Neuropsychologia 44 (2006) 679–685

In-depth analysis of spatial cognition in Williams syndrome: A criticalassessment of the role of the LIMK1 gene

Victoria Gray a,∗, Annette Karmiloff-Smith b, Elaine Funnell a, May Tassabehji c

a Psychology Department, Royal Holloway, University of London, UKb Neurocognitive Development Unit, Institute of Child Health, London WC1N 1EH, UK

c Academic Unit of Medical Genetics, University of Manchester, St. Mary’s Hospital, UK

Received 26 April 2005; received in revised form 3 August 2005; accepted 18 August 2005Available online 10 October 2005

Abstract

The LIM kinase1 protein (LIMK1) is thought to be involved in neuronal development and brain function. However, its role in spatial cognitionin individuals with Williams syndrome (WS) is currently ambiguous, with conflicting reports on the cognitive phenotypes of individuals who donot have classic WS but harbour partial deletions including LIMK1. Two families with partial WS deletions have been described with deficitsi1wWGtpihtttg©

K

1

oDmiE

a

a

0d

n visuospatial cognition (Frangiskakis, J. M., Ewart, A. K., Morris, C. A., Mervis, C. B., Bertrand, & J., Robinson, et al. (1996). LIM-kinasehemizygosity implicated in impaired visuospatial constructive cognition. Cell, 86, 59–69), in contrast to others with similar partial deletionsho did not display spatial impairments (Tassabehji, M., Metcalfe, K., Karmiloff-Smith, A., Carette, M. J., Grant, J., & Dennis, N., et al. (1999).illiams syndrome: Use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. American Journal of Humanenetics, 64, 118–125). To determine the role of LIMK1 in the highly penetrant visuospatial deficits associated with classic WS, it is essential

o investigate the discrepancies between the two studies. Previous research used a standardised task to measure spatial cognition, which may notick up subtle impairments. We therefore undertook more extensive testing of the spatial cognition of two adults with partial genetic deletionsn the WS critical region (LIMK1 and ELN only), who had not displayed spatial impairments in the previous study, and compared them to twoigh-functioning adults with WS matched on verbal ability. All participants completed a broad battery of 16 perceptual and constructive spatialests, and the clear-cut spatial difficulties observed in the WS group were not found in the partial deletion group. These findings rule out the claimhat the deletion of one copy of LIMK1 is alone sufficient to result in spatial impairment, but leave open the possibility that LIMK1 contributes tohe WS cognitive deficits if deleted in combination with other genes within the WS deletion. We conclude that a deeper assessment of WS at theenetic level is required before the contribution of specific genes to phenotypic outcomes can be fully understood.

2005 Elsevier Ltd. All rights reserved.

eywords: Williams syndrome (WS); Patial deletion patients (PD); Spatial cognition; LIM kinase1 (LIMK1)

. Introduction

Williams syndrome (WS) is a rare neurodevelopmental dis-rder occurring in approximately 1 in 20,000 live births (Morris,empsey, Leonard, Dilts, & Blackburn, 1988). It is caused by aicrodeletion on one copy of chromosome 7 (at locus 7q11.23),

nvolving at least 28 genes (Donnai & Karmiloff-Smith, 2000;wart, Morris, & Atkinson, 1993; Lowery et al., 1995; Morris et

∗ Corresponding author. Present address: Psychological Services (Paedi-trics), RLCH Alder Hey, Eaton Road, Liverpool L12 2AP, UK.

E-mail addresses: victoria.gray@rlc.nhs.uk (V. Gray),.karmiloff-smith@ich.ucl.ac.uk (A. Karmiloff-Smith).

al., 1988; Nickerson, Greenberg, Keating, McCaskill, & Shaf-fer, 1995; Tassabehji et al., 1999). Physically, individuals withWS have a dysmorphic face, with a flat nasal bridge, flared nos-trils, long filtrum, wide mouth and prominent cheeks. There areoften connective tissue abnormalities and a high frequency ofcardiovascular difficulties (Beuren, Apitz, & Harmjanz, 1962;Williams, Barratt-Boyes, & Lowe, 1961), including supravalvu-lar aortic stenosis (SVAS). Behaviourally, individuals with WStend to be overly friendly to strangers and display a generallack of social judgement. They also tend to show extreme anx-iety in new situations where unexpected things might happen(Tager-Flusberg, Boshatt, & Baron-Cohen, 1998). The full intel-ligence quotient (FIQ) of individuals with WS ranges from40 to 100, with a mean of 56 (Bellugi, Litchtenberger, Mills,

028-3932/$ – see front matter © 2005 Elsevier Ltd. All rights reserved.oi:10.1016/j.neuropsychologia.2005.08.007

680 V. Gray et al. / Neuropsychologia 44 (2006) 679–685

Galaburda, & Korenberg, 1999). However, this camouflagesa very uneven cognitive profile, which has been commonlydescribed in terms of a marked contrast between verbal andspatial abilities. Older children and adults with WS have beenreported to show relatively proficient verbal abilities alongsidedeficient spatial abilities (Bellugi, Wang, & Jernigan, 1994;Karmiloff-Smith, 1998; Mervis, Morris, Bertrand, & Robinson,1999).

