22q11 Deletion Syndrome Neuropsychological and Neuropsychiatric Correlates

Neuropsychological and Neuropsychiatric

Correlates

A Clinical Study of 100 Cases

Lena Niklasson

Institute of Neuroscience and Physiology Child and Adolescent Psychiatry

22q11 Deletion Syndrome

Neuropsychological and Neuropsychiatric Correlates A Clinical Study of 100 Cases

Lena Niklasson

Institute of Neuroscience and Physiology, Child and Adolescent Psychiatry, Göteborg University, Sweden

ABSTRACT

Objectives: Examine the prevalence and type of Autism Spectrum Disorder (ASD) and

Attention-'H¿FLW+\SHUDFWLYLW\'LVRUGHU$'+'/HDUQLQJ'LVDELOLW\/'EHKDYLRXUDOSUR¿OHLQWHOOHFWXDO DELOLW\SUR¿OHDQGH[HFXWLYHIXQFWLRQLQT'HOHWLRQ6\QGURPHT'6DQGWRVWXG\WKHLPSDFW RI$'+'DQG$6'RQWKHVHIXQFWLRQV Methods: 2QHKXQGUHGLQGLYLGXDOVIHPDOHPDOH\HDUVRIDJHZLWKT'6FRQ¿UPHG E\),6+DQDO\VLVZHUHLQFOXGHG7KH\ZHUHWKH¿UVWUHIHUUHGT'6FDVHVRIZKRPFDPH IURPDPXOWLGLVFLSOLQDU\WHDPDVSDUWRIURXWLQHT'6DVVHVVPHQWVDQGZHUHUHIHUUHGGLUHFWO\WR D&KLOG1HXURSV\FKLDWU\&OLQLFIRUOHDUQLQJDQGRUEHKDYLRXUSUREOHPV1HXURSV\FKRORJLFDOHYDOXD-WLRQPDGHXVHRIDWHVWEDWWHU\GHVLJQHGWRSURYLGHLQIRUPDWLRQFRQFHUQLQJGHYHORSPHQWDOLQWHOOHFWXDO OHYHODQGSUR¿OHYLVXRPRWRUGHYHORSPHQWH[HFXWLYHIXQFWLRQVSODQQLQJDELOLW\DQGDWWHQWLRQDQG PHQWDOLVDWLRQVNLOOV1HXURSV\FKLDWULFDVVHVVPHQWVLQFOXGHGVWUXFWXUHGDQGVHPLVWUXFWXUHGLQWHUYLHZV with parent(s), an evaluation of the individual including psychiatric assessment, physical examination, DQG DJHDSSURSULDWH QHXURORJLFDO H[DPLQDWLRQ 3DUHQWV FRPSOHWHG WKH $XWLVP 6SHFWUXP 6FUHHQLQJ Questionnaire, the Conners Brief Parent Rating Scale, the Child Behavior Checklist, and the Five 7R)LIWHHQ)7)TXHVWLRQQDLUH&RPSUHKHQVLYHGLDJQRVHVRI$6'DQG$'+'ZHUHPDGHE\DSV\-chiatrist according to the DSM-IV taking the results of the various examinations (interview, medical H[DPLQDWLRQVREVHUYDWLRQDQGWKH)7)TXHVWLRQQDLUHLQWRDFFRXQW Results: 7KHSUHYDOHQFHRI$6'DQGRU$'+'ZLWKRUZLWKRXW/'ZDVRIZKRPKDG$' +'³RQO\´$6'³RQO\´DQGDFRPELQDWLRQRIWKHVHWZRGLDJQRVHV,QDGGLWLRQKDG/' ³RQO\´PHDQLQJWKDWWKHUHZHUHZLWKRXWDQ\RIWKHVHGLDJQRVHV$XWLVWLFGLVRUGHUZDVIRXQGWR EHTXLWHUDUH2WKHUSV\FKLDWULFGLDJQRVHVZHUHIRXQGPDLQO\DPRQJWKHDGXOWV$OWRJHWKHU PHWFULWHULDIRU/'DQGWKHPHDQ,4ZDVZLWKDQRUPDOGLVWULEXWLRQDURXQGWKLVPHDQ+LJKHU,4 IRUIHPDOHVFRPSDUHGWRPDOHVDQGDQHJDWLYHWUHQGIRU,4ZLWKLQFUHDVLQJDJHZHUHIRXQG$QRYHU-UHSUHVHQWDWLRQRIJLUOVZDVIRXQGRQO\LQWKHJURXSZLWKRXW$6'$'+'/',QWKHVFKRRODJHJURXS DQGLQWKHDGXOWJURXSVLJQL¿FDQWO\KLJKHUYHUEDO,4WKDQSHUIRUPDQFH,4ZDVIRXQG,QFRQWUDVWLQ WKH\RXQJHVWJURXSWKHORZHVWUHVXOWZDVIRXQGLQWKH³+HDULQJDQG6SHHFK´VXEVFDOH*ULI¿WKV0HQ-WDOVFDOHUHÀHFWLQJDGHOD\LQH[SUHVVLYHODQJXDJHLQWKHHDUO\\HDUV7KHVWUHQJWKZLWKLQWKHYHUEDO DUHDZDVPDLQO\GXHWRJRRG9RFDEXODU\'H¿FLWVLQSHUIRUPDQFHDELOLW\ZHUHIRXQG7KHLQWHOOHFWXDO DQGWKHYLVXRPRWRULPSDLUPHQWVZHUHUHODWHGWRT'6SHUVHZKLOHWKHSUHVHQFHRI$6'$'+' KDGDQHJDWLYHLPSDFWRQSODQQLQJDELOLW\LQFKLOGUHQ7KHDELOLW\WRVXVWDLQDWWHQWLRQZDVIRXQGWREH FULWLFDOO\LPSDLUHGLQVFKRRODJHFKLOGUHQZLWKT'6$FFRUGLQJWRUHVXOWVRIWKHTXHVWLRQQDLUHV DYDULHW\RIEHKDYLRXUSUREOHPVZHUHUHSRUWHG$FKDUDFWHULVWLFFRPELQDWLRQRILQLWLDWLQJGLI¿FXOWLHV DQGD³ODFNRIPHQWDOHQHUJ\´ZDVREVHUYHGLQWKHPDMRULW\

