
As a syndrome with a proven genetic origin, it is likely that the neuromorphologic
variations observed in WMS are caused by aberrant brain development. Both
the corpus callosum and the cerebral hemispheres develop in a rostrocaudal
direction.30, 31 Premature termination
of brain development on the rostrocaudal axis could produce cortical shapes
much like that in the subjects with WMS described here. Furthermore, there
are several genes in the 7q11.23 region that are differentially expressed
in the brain, including syntaxin, CYLN2, LIM-kinase1, and WBSCR11.32, 33, 34, 35
Hemizygosity for LIM-kinase1, for example, has been
correlated with visuospatial impairment for both subjects with WMS and subjects
with microdeletions of only the ELN and LIM-kinase genes.36 Though the function
of LIM-kinase1 is unknown, proteins with LIM domains
are implicated as developmental regulators of cell differentiation.37
Another gene in the WMS critical region, FZD9
(formerly known as FZD3, the human homologue of Drosphilia's frizzled gene), is expressed strongly in adult
brains and seems to play a key role in global brain development.38 FZD9 is related to the Wnt gene
family, the genes of which encode for secreted signaling glycoproteins and
are known to be involved in controlling early cell development, tissue differentiation,
segmentation, and dorsal-ventral polarity.39
A gene with such properties is a likely candidate for controlling the development
along the anterior-posterior axis. Indeed, recent findings have found that
the mouse homolog of FZD9, called Fzd9, is highly expressed in the central nervous system during its
development and is expressed most strongly in the telencephalon.40
Furthermore, the pattern of expression during development varies along the
rostrocaudal axis. The FZD9 gene has also been implicated
in the development of midbrain and cerebellar structures.38
Further studies focused on associations among neuroanatomy, neuropsychology,
and neurogenetics in WMS are likely to reveal important information regarding
the neurobiological origins of the WMS phenotype.
AUTHOR INFORMATION
Accepted for publication January 1, 2000.
The research presented in this manuscript was supported by grants HD33113
(Dr Bellugi) and MH01142 and HD31715 (Dr Reiss) from the National Inistitutes
of Health, Bethesda, Md. This work was also partially supported by a grant
from the University of California, Davis, Medical Investigation of Neurodevelopmental
Disorders (M.I.N.D.) Institute, Davis, Calif (Dr Reiss).
We are grateful to the participants for their participation in these
studies and to the local, regional, and national Williams Syndrome Associations
(locations available on request).
From the Stanford Psychiatry Neuroimaging Laboratory, Department of
Psychiatry and Behavioral Sciences, Stanford University School of Medicine,
Stanford, Calif (Mr Schmitt and Drs Eliez and Reiss); and the Laboratory for
Cognitive Neuroscience, the Salk Institute for Biological Studies, La Jolla,
Calif (Dr Bellugi).
Reprints: Allan L. Reiss, MD, Department of Psychiatry and Behavioral
Sciences, Stanford University School of Medicine, 401 Quarry Rd, Stanford,
CA 94305-5719 (e-mail: reiss{at}stanford.edu).
REFERENCES
| |
1. Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams
syndrome. Nat Genet. 1993;5:11-16.
FULL TEXT
|
ISI
| PUBMED
2. Brondum-Nielsen K, Beck B, Gyftodimou J, et al. Investigation of deletions at 7q11.23 in 44 patients referred for Williams-Beuren
syndrome, using FISH and four DNA polymorphisms. Hum Genet. 1997;99:56-61.
ISI
| PUBMED
3. Korenberg J, Chen X-N, Hirota H, et al. Genome structure and cognitive map of Williams Syndrome. J Cogn Neurosci. 2000;12:89-107.
4. Korenberg J, Chen X-N, Lai Z, Yimlamia D, Bisighini R, Bellugi U. Williams syndrome: the search for the genetic origins of cognition
[abstract]. Hum Genet. 1997;61:A103.
5. Korenberg J, Chen X-N, Mitchell S, et al. The genomic organization of Williams syndrome [abstract]. Hum Genet. 1996;59(suppl):A386.