The chromosomal deletion at 7q11.23 is often referred to asthe WS critical region (WSCR). Most individuals with WS havesimilar, although not identical, deletions of ∼1.5 Mb of genomicDNA on one chromosome 7 homologue (Tassabehji et al., 1999).Identification of the genes located on the relevant chromosomalsegments may allow the characterisation of genes that con-tribute to the specific cognitive and behavioural features of WS(Tassabehji et al., 1999). Unravelling the genotype/phenotyperelations of WS is likely to rely heavily on studies of individualswith partial chromosomal deletions and/or partial WS. Stud-ies of individuals with partial smaller deletions on one copy ofchromosome 7, including only two genes, ELN and LIMK1, arebeginning to provide clues to the genes responsible for the sub-sets of WS features (Karmiloff-Smith et al., 2002; Tassabehjiet al., 1999). The first deleted gene identified in the WS criticalregion was Elastin (ELN; Ewart et al., 1993) which causes theheart condition SVAS, and is the only firm geneotype–phenotypecorrelation determined to date (Tassabehji et al., 1999).

wiafisrphdgtdagabcottEdaSiftcde

such, was a good candidate for these observations, so the authorsproposed a direct link between LIMK1 and spatial impairment.

Tassabehji et al. (1999) identified four UK individuals withisolated SVAS, who had partial deletions at the WS genomiclocus. Two of these individuals had identical deletions to thosein the Frangiskakis study, i.e., only ELN and LIMK1, and twohad larger partial deletions, but still smaller than classic WScases. To determine whether a reduction of LIMK1 gene func-tion to half the normal levels has pathological consequences thatresult in spatial impairment, identical tasks were used to thoseemployed in the Frangiskakis et al. (1996) study. None of the UKindividuals with partial deletions displayed the spatial difficul-ties characteristic of the WS cognitive profile. There was in factno discrepancy between their verbal and spatial scores, whichwere all in the normal range. However, qualitative assessmentof the two individuals with deletions of only ELN and LIMK1indicated a local processing preference on the Rey–Osterriethcomplex figure test (Osterrieth, 1944; Rey, 1941). Although thisis a strategy reported to be used by individuals with WS, theindividuals with partial deletions did not show the same lowtotal score consistently obtained in WS, as they both scored inthe normal range. The authors concluded that LIMK1 may playa subtle, as yet to be determined, role in affecting spatial abil-ities in WS, but that the deletion of one copy of this gene wasunlikely to be sufficient to result in serious spatial impairments.

Mervis et al. (1999) criticised these findings, claiming that theiaWvat(umwsabceW

wdtLoWt(aptpps

LIM kinase 1 (LIMK1) (Proschel, Blouin, Gutowski, Lud-ig, & Noble, 1995) is a serine protein kinase that is involved

n reorganization of the actin cytoskeleton by phosphorylatingnd inactivating the protein cofilin, which depolymerises actinlaments. Actin cytoskeletal reorganization is important for cellhape and promotion of cell movement and is also involved inegulating axon formation (Bradke & Dotti, 1999). LIMK1 isredominantly expressed in the central nervous system, and itas recently been shown that it regulates Golgi dynamics ineveloping neurons and is important for promoting axon out-rowth and the delivery of proteins to growth cones involved inhe development of neuronal polarity (Rosso et al., 2004). Evi-ence from mouse models and functional experiments showinglterations in spine morphology and in synaptic function, sug-est that LIMK1 is involved in neuronal development (Meng etl., 2002). Deletion of one copy of the LIMK1 gene has alsoeen reported to be involved in abnormal brain function asso-iated with WS (Frangiskakis et al., 1996). However, the rolef LIMK1 in the cognitive profile of WS individuals has yeto be unambiguously defined. Frangiskakis et al. (1996) iden-ified 15 individuals from 2 US families with deletions of onlyLN and LIMK1. These individuals with smaller chromosomaleletions did not display all the behavioural or physical char-cteristics typically shown by individuals with WS, except forVAS, which is caused by lack of elastin. However, on test-

ng with the Differential Ability Scale (DAS; Elliot, 1990), theamily members with partial deletions were reported to showhe characteristic WS cognitive profile, exhibiting poor spatialonstructional skills and proficient verbal ability. Analysis toetermine the expression patterns of LIMK1 found that it wasxpressed in several different regions of the adult brain and, as

ndividuals with partial deletions in the UK study had above aver-ge intelligence (verbal IQ: 96 and 98) compared to the typical