Discussion and conclusions: 7KHYDVWPDMRULW\RIDOOZLWKT'6KDGEHKDYLRXUDQGRUOHDUQLQJ SUREOHPVDQGPRUHWKDQPHWFULWHULDIRUHLWKHU$6'$'+'RUERWKHYHQWKRXJKW\SLFDODX-WLVWLFGLVRUGHUZDVUDWKHUXQFRPPRQ+DOIWKHJURXSKDG/'7KHPDMRULW\RIWKHJURXSZLWK,4LQ WKHQRUPDOWRORZQRUPDOUDQJHKDGOHDUQLQJGLI¿FXOWLHV0DQ\LQGLYLGXDOVZLWKT'6KDGVRFLDO LQWHUDFWLRQGLI¿FXOWLHVWKDWLQWKHSUHVHQFHRIUHODWLYHO\JRRGZRUGVNLOOVDSSHDUHGWREHUHODWHGWR LQLWLDWLRQSUREOHPVDQGODQJXDJHXVHGH¿FLWV*LYHQWKHKLJKUDWHDQGYDULHW\RISUREOHPVIRXQGDQHX-ropsychiatric assessment, including neuropsychological testing, should be performed in all cases of T'66XFKDVVHVVPHQWZLOOSURYLGHHVVHQWLDOLQIRUPDWLRQDERXWVWUHQJWKVDQGGLI¿FXOWLHVFUXFLDO IRUSURYLGLQJRSWLPDOVXSSRUWIRULQGLYLGXDOVZLWKT'6

Key words:T'HOHWLRQ6\QGURPH$XWLVP6SHFWUXP'LVRUGHU$WWHQWLRQ'H¿FLW+\SHUDFWLYLW\ Disorder, Learning Disability, neuropsychology

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Strengths and limitations 5

Research implications 57

Clinical implications 58

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INTRODUCTION

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Historical background

,QWKHFKURPRVRPDOGHOHWLRQZDVUHSRUWHGLQDVVRFLDWLRQZLWKWKUHHGLVWLQFW syndromes, namely DiGeorges Syndrome (DGS), Velo-Cardio-Facial Syndrome 9&)6DQG&RQRWUXQFDO$QRPDO\)DFH6\QGURPH&$)6'ULVFROOHWDO 6FDPEOHU HW DO  %XUQ HW DO  '*6 ZDV RULJLQDOO\ FKDUDFWHUL]HG E\ &RQJHQLWDO +HDUW 'HIHFWV &+' K\SRSDUDWK\URLGLVP DQG LPPXQH GH¿FLHQF\ 'L*HRUJHHWDO9&)6ZDVDVVRFLDWHGZLWKFOHIWSDODWH&+'DQRPDORXV IDFHDQGOHDUQLQJGLI¿FXOWLHV6KSULQW]HQHWDODQG&$)6ZDVFKDUDFWHU-L]HGE\FRQRWUXQFDO&+'DQGDGLVWLQFWIDFLDODSSHDUDQFH.LQRXFKLHWDO 7KHVHWKUHHFOLQLFDOV\QGURPHVKDYHRYHUODSSLQJV\PSWRPSUHVHQWDWLRQVDQGVKDUH DFRPPRQFKURPRVRPDOGHOHWLRQ7KXVT'6UHÀHFWVYDULRXVRXWFRPHVRIWKH VDPHXQGHUO\LQJJHQHWLFGHIHFW

The genetics of 22q11DS

7KHJHQHWLFGLDJQRVLVRIT'6FDQEHHVWDEOLVKHGRQWKHEDVLVRIDEORRGWHVWXV- LQJÀXRUHVFHQFHLQVLWXK\EULGL]DWLRQ),6+DQDO\VLV'ULVFROOHWDO6FDP-EOHU HW DO  7KLV PHWKRG SLFNV XS DSSUR[LPDWHO\  RI LQGLYLGXDOV ZKR have the deletion meaning that there are some individuals where the deletion is not LGHQWL¿HGRUZKHUHDQDW\SLFDOGHOHWLRQRFFXUV*RWKHOIDQG/RPEURVR,QD PDMRULW\RIFDVHVWKHGHOHWLRQRFFXUVSRQWDQHRXVO\RUde novo+RZHYHULQDERXW  WKHUH KDV EHHQ IDPLOLDO WUDQVPLVVLRQ RI WKH GHOHWLRQ 5\DQ HW DO  6ZLOOHQHWDO'LJLOLRHWDO7KHPRGHRILQKHULWDQFHLVDXWRVRPDO GRPLQDQWPHDQLQJWKDWZLWKRQHDIIHFWHGSDUHQWWKHUHLVDULVNRIWUDQVPLW-WLQJWKHGHOHWLRQ7KHORQJDUPRIFKURPRVRPHLVULFKLQJHQHVDQGPDQ\RIWKH JHQHVPDSSLQJWRWKHGHOHWLRQKDYHEHHQVWXGLHGLQVRPHGHWDLO'HVSLWHWKHVHHI-IRUWVQRVLQJOHJHQHKDV\HWEHHQVKRZQWRSOD\DQ\VSHFL¿FFRUHUROHLQT'6 HYHQLIWKHUHKDYHEHHQPDQ\FDQGLGDWHJHQHV6FDPEOHUHWDO