6. Williams JCP, Barrat-Boyes BG, Lowe JB. Supravalvular aortic stenosis. Circulation. 1961;24:1311-1318.
FREE FULL TEXT
7. Nicholson WR, Hockey KA. Williams syndrome: a clinical study of children and adults. J Paediatr Child Health. 1993;29:468-472.
ISI
| PUBMED
8. Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL. Natural history of Williams syndrome: physical characteristics. J Pediatr. 1988;113:318-326.
FULL TEXT
|
ISI
| PUBMED
9. Wang PP, Bellugi U. Evidence from two genetic syndromes for a dissociation between verbal
and visual-spatial short-term memory. J Clin Exp Neuropsychol. 1994;16:317-322.
ISI
| PUBMED
10. Wang PP, Doherty S, Rourke SB, Bellugi U. Unique profile of visuo-perceptual skills in a genetic syndrome. Brain Cogn. 1995;29:54-65.
FULL TEXT
|
ISI
| PUBMED
11. Bellugi U, Bihrle A, Jernigan T, Trauner D, Doherty S. Neuropsychological, neurological, and neuroanatomical profile of Williams
syndrome. Am J Med Genet Suppl. 1990;6(suppl):115-125.
12. Bellugi U, Lichtenberger L, Mills D, Galaburda A, Korenberg JR. Bridging cognition, the brain and molecular genetics: evidence from
Williams syndrome. Trends Neurosci. 1999;22:197-207.
FULL TEXT
|
ISI
| PUBMED
13. Bellugi U, Klima E, Wang P. Cognitive and neural development: clues from genetically based syndromes. In: Magnussen D, ed. The Life-Span Development
of Individuals: Behavioral, Neurobiological, and Psychosocial Perspectives:
The Nobel Symposium. New York, NY: Cambridge University Press; 1996.
14. Bellugi U, Lichtenberger L, Jones W, Lai Z, St George MI. The neurocognitive profile of Williams syndrome: a complex pattern
of strengths and weaknesses. J Cogn Neurosci. 2000;12:7-29.
15. Jernigan TL, Bellugi U, Sowell E, Doherty S, Hesselink JR. Cerebral morphologic distinctions between Williams and Down syndromes. Arch Neurol. 1993;50:186-191.
ABSTRACT
16. Wang PP, Hesselink JR, Jernigan TL, Doherty S, Bellugi U. Specific neurobehavioral profile of Williams' syndrome is associated
with neocerebellar hemispheric preservation. Neurology. 1992;42:1999-2002.
FREE FULL TEXT
17. Reiss AL, Eliez S, Schmitt JE, et al. Neuroanatomy of Williams syndrome: a high-resolution MRI study. J Cogn Neurosci. 2000;12:65-73.
18. Talairach J, Tournoux P, Musolino A, Missir O. Stereotaxic exploration in frontal epilepsy. Adv Neurol. 1992;57:651-688.
PUBMED
19. Kates WR, Warsofsky IS, Patwardhan A, et al. Automated Talairach-based parcellation and measurement of cerebral
lobes in children. Psychiatry Res. 1999;91:11-30.
ISI
| PUBMED
20. Reiss AL. Brainimage. Stanford, Calif: Stanford University; 1999.
21. Peterson BS, Leckman JF, Duncan JS, et al. Corpus callosum morphology from magnetic resonance images in Tourette's
syndrome. Psychiatry Res. 1994;55:85-99.
FULL TEXT
|
ISI
| PUBMED
22. Allen LS, Richey MF, Chai YM, Gorski RA. Sex differences in the corpus callosum of the living human being. J Neurosci. 1991;11:933-942.
ABSTRACT
23. Baumgardner TL, Singer HS, Denckla MB, et al. Corpus callosum morphology in children with Tourette syndrome and attention
deficit hyperactivity disorder. Neurology. 1996;47:477-482.