S population. They maintained that, owing to their enhancederbal ability, the UK individuals with partial deletions wereble to overcome their spatial difficulties by talking themselveshrough the spatial tasks. However, Donnai and Karmiloff-Smith2000) challenged these claims, pointing out that these individ-als were unlikely to be able to mask serious spatial difficultieserely by using higher verbal ability, because adults with WSith high verbal IQs had been tested, and yet they display the

erious spatial impairment typical of individuals with WS. It haslso been noted that even when individuals with WS do use ver-al ability to assist them in the completion of spatial tasks, theyontinue to display considerable deficits in this area (Atkinsont al., 2003; Bellugi, Sabo, & Vaid, 1988; Mervis et al., 1999;ang, Doherty, Rouke, & Bellugi, 1995).It remains possible, however, that the standardised test used

as not sufficiently sensitive to capture a more subtle spatialeficit. The current study therefore re-assesses in far more detailhe two individuals with partial deletions (of only ELN andIMK1) described by Tassabehji et al. (1999), on a wide rangef spatial tasks, and compares them to two individuals withS specifically selected to have a higher verbal IQ than the

ypical WS population. This made them more closely matchedon verbal ability) to the individuals with partial deletions andllowed us to evaluate the proposal that the individuals withartial deletions were overcoming spatial difficulties by usingheir high verbal ability (Mervis et al., 1999). Based on ourrevious findings, however, we predicted that individuals withartial deletions would not differ significantly from a normativeample on tests of spatial cognition, whereas those with WS,

V. Gray et al. / Neuropsychologia 44 (2006) 679–685 681

Table 1Equivalent IQ scores, based on standard scores from the BAS-II, for typicalindividuals with WS (WS), the two high-functioning WS participants (WS1WS2), and the partial deletion patients (PD1, PD2)

Typical WS WS1 WS2 PD1 PD2

Verbal 59 79 112 98 96Spatial 45 47 55 88 100

despite their high verbal ability, would. This study thereforeinvestigates the important discrepancies between the neurolog-ical phenotypes in the US and UK studies, and assesses the roleof LIMK1 in the highly penetrant visuospatial deficits associatedwith classic WS.

2. Methods

2.1. Participants

Two individuals with WS (WS1 and WS2) – with deletions confirmed bymolecular testing – were selected on the basis that their verbal IQs were higherthan the average WS population, to ensure a stringent test of our hypothesis. Thischoice made them more closely matched (on verbal ability) to the participantswith partial deletions (see Table 1). Full IQ matching was obviously not possi-ble, given the uneven cognitive profile exhibited by individuals with WS. It is tobe noted that despite their high verbal skills, both of the WS participants exhib-ited the characteristic WS cognitive profile. On previous testing, they displayedmarked spatial deficits in relation to proficient verbal skills (Karmiloff-Smithet al., 2002; Tassabehji et al., 1999). WS1 was a 34-year-old Caucasian male;WS2 was a 46-year-old Caucasian female.

Two individuals (PD1 and PD2) with previously defined genetic deletionsin the WSCR including only two genes, ELN and LIMK1 (Tassabehji et al.,1999), were relatively well matched on chronological age and on verbal abilityto the two participants with WS (see Table 1). These individuals did not exhibitany behavioural or physical features characteristic of the WS phenotype, otherthan SVAS. On previous cognitive assessment, but much more limited thanthe current study, PD1 and PD2 did not show a dissociation between verbaland spatial ability, exhibiting proficient skills in both domains (Tassabehji et al.,1sp

3

ptutatsup

scEbvf

Table 2Inter-rater reliability coefficients

Test Reliability coefficient

Clock face .95

Rey figureCopy .98Immediate recall .99Delayed recall .99

Taylor figureCopy .98

ing judgments. Two inter-raters were therefore used to assessthe reliability of the scores awarded to participants on thesetests (see Table 2). Reliability was calculated using Cronbach’salpha (Bland & Altman, 1997). These data show that the scoresawarded here were reliable.

3.1. Rey–Osterrieth complex figure test(Osterrieth, 1944; Rey, 1941)

Standard methods of presentation were applied. Participantswere given unlimited time to copy the figure and were askedto recall the figure from memory: first after three minutes(immediate recall) and again after 30 min (delayed recall). TheRey–Osterrieth 36-point scoring system was used (Meyers &Meyers, 1995).