The “physical phenotype” of 22q11DS

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Introduction  0F*LQQHWDO)*LYHQWKHGLYHUVHUHJLRQVRIWKHERG\DIIHFWHGLWLVUHDVRQ-DEOHWRDVVXPHWKDWWKHGLYHUVHIHDWXUHVVHHQLQT'6DUHFRQWULEXWHGE\DWOHDVW VHYHUDOLIQRWPDQ\JHQHV$QWVKHOHWDOTGHOHWLRQV\QGURPHLVDIWHU 'RZQV\QGURPHWKHPRVWIUHTXHQWJHQHWLFFRQGLWLRQDVVRFLDWHGZLWKFDUGLRYDV-FXODUDQRPDOLHV*RRGVKLSHWDO9HORSKDU\QJHDOLPSDLUPHQWLVRQHRIWKH very common features of the syndrome and is found in patients with or without FOHIWSDODWH,WOHDGVWRVSHHFKDEQRUPDOLWLHVPRVWRIWHQK\SHUQDVDOVSHHFKZKLFK LVRQHRIWKHPRVWW\SLFDOV\PSWRPVLQLQGLYLGXDOVZLWKWKHV\QGURPH0DQ\LQ-GLYLGXDOVZLWKT'6KDYHDFKDUDFWHULVWLFSDWWHUQRIPLOGO\G\VPRUSKLFIDFLDO appearance and is characterised by a prominent nose, a broad nasal bridge, bul-ERXVQDVDOWLSPDODUÀDWQHVVDQGKRRGHGH\HOLGV0F'RQDOG0F*LQQHWDO 0DWVRXNRHWDO

The “behavioural phenotype” of 22q11DS

$EHKDYLRXUDOSKHQRW\SHKDVEHHQGH¿QHGE\)OLQWDV³DEHKDYLRXUDOSDW-tern, including cognitive processes and social interaction style, consistently asso-FLDWHGZLWKDQGVSHFL¿FWRDV\QGURPHZLWKDFKURPRVRPDORUJHQHWLFDHWLRORJ\´ Finegan suggests that knowledge gained in research in behavioural phenotypes can play a critical role in syndrome delineation, illuminating intrasyndrome vari-ability, understanding intersyndrome similarities and differences, understanding brain-behaviour relationships and the genetic bases of behaviour, and informing FOLQLFDOPDQDJHPHQWDQGSUHYHQWLRQ)LQHJDQHWDO7KHEHKDYLRXUDOSKHQR- W\SHLQT'6LVYHU\FRPSOH[ZLGHDQGYDULDEOHLQWKHVDPHZD\DVWKHSK\VL-FDOIHDWXUHVRIWKHV\QGURPH,QGLYLGXDOVZLWKWKLVV\QGURPHDUHUHSRUWHGWRKDYHD characteristic behavioural phenotype regarding intelligence, language, behaviour, DQGSV\FKLDWULFGLVRUGHUV:DQJHWDO*ROGEHUJHWDO6ZLOOHQHWDO D*HUGHVHWDO0RVVHWDO)HLQVWHLQHWDO 3ULQ]LHHWDO0XUS\HWDO%DVVHWHWDO%HKDYLRXUVW\OHVUDQJ-ing from shyness and social withdrawal on the one hand to and impulsivity and GLVLQKLELWLRQRQWKHRWKHUKDYHEHHQUHSRUWHG*ROGLQJ.XVKQHUHWDO6ZLO-OHQHWDO7KHEHKDYLRXUDOSUR¿OHPRVWRIWHQUHSRUWHGE\SDUHQWVWHQGVWR be social relationship problems (especially problems in relation with peers), with-GUDZQEHKDYLRXUVDQGDWWHQWLRQSUREOHPV(OLH]HWDO6ZLOOHQHWDO :KHQDJURXSRIFKLOGUHQZLWKT'6ZDVFRPSDUHGZLWKDQRQT'6JURXS of children with learning disability and speech-language impairment, the only dif-IHUHQFHVQRWHGZHUHDKLJKHULQFLGHQFHRIZLWKGUDZDOLQWKHT'6JURXSDQG DJJUHVVLYHEHKDYLRXULQWKHFRPSDULVRQJURXS6ZLOOHQHWDO Neuropsychiatric disorders ³1HXURSV\FKLDWULFGLVRUGHUV´DUHGLDJQRVHGDQGGH¿QHGRQWKHEDVLVRIVSHFL¿F FRPELQDWLRQVRIYDULRXVGLI¿FXOWLHVPRVWFRPPRQO\LQDFFRUGDQFHZLWKWKH'60 ,9'LDJQRVWLFDQG6WDWLVWLFDO0DQXDORI0HQWDO'LVRUGHUVRUWKH,&' ,QWHUQDWLRQDO&ODVVL¿FDWLRQRI'LVHDVHV6RPHRIWKHSUHYDOHQWDQGPRVW researched neuropsychiatric disorders are Autism Spectrum Disorder (ASD) and $WWHQWLRQ'H¿FLW+\SHUDFWLYLW\'LVRUGHU$'+'.