FREE FULL TEXT
24. Andreasen NC, Rajarethinam R, Cizadlo T, et al. Automatic atlas-based volume estimation of human brain regions from
MR images. J Comput Assist Tomogr. 1996;20:98-106.
FULL TEXT
|
ISI
| PUBMED
25. Talairach J, Tournoux P. Co-Planar Stereotaxic Atlas of the Human Brain. New York, NY: Thieme Medical Publishers Inc; 1988:122.
26. Aylward EH, Reiss A. Area and volume measurement of posterior fossa structures in MRI. J Psychiatr Res. 1991;25:159-168.
FULL TEXT
|
ISI
| PUBMED
27. Wang PP, Doherty S, Hesselink JR, Bellugi U. Callosal morphology concurs with neurobehavioral and neuropathological
findings in two neurodevelopmental disorders. Arch Neurol. 1992;49:407-411.
ABSTRACT
28. Schimitt JE, Eliez S, Warsofsky IS, Bellugi U, Reiss AL. Corpus callosum morphology in Williams syndrome: relationship to genetics
and behavior. Dev Med Child Nero. 2001. In press.
29. de Lacoste MC, Kirkpatrick JB, Ross ED. Topography of the human corpus callosum. J Neuropathol Exp Neurol. 1985;44:578-591.
ISI
| PUBMED
30. Barkovich AJ, Norman D. Anomalies of the corpus callosum: correlation with further anomalies
of the brain. AJR Am J Roentgenol. 1988;151:171-179.
FREE FULL TEXT
31. Huttenlocher PR. Morphometric study of human cerebral cortex development. Neuropsychologia. 1990;28:517-527.
FULL TEXT
|
ISI
| PUBMED
32. Nakayama T, Matsuoka R, Kimura M, et al. Hemizygous deletion of the HPC-1/syntaxin 1A gene (STX1A) in patients with Williams syndrome. Cytogenet Cell Genet. 1998;82:49-51.
FULL TEXT
|
ISI
| PUBMED
33. Osborne LR, Campbell T, Daradich A, Scherer SW, Tsui LC. Identification of a putative transcription factor gene (WBSCR11) that is commonly deleted in Williams-Beuren syndrome. Genomics. 1999;57:279-284.
FULL TEXT
|
ISI
| PUBMED
34. Wang JY, Frenzel KE, Wen D, Falls DL. Transmembrane neuregulins interact with LIM kinase 1, a cytoplasmic
protein kinase implicated in development of visuospatial cognition. J Biol Chem. 1998;273:20525-20534.
FREE FULL TEXT
35. Hoogenraad CC, Eussen BH, Langeveld A, et al. The murine CYLN2 gene: genomic organization,
chromosome localization, and comparison to the human gene that is located
within the 7q11.23 Williams syndrome critical region. Genomics. 1998;53:348-358.
FULL TEXT
|
ISI
| PUBMED
36. Frangiskakis JM, Ewart AK, Morris CA, et al. LIM-kinase1 hemizygosity implicated in impaired
visuospatial constructive cognition. Cell. 1996;86:59-69.
FULL TEXT
|
ISI
| PUBMED
37. Schmeichel KL, Beckerle MC. The LIM domain is a modular protein-binding interface. Cell. 1994;79:211-219.
FULL TEXT
|
ISI
| PUBMED
38. Wang YK, Samos CH, Peoples R, Perez-Jurado LA, Nusse R, Francke U. A novel human homologue of the Drosophila
frizzled wnt receptor gene binds wingless protein
and is in the Williams syndrome deletion at 7q11.23. Hum Mol Genet. 1997;6:465-472.
FREE FULL TEXT
39. Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997;11:3286-3305.
FREE FULL TEXT
40. Wang YK, Sporle R, Paperna T, Schughart K, Francke U. Characterization and expression pattern of the frizzled gene Fzd9,
the mouse homolog of FZD9 which is deleted in Williams-Beuren
syndrome. Genomics. 1999;57:235-248.
FULL TEXT
|
ISI
| PUBMED
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