3.2. Taylor complex figure test (Taylor, 1979)

Standard methods of presentation and scoring were applied.Participants were given unlimited time to copy the figure. A36-point scoring system was used (Lezak, 1995).

3.3. Clock face drawing task (Boston parietal lobe battery;Goodglass & Kaplan, 1972)

Participants were instructed to draw a clock face, to put inatK

3

tplob

3

pat

999). PD1 was a 35-year-old Caucasian male (referred to as PM in our previoustudy). PD2, the brother of PD1, was a 41-year-old Caucasian male (TM, in ourrevious study).

. Test administration

Sixteen different spatial tasks were administered to the fourarticipants, covering a wide variety of perceptual and construc-ive spatial cognition tests. Some of these had previously beensed to assess a WS population, but not individuals with par-ial deletions. Some of the tests were novel tests for both groupsnd were chosen from the neuropsychological literature becausehey are known to pick up subtle deficits in perceptual and con-tructive spatial cognition. Brief descriptions of the spatial testssed in this study are given below. Further details of the stimuli,rocedure and scoring methods are provided in Appendix A.

A normative data set was collected for those tests for whichtandardised data were not available. The normative data wereollected from 10 individuals (six female, four male) for whomnglish was their first language. The normative group was agedetween 30 and 55 years (mean: 37.10 years) and had a meanerbal IQ of 107 (range 92–118). Several of the scoring systemsor tests employed in this study were based on subjective scor-

ll the numbers, and to set the hands for 10 past 11. A quanti-ative method of scoring was used (Rouleau, Salomon, Butters,ennedy, & Maguire, 1992).

.4. Drawing a ground plan

Participants were shown a sample drawing before being askedo draw a plan of the ground-floor of their flat, or house, on paperlaced along their horizontal plane. Spacing errors were calcu-ated as a percentage of rooms that were drawn independentlyf other rooms: that is, without representation of the connectionetween separate areas of space.

.5. Writing letters in lower case

Participants were asked to write letters in lower case on plainaper placed along their horizontal plane. Each letter of thelphabet was sounded out and named by the experimenter beforehe participant wrote the letter. Only legible, lower case letters

682 V. Gray et al. / Neuropsychologia 44 (2006) 679–685

were counted as correct. For each participant, the number ofcorrect responses was compared with the mean control score.

3.6. Block design subtest of the WASI (Wechsler, 1999)

Standard methods of presentation and scoring were applied.

3.7. Orientation stamping task

This task was adapted from Goodale et al. (1994). The partic-ipants were asked to place a rectangular stamp (covered in redink) inside a rectangle drawn centrally on a white paper disc.The disc was rotated between trials so that the central rectanglevaried in orientation relative to the edge of the table (0◦, 45◦,90◦, or 135◦). Responses in which the red ink spread beyond theoutlines of the rectangle were considered as errors. The numberof errors was compared with the average control error score.

3.8. Reaching task

The apparatus was based upon a test developed by McCloskeyet al. (1995). Participants reached ballistically for a woodenblock placed at one of ten different positions that differed in dis-tance and orientation from the participant. The block was placedwith vision occluded. The glasses were then cleared revealing

that contained a central rectangle (8 cm × 2.5 cm) – referred toas a ‘slot’ – until the orientation of the slot matched the orien-tation of a second slot on an identical target disc. The averagedeviation in orientation made by each participant was comparedto the control average.

3.12. Faces in places: simultaneous condition (Funnell &Hughes, 2001)

Participants were asked to match a face presented in a block offour boxes to the identical box in an empty block. The two blockswere placed on the same page either horizontally, vertically ordiagonally. The number of correct responses was compared withthe average score of the controls.

3.13. Faces in places: serial condition (Funnell & Hughes,2001)

This condition followed the simultaneous condition (Test 12).Participants were asked to remember the position of a face pre-sented in a single block of four boxes and then to point, frommemory, to the identical box in an empty block of four boxespresented on a separate page. Pairs of blocks on separate pageswere positioned vertically, horizontally, or diagonally to eachother. The number of correct responses was compared with the

the position of the block to the participants. Participants wereasked to reach for the block either in full vision (visually-guidedcondition) or with vision occluded again (memory condition).Reaching movements which deviated from the most direct lineto the block were counted as errors and compared with controldata.

3.9. Developmental test of visual perception (DTVP;Hammill, Pearson, & Voress, 1993): motor enhancedsub-tests

This test, which was developed for use with children aged fourto eleven years, contains four motor-enhanced spatial tasks thatrequire the use of a pencil (eye–hand co-ordination, shape copy-ing, spatial relations and visual-motor speed). Standard scoresassigned to participants were based on the highest age range ofnormative data available (10.0–10.11 years).