 DSM-IV Autistic disorder VLPLODUWR,&' $$WRWDORIVL[RUPRUHLWHPVIURPDQGZLWKDWOHDVWWZR IURPDQGRQHHDFKIURPDQG

(1) qualitative impairment in social interaction

(a) marked impairment in the use of multiple nonverbal behaviours such DV H\HWRH\H JD]H IDFLDO H[SUHVVLRQ ERG\ SRVWXUHV DQG JHVWXUHV WR regulate social interaction

(b) failure to develop peer relationships appropriate to developmental level

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(d) lack of social and emotional reciprocity

(2) qualitative impairments in communication

(a) delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime)

ELQLQGLYLGXDOVZLWKDGHTXDWHVSHHFKPDUNHGLPSDLUPHQWLQWKHDELOLW\ to initiate or sustain a conversation with others

(c) stereotyped and repetitive use of language or idiosyncratic language (d) lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level

(3) restricted repetitive and stereotyped patterns of behaviour, inter-ests, and activities

(a) encompassing preoccupation with one or more stereotyped and re-stricted patterns of interest that is abnormal either in intensity or focus E DSSDUHQWO\ LQÀH[LEOH DGKHUHQFH WR VSHFL¿F QRQIXQFWLRQDO URXWLQHV and rituals

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DSM-IV criteria for PDD-NOS

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*LOOEHUJVSURSRVHG criteria for atypical autism

Autistic disorder’s social interaction criterion met plus a total of at least 4 symptoms but not full criteria for Autistic disorder or Gillberg’s Asperg-er syndrome met

Table 1. Diagnostic criteria for DSM-IV autistic disorder, DSM-IV PDD-NOS, and Gillberg´s atypical autism

ASD

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Introduction



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Table 2. Diagnostic criteria for Gillberg’s Asperger syndrome

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Asperger syndrome criteria

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-inability to interact with peers -lack of desire to interact with peers -lack of appreciation of social cues

-socially and emotionally inappropriate behaviour

$OODEVRUELQJQDUURZLQWHUHVWDWOHDVWRQHRIWKHIROORZLQJ -exclusion of other activities

-repetitive adherence more rote than meaning

,PSRVLWLRQRIURXWLQHVDQGLQWHUHVWVDWOHDVWRQHRIWKHIROORZLQJ -on self, in aspects of life

-on others

6SHHFKDQGODQJXDJHSUREOHPVDWOHDVWWKUHHRIWKHIROORZLQJGH-layed development

VXSHU¿FLDOO\SHUIHFWH[SUHVVLYHODQJXDJH -formal, pedantic language

-odd prosody, peculiar voice characteristics

LPSDLUPHQWRIFRPSUHKHQVLRQLQFOXGLQJPLVLQWHUSUHWDWLRQVRIOLWHUDO implied meanings

1RQYHUEDOFRPPXQLFDWLRQSUREOHPVDWOHDVWRQHRIWKHIROORZLQJ -limited use of gestures

FOXPV\JDXFKHERG\ODQJXDJH

-limited facial expression -inappropriate expression SHFXOLDUVWLIIJD]H

0RWRUFOXPVLQHVV

 AD/HD 7KHSUHYDOHQFHUDWHIRU$'+'LVPXFKKLJKHUWKDQIRU$6'DQGLVXVXDOO\UH-SRUWHGDWDERXWRIWKHJHQHUDOSRSXODWLRQRI6ZHGLVKVFKRROFKLOGUHQ.DGHVM| DQG*LOOEHUJ*LOOEHUJDQG5DVPXVVHQ,QGLYLGXDOVZLWK$'+'KDYH GH¿FLWVLQDWWHQWLRQLPSXOVHFRQWURODQGK\SHUDFWLYLW\7KHUHDUHWKUHHVXEW\SHV RI$'+'PDLQO\LQDWWHQWLYHPDLQO\K\SHUDFWLYHDQGWKHFRPELQHGVXEW\SH7D-EOH

Table 3. Diagnostic criteria for DSM-IV AD/HD

Inattention (six or more)

Hyperactivity /Impulsivity (six or more) often fails to give close attention to details

or makes careless mistakes in schoolwork, work, or other activities

RIWHQ ¿GJHWV ZLWK KDQGV RU IHHW RU VTXLUPV in seat

RIWHQ KDV GLI¿FXOW\ VXVWDLQLQJ DWWHQWLRQ LQ tasks or play activities

often leaves seat in classroom or in other situations in which remaining seated is ex-pected

often does not seem to listen when spoken to directly

often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to sub-MHFWLYHIHHOLQJVRIUHVWOHVVQHVV

often does not follow through on instruc-WLRQVDQGIDLOVWR¿QLVKVFKRROZRUNFKRUHV or duties in the workplace

RIWHQ KDV GLI¿FXOW\ SOD\LQJ RU HQJDJLQJ LQ OHLVXUHDFWLYLWLHVTXLHWO\

RIWHQKDVGLI¿FXOW\RUJDQL]LQJWDVNVDQGDF-tivities

is often "on the go" or often acts as if "driven by a motor"

often avoids, dislikes, or is reluctant to en-JDJH LQ WDVNV WKDW UHTXLUH VXVWDLQHG PHQWDO effort (such as schoolwork or homework)

often talks excessively

often loses things necessary for tasks or ac- WLYLWLHVHJWR\VVFKRRODVVLJQPHQWVSHQ-cils, books, or tools)

RIWHQ EOXUWV RXW DQVZHUV EHIRUH TXHVWLRQV have been completed *

is often easily distracted by extraneous stimuli

RIWHQKDVGLI¿FXOW\DZDLWLQJWXUQ

is often forgetful in daily activities RIWHQ LQWHUUXSWV RU LQWUXGHV RQ RWKHUV HJ butts into conversations or games) *

$(LWKHUVL[RUPRUHRIWKHIROORZLQJV\PSWRPVRILQDWWHQWLRQDQGRUVL[RUPRUHV\PSWRPVRIK\SHUDFWLYLW\LPSXOVLYLW\ KDYHSHUVLVWHGIRUDWOHDVWPRQWKVWRDGHJUHHWKDWLVPDODGDSWLYHDQGLQFRQVLVWHQWZLWKGHYHORSPHQWDOOHYHO %6RPHK\SHUDFWLYHLPSXOVLYHRULQDWWHQWLYHV\PSWRPVWKDWFDXVHGLPSDLUPHQWZHUHSUHVHQWEHIRUHDJH\HDUV &6RPHLPSDLUPHQWIURPWKHV\PSWRPVLVSUHVHQWLQWZRRUPRUHVHWWLQJVHJDWVFKRRO>RUZRUN@DQGDWKRPH '7KHUHPXVWEHFOHDUHYLGHQFHRIFOLQLFDOO\VLJQL¿FDQWLPSDLUPHQWLQVRFLDODFDGHPLFRURFFXSDWLRQDOIXQFWLRQLQJ (7KHV\PSWRPVGRQRWRFFXUH[FOXVLYHO\GXULQJWKHFRXUVHRID3HUYDVLYH'HYHORSPHQWDO'LVRUGHU6FKL]RSKUHQLDRURWKHU 3V\FKRWLF'LVRUGHUDQGDUHQRWEHWWHUDFFRXQWHGIRUE\DQRWKHUPHQWDOGLVRUGHUHJ0RRG'LVRUGHU$Q[LHW\'LVRUGHU'LV-VRFLDWLYH'LVRUGHURUD3HUVRQDOLW\'LVRUGHU V\PSWRPVRI³LPSXOVLYLW\

Introduction  Learning Disability /HDUQLQJ'LVDELOLW\/'0HQWDO5HWDUGDWLRQ05LVGH¿QHGDV)6,4LQLQ-GLYLGXDOVVKRZLQJIXQFWLRQDOLPSDLUPHQWDQGGH¿FLWVLQVRFLDODGDSWDWLRQ'60 ,9'HSHQGLQJRQWHVWVXVHGDQGWKHOHYHORILPSDLUPHQWUHTXLUHGIRUGLDJQRVLV SUHYDOHQFHUDWHVLQWKHJHQHUDOSRSXODWLRQUDQJHIURPDERXWWR*LOOEHUJ 0LOG/'LVGH¿QHGDV)6,4PRGHUDWH/'DV)6,4DQGVHYHUH /')6,4&KLOGUHQZLWK$6'DQGRU$'+'KDYHKLJKHUUDWHVRI/'WKDQ XQVHOHFWHGJURXSVIURPWKHJHQHUDOSRSXODWLRQ ASD in 22q11DS

6RFLDO VNLOOV GH¿FLWV LQFOXGLQJ ZLWKGUDZQ EHKDYLRXUV DQG VK\QHVV GLI¿FXOWLHV initiating and maintaining social interactions, and limited facial expressions, are FRPPRQO\ HQFRXQWHUHG LQ LQGLYLGXDOV ZLWK $XWLVP 6SHFWUXP 'LVRUGHUV $6' 6HYHUDOVWXGLHVUHSRUWHGWKDWWKHVHWUDLWVZHUHIRXQGLQLQGLYLGXDOVZLWKT'6 (OLH]HWDO*HUGHVHWDO6ZLOOHQHWDO'XULQJWKHODVW\HDUV $6'KDVEHHQUHSRUWHGLQVWXGLHVLQT'62XURZQJURXSZDV¿UVWWRUHSRUW RQWKHSUHYDOHQFHRI$6'LQT'6:HIRXQGWKDWRILQGLYLGXDOV met criteria for ASD, but only one individual met criteria for autistic disorder 1LNODVVRQHWDO,QDIXUWKHUVWXG\RISDWLHQWVDJHVWKURXJK\HDUV KLJKUDWHVRI$6'DQGSV\FKRWLFV\PSWRPV9RUVWPDQHWDO ZHUHIRXQG7KHFRQFOXVLRQGUDZQZDVWKDWDXWLVWLFDQGSV\FKRWLFGLVRUGHUVVKRXOG be considered to be main elements in the behavioural phenotype of children with T'6,QRQHVWXG\E\)LQHHWDOWKHSUHVHQFHRI$6'ZDVDVVHVVHGLQ DJURXSRIFKLOGUHQE\FDUHJLYHUVFUHHQLQJPHDVXUHVRI$6'EHKDYLRXUVIRO-lowed by ADI-R (Autism Diagnostic Interview-Revised) assessment in those with VFRUHVLQGLFDWLQJVLJQL¿FDQWOHYHOVRIVXFKEHKDYLRXUV$FFRUGLQJWR$',5DV-VHVVPHQWFKLOGUHQTXDOL¿HGIRUDGLDJQRVLVRI$6'DQGIRURIWKHVHRI the whole group) a diagnosis of autistic disorder was considered appropriate (Fine HWDO,QDQRWKHUUHFHQWVWXG\WKHSKHQRW\SHLQWZRJURXSVZLWKT'6 ZLWKRUZLWKRXW$6'ZHUHVWXGLHG,QWKHZKROHJURXSQ DJHUDQJH\HDUV  \HDUV  LQGLYLGXDOV  PHW FULWHULD EDVHG XSRQ $',5 IRU $6' RI ZKRPFKLOGUHQRIWKHZKROHJURXSPHWFULWHULDIRUDXWLVWLFGLVRUGHU,QWKLV VXEJURXSZLWK$6'KDGDFRRFFXUULQJSV\FKLDWULFGLVRUGHUFRPSDUHGZLWK LQWKHJURXSZLWKT'6³RQO\´$QWVKHOHWDO&RQYHUVHO\LQRQH VWXG\LQGLYLGXDOVZLWKDVWULFWGLDJQRVLVRIDXWLVPZHUHWHVWHGIRUTGHOH-WLRQ1RGHOHWLRQVZHUHIRXQGLQGLFDWLQJWKDWIRUDQLQGLYLGXDOZLWKFODVVLFDXWLVP LQWKHDEVHQFHRIRWKHULQGLFDWLRQVLWLVXQOLNHO\WKDWKHVKHZLOOKDYHT'6 2JLOYLHHWDO AD/HD in 22q11DS $WWHQWLRQGH¿FLWVDUHFRPPRQLQLQGLYLGXDOVZLWKT'6ZLWK$'+'UDWHVRI DERXWLQVHYHUDOVWXGLHV$QWVKHOHWDO*RWKHOIHWDO)HLQVWHLQHW DO3DSRORVHWDO2QHVWXG\RISDWLHQWVIRXQGPHWFULWHULDIRU $'+'*RWKHOIHWDO7KHUHZDVDVLJQL¿FDQWO\JUHDWHUSUHYDOHQFHRI $'+'LQWKH¿UVWGHJUHHUHODWLYHVRIWKHSDWLHQWVZLWK$'+'WKDQLQWKRVHZLWK-RXW7KHWZRJURXSVZLWKRUZLWKRXW$'+'KDGVLPLODU,4VFRUHVWRWDOYHUEDO and performance) and had similar average degree of severity of facial