3.10. Star cancellation test (Halligan, Cockburn, & Wilson,1991; Wilson, Cockburn, & Halligan, 1987)

Participants were asked to cross through all the small stars(N = 54) presented in a scattered array of words, letters and starsprinted on a sheet of A4 paper, presented centrally. Standardmethods of scoring were used.

3.11. Orientation matching task

This two-dimensional task was adapted from a three-dimensional task developed by Goodale, Milner, Jackobson, andCarey (1991). The participant was required to turn a white disc

average score of the controls.

3.14. Lines and shapes (Funnell & Hughes, 2001)

Participants were asked to copy a small printed arch, placedat the end of one line, to the identical position on a similar, butempty, line. Lines were either horizontal or vertical and wereplaced side by side on the page. A trial was scored as correctif the arch was reproduced in the same position and the sameorientation as the target. Participant’s scores were compared withthe average control data.

3.15. Clock face recognition

Participants were shown four clock faces and were asked topoint to the clock face that was showing the time of ten pasteleven. A correct response was considered to reflect normal per-formance.

3.16. Motor reduced sub-tests of the developmental test ofvisual perception (Hammill et al., 1993)

Participants were asked to carry out the four motor-reducedtests that complete the DTVP (see Test 9 above). These testsrequire a pointing response and include the selection of shapesdepending upon variations in position in space, figure-ground,visual closure and form constancy. Standard procedures of pre-sentation and scoring were observed. Standard scores for theadult participants were based on the highest age range of nor-mative data available (10.0–10.11 years).

V. Gray et al. / Neuropsychologia 44 (2006) 679–685 683

4. Results

The results for tasks where significant differences emergedbetween participants are presented in Table 3. Since the testsyielded different types of measures, we compared each scorewith the normative data to derive a z-score. Test scores that aresignificantly below the norm are indicated in Table 3. It is clearthat both individuals with WS (WS1 and WS2) were signifi-cantly impaired on two of the visual–perceptual tests of spatialprocessing: orientation matching, and faces in places (simulta-neous condition), as well as on six of the constructional tests:clock face drawing, ground floor drawing, Rey figure delayedrecall, Taylor figure recall, writing in lower case to dictation andcopying shapes to lines. They also had problems in the clearvision condition of the reaching task.

By contrast, the two individuals with partial deletions (PD1and PD2) had problems with only one test, writing in lower case,which also proved difficult for the WS patients. Errors consistedmainly of upper case letters with some additional illegible let-ter forms. Distributions of these error types were similar acrossWS participants (10 upper case errors and 4 illegible letters) andPD participants (9 upper case errors and 3 illegible letters). Inboth groups, letters were written at normal size. Otherwise thePD participants displayed no deficits in the 15 remaining spa-tial tasks. A comparison between the number of test results thatwere significantly below the norm and the number within thentb(

5

(dsm

exhibited normal proficiency on 15 of the 16 spatial tests andexperienced difficulty on only one (writing in lower case). Onthis test, the errors made by the partial deletion patients weresimilar to those made by the two individuals with WS, and maywarrant further investigation in both groups or may be simplydue to a problem inherent in the task itself.

The data in this study support and extend our previous find-ings (Tassabehji et al., 1999) that the individuals described withpartial deletions in the WS region (that do not extend to thetelomeric critical region) do not show the characteristic spatialimpairment exhibited by individuals with WS. The data cannotbe explained in terms of differences in verbal ability betweenthe two groups, as originally suggested by Mervis et al. (1999),because the verbal abilities of all participants in our study werewithin the normal range, with the verbal IQ of one of the indi-viduals with WS (112 on the BAS-II) well above that of bothpartial deletion patients (98 and 96, respectively).

The current research does not therefore support the claims ofFrangiskakis et al. (1996), who reported spatial impairment inindividuals with partial deletions, similar to PD1 and PD2, andsuggested that a 50% reduction in the level of LIMK1 gene func-tion causes this cognitive abnormality. In fact, there are manycases where humans are able to function normally with onlya 50% level of gene action, sometimes because of functionalredundancy between genes of the same family. It is possiblethat the differences between our cases with partial deletions andtrddtd

tLoLt

TN elow

T

RCIDTCGWBRLOF

*

ormal range revealed a highly significant difference betweenhe combined scores of the individuals with WS and the com-ined scores of the individuals with partial deletions (chi square1) = 15.8, p < 0.001).