dysmor-

SKLVPDQGFDUGLDFDQGFOHIWSDODWHDQRPDOLHV7KHFRQFOXVLRQGUDZQLQWKHVWXG\ ZDVWKDW$'+'LQT'6KDVDJHQHWLFEDFNJURXQGDQGWKDWWKHUHODWHGGHYHO-RSPHQWDOIDFWRUVDQGSK\VLFDOLOOQHVVHVSOD\DOHVVHUUROH

Other psychiatric diagnoses in 22q11DS

Psychiatric disorders have been reported as co-occurring to ASD but have also EHHQ DVVRFLDWHG ZLWK QRQ$'+'QRQ$6' LQ T'6  $Q[LHW\ GLVRUGHU DQG PRRGGLVRUGHUKDYHEHHQUHSRUWHGWREHFRPPRQ%DNHUHWDOIRXQGWKDW WKHUDWHVRIPRRGGLVRUGHUVDQGDQ[LHW\GLVRUGHUVZHUHVLJQL¿FDQWO\KLJKHULQWKH T'6JURXSWKDQLQ,4PDWFKHGFRQWUROV,QDQRWKHUVWXG\ RIFKLOGUHQDJHG\HDUVPHWWKH'60,9FULWHULDIRU2EVHVVLYH&RPSXO- VLYH'LVRUGHU2&'7KHPRVWFRPPRQ2&'V\PSWRPVZHUHUHODWHGWRDJJUHV-VLRQVRPDWLFZRUULHVUHSHWLWLYHTXHVWLRQLQJDQGFOHDQLQJ0RUHRYHULQGLYLGXDOV KDGSV\FKRWLFGLVRUGHU*RWKHOIHWDOE %LSRODUVSHFWUXPGLVRUGHUVDQGVFKL]RSKUHQLDKDYHDOVREHHQUHSRUWHGWREHFRP-PRQLQDGXOWVZLWKWKHV\QGURPH,QDJURXSRIDGXOWVPHW'60,9 criteria for bipolar spectrum disorders with full syndromal onset in late childhood RUHDUO\DGROHVFHQFH3DSRORVHWDO+LJKUDWHVRISV\FKRWLFGLVRUGHUVSDU-WLFXODUO\VFKL]RSKUHQLDKDYHEHHQUHSRUWHG*RWKHOIHWDO%DVVHWHWDO 8VLVNLQHWDO0XUSK\HWDO,QWKHVWXG\E\0XUSK\RXW RIRIDGXOWVZLWKT'6ZHUHIRXQGWRKDYHDSV\FKRWLFGLVRUGHURIZKRP PHW'60,9FULWHULDIRUVFKL]RSKUHQLD,QDGGLWLRQRIWKHVHDGXOWV KDGGHSUHVVLRQZLWKRXWSV\FKRWLFIHDWXUHV0XUSK\HWDO$YHU\LQWHUHVW-LQJTXHVWLRQLVLILWLVSRVVLEOHWRLGHQWLI\HDUO\ULVNIDFWRUVIRUWKHGHYHORSPHQWRI SV\FKRWLFGLVRUGHUV,QDUHFHQWVWXG\FKLOGUHQZLWKT'6DQGFRPSDULVRQ VXEMHFWVZLWKLGLRSDWKLFGHYHORSPHQWDOGLVDELOLW\PDWFKHGIRUDJHDQG,4XQGHU-went a baseline evaluation and after 5 years they underVXEMHFWVZLWKLGLRSDWKLFGHYHORSPHQWDOGLVDELOLW\PDWFKHGIRUDJHDQG,4XQGHU-went a follow-up evaluation *RWKHOIHWDO7KHWZRJURXSVKDGVLPLODUEDVHOLQHQHXURSV\FKLDWULFSUR-¿OHVEXWDWIROORZXSRIWKHVXEMHFWVZLWKT'6KDGGHYHORSHGSV\FKRWLF GLVRUGHUV DV FRPSDUHG ZLWK  RI FRPSDULVRQ VXEMHFWV ,Q WKH T'6 JURXS baseline sub threshold psychotic symptoms interacted with baseline symptoms of DQ[LHW\ DQG GHSUHVVLRQ WR SUHGLFW  RI WKH YDULDQFH LQ VHYHULW\ RI SV\FKRVLV DWIROORZXSHYDOXDWLRQ/RZHUEDVHOLQHYHUEDO,4ZDVDOVRDVVRFLDWHGZLWKPRUH VHYHUH SV\FKRWLF V\PSWRPV DW IROORZXS HYDOXDWLRQ ,Q DQRWKHU VWXG\ SV\FKRWLF V\PSWRPVZHUHIRXQGLQUHSRUWLQJUHFXUUHQWKDOOXFLQDWLRQVDQGZHUHDVVR-FLDWHGZLWKGHFUHDVHG9HUEDO,4LQDSUHDGROHVFHQWJURXSQ 'HEEDQpHWDO &RPSDUHGZLWKFKLOGUHQZLWKRXWSV\FKRWLFV\PSWRPVWKH\ZHUHSHUFHLYHG by their parent as more anxious-depressed and withdrawn, with reduced adaptive VRFLDOL]DWLRQVNLOOV$'+'PD\FRQVWLWXWHDULVNIDFWRUIRUWKHODWHUGHYHORSPHQW RIELSRODUGLVRUGHULQT'6&KLOGUHQZLWKT'6DQG$'+'ZHUHFRP-SDUHGZLWKDJURXSZLWKOHDUQLQJGLVDELOLW\DQG$'+'VKRZLQJQRGLIIHUHQFHVLQ UDWHRIPDQLFV\PSWRPVEHWZHHQWKHVHWZRJURXSV+RZHYHUWKHPDQLFV\PSWRPV IRXQGLQWKHT'6ZHUHUHODWHGWRIRXU&%&/VXEVFDOHVDQ[LHW\VRPDWL]DWLRQ thought and conduct problems) compared with only one (conduct problem) in the FRQWUROJURXS$QHMDHWDO

Introduction



The neuropsychology of 22q11DS

Assessing intellectual and developmental levels

7KHPHWKRGVPRVWIUHTXHQWO\XVHGIRUWKHDVVHVVPHQWRIRYHUDOOLQWHOOHFWXDOOHYHO WRGD\ DUH WKH :HFKVOHU VFDOHV 7KH\ DUH WUDQVODWHG DQG XVHG DOO RYHU WKH ZRUOG ZKLFKPDNHVLWSRVVLEOHWRFRPSDUHUHVXOWVIRXQGLQGLIIHUHQWFRXQWULHV:HFKVOHU GH¿QHGLQWHOOLJHQFHDV³WKHFDSDFLW\RIWKHLQGLYLGXDOWRDFWSXUSRVHIXOO\WRWKLQN UDWLRQDOO\DQGWRGHDOHIIHFWLYHO\ZLWKKLVRUKHUHQYLURQPHQW´:HFKVOHU 7KHUHDUHFXUUHQWO\WKUHHYHUVLRQVRIWKH:HFKVOHUVFDOHVWKDWDUHLQZLGHVSUHDGXVH LQ6ZHGHQWKH:336,5:HFKVOHU3UHVFKRRODQG3ULPDU\6FDOHRI,QWHOOLJHQFH 5HYLVHG:HFKVOHUWKH:,6&,,,:HFKVOHU,QWHOOLJHQFH7HVWIRU&KLOGUHQ :HFKVOHU  DQG WKH :$,65 :HFKVOHU $GXOW ,QWHOOLJHQFH 6FDOH 5HYLVHG :HFKVOHU  7KH VFDOHV SURYLGH PHDVXUHV RI JOREDO DELOLW\ )XOO VFDOH ,4  )6,4 ZLWK 9HUEDO 9,4 DQG SHUIRUPDQFH ,4 3,4 VXEVFRUHV  2Q WKH :,6& and the WAIS separate statistical factors can be derived as suggested by Kauf-PDQ9HUEDO&RPSUHKHQVLRQFRPSULVLQJWKHVXEWHVWV,QIRUPDWLRQ9RFDEXODU\ Comprehension and Similarities), Perceptual Organisation (Picture Completion, 3LFWXUH$UUDQJHPHQW%ORFN'HVLJQDQG2EMHFW$VVHPEO\DQG)UHHGRPIURP Dis-WUDFWLELOLW\ $ULWKPHWLF DQG 'LJLW 6SDQ ,Q DGGLWLRQ RQ WKH :,6&,,, WKHUH LV D IDFWRUFDOOHG3URFHVVLQJ6SHHG&RGLQJDQG6\PERO6HDUFK.DXIPDQ7KH .DXIPDQIDFWRUVDUHQRWLQFOXGHGLQWKH:336,5)RUWKH\RXQJHVWSUHVFKRRODJH group developmental scales have to be used for assessment of overall function-LQJGHYHORSPHQWDOOHYHO,Q6ZHGHQWKH*ULI¿WKV'HYHORSPHQWDOVFDOH*ULI¿WKV LVWKHPRVWZLGHO\XVHGPHWKRGIRUDVVHVVLQJFKLOGUHQRIDFKURQRORJLFDODQG PHQWDODJHRI \HDUVRIDJH ,QWHOOHFWXDODQGGHYHORSPHQWDOOHYHODQGSUR¿OHLQT'6 2QHRIWKHPRVWZHOOHVWDEOLVKHGIHDWXUHVRIT'6LVDJHQHUDOLQWHOOHFWXDOLP-SDLUPHQW0HDQ,4KDVEHHQUHSRUWHGWREHLQWKHORZERUGHUOLQHUDQJH6ZLOOHQ HWDO*HUGHVHWDO0RVVHWDO1LNODVVRQHWDOZLWKD EHOOVKDSHGGLVWULEXWLRQRIFDVHVDURXQGDPHDQRIDERXW7KHSUHYDOHQFHRI PHQWDOUHWDUGDWLRQ05OHDUQLQJGLVDELOLW\/'KDVEHHQUHSRUWHGWREH 0LOG /' )6,4  LV FRPPRQ ZKLOH VHYHUH /' )6,4  DSSHDUV WR EH UDUH6ZLOOHQHWDO0RVVHWDO*HUGHVHWDO1LNODVVRQHWDO 6HYHUDOVWXGLHVKDYHVKRZQDKLJKHU9,4FRPSDUHGZLWK3,46ZLOOHQHWDO *HUGHVHWDO0RVVHWDO:RRGLQHWDO1LNODVVRQHWDO 6XFKDSUR¿OHFDQEHVXJJHVWLYHRIVRFDOOHGQRQYHUEDOOHDUQLQJGLVDELOLW\ 5RXUNH0RVVLQDVWXG\RILQGLYLGXDOVZLWKWKHV\QGURPHIRXQGWKDW D EHWWHU ZD\ RI GHVFULELQJ WKH SUR¿OH LQ WHUPV RI D W\SLFDO GLVWULEXWLRQV RQ WKH .DXIPDQIDFWRUVFRUHV0RVVHWDO9HUEDO&RPSUHKHQVLRQZDVPXFKEHWWHU WKDQ3HUFHSWXDO2UJDQL]DWLRQ7KHFRQWUDVWEHWZHHQWKHVHWZRIDFWRUVZDVODUJHU WKDQWKHYHUEDOSHUIRUPDQFH,4VSOLW0XFKKDVEHHQPDGHRIWKHYHUEDO³VWUHQJWK´ LQ T'6 RQFH WKH FKLOGUHQ UHDFK VFKRRO DJH  3RVVLEO\ PDMRU SUREOHPV ZLWK visual-perceptual abilities have not been highlighted in the same way so far, even WKRXJKWKHUHKDYHEHHQVWXGLHVIRFXVLQJRQGH¿FLWVZLWKYLVXDOSHUFHSWXDODELOLWLHV /DMLQHVV2¶1HLOOHWDO6RELQHWDO6LPRQHWDO%HDUGHQHWDO /RZVFRUHVIRUWKHIDFWRU3HUFHSWXDO2UJDQLVDWLRQLQGLFDWHGH¿FLWVLQLQWH-