. Discussion

Our hypothesis that the individuals with partial deletionsPM and TM; Tassabehji et al., 1999) would not significantlyiffer from a normative sample on a wide variety of tests ofpatial construction and spatial perception was supported by theuch broader spatial cognition data presented in this paper. They

able 3umber correct and normal deviate scores for test results that are significantly b

est WS1

ey–Osterrieth figureopy 14.5/36*

mmediate recall 4.5/36***

elayed recall 5/36***

aylor figure 16/36***

lock face drawing 4/10***

round plan drawing ***

riting in lower case 20/26***

lock design – WASI 4/13*

eaching – clear vision 13/20***

ines and shapes 13/15*

rientation matching **

aces in places 14/16*

* p < .05 (z > −1.96).** p < .01 (z > −2.33).** p < .005 (z > −2.58).

hose in the latter study occur at a genetic level. Deletion, dis-uption or mutation of other gene(s) outside the genomic regionefined on 7q11.23 or on other chromosomes that have not beenetected could contribute to the spatial deficits described. Theyhus warrant a more thorough genetic assessment to confirm anyifferences between the affected individuals.

What is clear from the greater breadth of cognitive datahat we have accrued from individuals deleted for one copy ofIMK1, but showing no phenotype other than elastin-associatednes (namely SVAS), is that either: (i) reduced quantities of theIMK1 protein alone do not have consequences on visuospa-

ial constructive cognition, a phenotype consistently seen in WS

the norm

WS2 PD1 PD2

21/36*

10.5/36*

22/36***

***

18/26*** 19/26*** 21/36***

18/20***

10/15***

**

14/16*

684 V. Gray et al. / Neuropsychologia 44 (2006) 679–685

individuals, or (ii) that abnormally low levels of LIMK1 canaffect spatial impairment but only in combination with reducedlevels of other proteins involved in brain function. The latteroccurs when other genes are deleted, as is the case in classicWS. Our findings highlight the need for deeper assessment ofWS at the genetic level before the contribution of specific genesto phenotypic outcomes can be fully understood.

Acknowledgments

The authors wish to thank the individuals who took part inthis study. A.K.-S. was partially funded by Fogarty/NIH GrantNo. R21TW06761-01. M.T. was funded by the Wellcome Trust(Grant # 061183).

Appendix A. Further essential details of lesser knowntests

A.1. Test 7: Orientation stamping task

The target comprised a white circular disc (diameter 13 cm)containing a black rectangle (8 cm × 2.5 cm). The test stim-uli were created by computer using Vectorworks. Each pat-tern was laser printed and photocopied. A stamp was preparedby fixing a strip of rubber to the end of a block of wood(6.5 cm × 7 cm × 1.5 cm). The rectangle appeared in one of fourdzo

A

gAfaphtwpgrtrtiwpf

A

ww

tical white discs of 13 cm diameter. On completion of eachrotation, a set-square was used to mark the top point on the rotat-able slot. This allowed the precise calculation of the number ofdegrees of error from the target orientation. The average numberof degrees of error made by each participant was compared withcontrol data.

A.4. Test 13: Faces in places: simultaneous condition

The stimuli consisted of two squares (4.6 cm2) divided intofour squares of equal size (2.3 cm2). There were 32 trialscomprised of 4 vertical, 4 horizontal and 8 diagonal arrange-ments, mixed together. The simultaneous condition was pre-sented before the serial condition (see Test 14).

A.5. Test 14: Faces in places: serial condition

The stimuli consisted of the squares described in the simul-taneous condition (see Test 13). The squares were presentedon separate pages and the relative spatial position of the twosquares in the simultaneous condition was preserved across thetwo pages. The first square was presented and the page was thenturned over so that the square was obscured. This was followedby a blank page and then the second square. There were 32 tri-als: 4 vertical, 4 horizontal and 8 diagonal arrangements mixedtogether.

A

dw1aSaisn

R

A

B

B

B

B

ifferent orientations placed 0◦, 45◦, 90◦, or 135◦ to the hori-ontal and each orientation was presented four times in randomrder.

.2. Test 8: Reaching task

The stimuli included a wooden block (3 cm3), a pair of clearlass spectacles that could be occluded, and a sheet of plain3 paper upon which ten locations were marked in pencil as

aint dots. The locations formed two semi-circles placed at 18nd 36 cm from the subject. The locations on these arcs werelaced at 0◦, 45◦ and 90◦ to the horizontal. The paper was placedorizontally and lined up so that the midline of the page matchedhe midline of the participant. Participants wore occluded glasseshile the block was placed and sat with their preferred handositioned at the mid-line. In the visually-guided condition thelasses were then cleared and the participants were asked toeach for the block immediately, using a ballistic movement. Inhe memory condition, the glasses were cleared momentarily toeveal the position of the block, and were then occluded. Oncehe glasses were occluded, the participant was asked to reachmmediately for the block using a ballistic movement. The blockas presented four times in each of the ten randomly interleavedositions. Forty trials were presented, 20 in clear vision and 20rom memory.

.3. Test 11: Orientation matching task

The test stimuli were created by computer, using Vector-orks. A black rectangle (8 cm × 2.5 cm), referred to as a ‘slot’,as laser printed and photocopied onto the centre of two iden-

.6. Test 15: Lines and shapes (Funnell & Hughes, 2001)

Two horizontal or two vertical lines (6.8 cm × 0.2 cm) wererawn side by side in black ink on A5 paper. The horizontal linesere separated by a gap of 4 cm and the vertical lines by a gap of0 cm. A small green arch (1.5 cm base width and 0.8 cm height)ppeared at one end of one of the two lines and facing the line.ixteen mixed trials were presented: eight with horizontal linesnd eight with vertical lines. A trial was scored as correct onlyf the arch was reproduced in the same relative position and theame orientation as the target. The quality of the drawing wasot scored.

eferences

tkinson, J., Braddick, O., Anker, S., Curran, W., Andrew, R., Wattam-Bell, J., et al. (2003). Neurobiological models of visuospatial cognition inchildren with Williams syndrome: Measures of dorsal-stream and frontalfunction. Developmental Neuropsychology, 23, 139–172.

ellugi, U., Litchtenberger, L., Mills, D., Galaburda, A., & Korenberg, J. R.(1999). Bridging cognition, the brain and molecular genetics: Evidencefrom Williams syndrome. Trends in Neurosciences, 22, 197–207.

ellugi, U., Sabo, H., & Vaid, J. (1988). Spatial deficits in children withWilliams syndrome. In J. Stiles-Davis, U. Kritchevshy, & U. Bellugi(Eds.), Spatial cognition: Brain bases and development (pp. 273–297).Hillsdale, NJ: Lawrence Erbaum Associates.

ellugi, U., Wang, P. P., & Jernigan, T. (1994). Williams syndrome: Anunusual neuropsychological profile. In S. H. Broman & J. Grafman (Eds.),Atypical cognitive developmental disorders: Implications for brain func-tion.. Hillsdale, NJ: Lawrence Erlbaum Associates.

euren, A. J., Apitz, J., & Harmjanz, D. (1962). Supravalvular aortic stenosisin association with mental retardation and a certain facial appearance.Circulation, 26, 1235–1240.

V. Gray et al. / Neuropsychologia 44 (2006) 679–685 685

Bland, J. M., & Altman, D. G. (1997). Cronbach’s alpha. BMJ, 314(7080),572.

Bradke, F., & Dotti, C. G. (1999). The role of local actin instability in axonformation. Science, 283, 1931–1934.

Donnai, D., & Karmiloff-Smith, A. (2000). Williams syndrome: From geno-type through to the cognitive phenotype. American Journal of MedicalGenetics, 97, 164–171.

Elliot, C. D. (1990). Differential ability scales. New York: The PsychologicalCorporation.

Ewart, A. K., Morris, C. A., & Atkinson, D. J. (1993). Hemizygosity atthe elastin locus in a developmental disorder, Williams syndrome. NatureGenetics, 5, 11–16.

Frangiskakis, J. M., Ewart, A. K., Morris, C. A., Mervis, C. B., Bertrand, J.,Robinson, B. F., et al. (1996). LIM-Kinase 1 hemizygosity implicated inimpaired visuospatial constructive cognition. Cell, 86, 59–69.

Funnell, E., & Hughes, D. (2001). Deficits in object co-ordinates in a nine-year old child. Cortex, 7, 353.

Goodale, M. A., Jackobson, L. S., Milner, A. D., Perrett, D. I., Benson,P. J., & Hietanen, J. K. (1994). The nature and limits of orientation andpattern processing supporting visuomotor control in a visual form agnosic.Journal of Cognitive Neuroscience, 6, 46–56.

Goodale, M. A., Milner, A. D., Jackobson, L. S., & Carey, P. (1991). Aneurological dissocaition between perceiving objects and grasping them.Nature, 349, 154–156.

Goodglass, H., & Kaplan, E. (1983). Boston diagnostic aphasia examination(BDAE). Philadelphia: Lea and Febiger.

Halligan, P. W., Cockburn, J., & Wilson, B. A. (1991). The behaviouralassessment of visual neglect. Neuropsychological Rehabilitation, 1, 5–32.

Hammill, D. D., Pearson, N. A., Voress, J. K. (1993). Developmental test ofvisual perception (2nd ed.: Examiner’s manual). Austin1: PRO-ED.

Karmiloff-Smith, A. (1998). Development itself is the key to understand-

K

L

L

M

M

Mervis, C. B., Morris, C. A., Bertrand, J., & Robinson, B. F. (1999). Williamssyndrome: Findings from an integrated program of research. In H. Tager-Flusberg (Ed.), Neurodevelopmental disorders: Contributions to a newframework from the cognitive neurosciences (pp. 65–110). Cambridge,MA: MIT Press.

Meyers, J. E., & Meyers, K. R. (1995). Rey complex figure test and recog-nition trial: Professional manual. Odessa: Psychological AssessmentResources Inc.

Morris, C. A., Dempsey, S. A., Leonard, C. O., Dilts, C., & Blackburn, B.L. (1988). Natural history of Williams syndrome: Physical characteristics.Journal of Paediatrics Medicines, 113, 318–326.

Nickerson, E., Greenberg, F., Keating, M. T., McCaskill, C., & Schaffer, L.G. (1995). Deletion of the elastin gene at 7q11.23 occur in ∼90% ofpatients with Williams syndrome. American Journal of Human Genetics,56, 1156–1161.

Osterrieth, P. A. (1944). Le test de copie d’une figure complexe. Archives dePsychologie, 30, 206–356.

Proschel, C., Blouin, M. J., Gutowski, N. J., Ludwig, R., & Noble, M. (1995).Limk1 is predominantly expressed in neural tissues and phosphorylatesserine, threonine and tyrosine residues in vitro. Oncogene, 11, 1271–1281.

Rey, L. B. (1941). L’examen psychologique dans les cas d’encephalopathietraumatique. Archives de Psychologie, 28, 286–340.

Rosso, S., Bollati, F., Bisbal, M., Peretti, D., Sumi, T., Nakamura, T., etal. (2004). LIMK1 regulates Golgi dynamics, traffic of Golgi-derivedvesicles, and process extension in primary cultured neurons. MolecularBiology of the Cell, 15, 3433–3449.

Rouleau, I., Salomon, D. P., Butters, N., Kennedy, C., & Maguire, K. (1992).Qualitative and qualitative analyses of clock face drawing in Alzheimer’sand Huntingdon’s diseases. Brain and Cognition, 18, 70–87.

Tager-Flusberg, H., Boshatt, J., & Baron-Cohen, S. (1998). Reading thewindows to the soul: Evidence of domain specific sparing in Williams

T

T

W

W

W

W

ing developmental disorders. Trends in Cognitive Sciences, 2(10), 389–398.

armiloff-Smith, A., Grant, J., Ewing, S., Carette, M. J., Metcalfe, K.,Donnai, D., et al. (2002). Using case study comparisons to explore geno-type/phenotype correlations in Williams–Beuren syndrome. Journal ofMedical Genetics, 39, 0–4.

ezak, M. D. (1995). Neuropsychological assessment (3rd ed.). New York:Oxford University Press.

owery, M. C., Morris, C. A., Ewart, A. K., Brothman, L. J., Zhu, X. L.,Leonard, C. O., et al. (1995). Strong correlation of elastin deletions,detected by FISH, with Williams syndrome: Evaluation of 235 patients.American Journal of Human Genetics, 57, 49–53.

cCloskey, M., Rapp, B., Yantis, S., Rubin, G., Bacon, W. C., Gordon, B.,et al. (1995). A developmental deficit in localizing objects from vision.Psychological Science, 6, 112–117.

eng, Y., Zhang, Y., Tregoubov, V., Janus, C., Cruz, L., Jackson, M., etal. (2002). Abnormal spine morphology and enhanced LTP in LIMK-1knockout mice. Neuron, 35, 121–133.

syndrome. Journal of Cognitive Neurosciences, 10, 631–639.assabehji, M., Metcalfe, K., Karmiloff-Smith, A., Carette, M. J., Grant,

J., Dennis, N., et al. (1999). Williams syndrome: Use of chromosomalmicrodeletions as a tool to dissect cognitive and physical phenotypes.American Journal of Human Genetics, 64, 118–125.

aylor, L. B. (1979). Psychological assessment of neurosurgical patients. InT. Rasmussen & R. Marino (Eds.), Functional neurosurgery. New York:Raven Press.

ang, P. P., Doherty, S., Rouke, S. B., & Bellugi, U. (1995). Unique profileof visuo-perceptual skills in a genetic syndrome. Brain and Cognition,29, 54–65.

echsler, D. (1999). Wechsler abbreviated scale of intelligence manual. NewYork: The Psychological Corporation.

illiams, J. C. P., Barratt-Boyes, B. G., & Lowe, J. B. (1961). Supravalvularaortic stenosis. Circulation, 24, 1311–1318.

ilson, B. A., Cockburn, J., Halligan, P. (1987). Behavioural inattention test.Titchfield, Fareham, Hants, England: Thames Valley Test Co.: NationalRehabilitative Services.