JUDWLQJYLVXDOVWLPXOLDQGQRQYHUEDOUHDVRQLQJDVZHOODVYLVXRVSDWLDOVNLOOV'H¿-

cient visuospatial skills, poor visual attention and problems with processing of new DQGFRPSOH[PDWHULDOZHUHGRFXPHQWHGLQDVPDOOVWXG\RISUHVFKRROFKLOGUHQ 6ZLOOHQHWDOE&KLOGUHQZLWKT'6LQDQRWKHUVWXG\SHUIRUPHGSRRUO\ compared with controls, on test of visual attentional orienting, visual enumeration DQG UHODWLYH QXPHULFDO PDJQLWXGH MXGJHPHQW 7KHVH SHUIRUPDQFH GH¿FLWV FRXOG QRW EH H[SODLQHG E\ D JOREDO GH¿FLW LQ SV\FKRPRWRU VSHHG 6LPRQ HW DO  &KLOGUHQZLWKT'6DQGFKLOGUHQZLWKDXWLVPVKRZHGVLPLODUGH¿FLWVLQIDFLDO PHPRU\/DMLQHV2¶1HLOOHWDO

Intellectual level in relation to gender and age in 22q11DS

6H[GLIIHUHQFHVLQFRJQLWLYHIXQFWLRQZHUHLQYHVWLJDWHGLQFKLOGUHQZLWKT'6 FRPSDUHGZLWKVLEOLQJVDQGQRQT'6FRQWUROV$QWVKHOHWDO7KHUH-VXOWV LQGLFDWHG WKDW ER\V ZLWK T'6 PD\ EH PRUH FRJQLWLYHO\ DIIHFWHG WKDQ JLUOV$QHJDWLYHDVVRFLDWLRQEHWZHHQDJHDQGFRJQLWLYHIXQFWLRQLQJZDVIRXQGLQ JLUOVEXWQRWLQER\V1HXURLPDJLQJLQYHVWLJDWLRQVKRZHGWKHVDPHVH[GLIIHUHQFHV RIIURQWDOOREHDVJHQHUDOO\VHHQLQJHQHUDOSRSXODWLRQER\V!JLUOVLQDOOJURXSV

Developmental aspects in 22q11DS

,QWKHSUHVFKRRO\HDUVGHYHORSPHQWDOGHOD\VRQPDMRUGHYHORSPHQWDOPLOHVWRQHV including speech and language, cognition and motor skills have been found (Gerdes HW DO  'HOD\HG VSHHFK DQG ODQJXDJH GHYHORSPHQW DUH ZHOO GRFXPHQWHG *ROGLQJ.XVKQHUHWDO6KHUHUHWDO*ODVHUHWDO3HUVVRQHW DO*HUGHVHWDO/DWHRQVHWRIYHUEDOVSHHFKZDVIRXQGLQDOOFKLOGUHQ ZKHQWKHQHXURGHYHORSPHQWDORXWFRPHZDVVWXGLHGLQDJURXSZLWKSUHVFKRRO FKLOGUHQ DJHV  WR  PRQWKV *HUGHV HW DO  ([SUHVVLYH ODQJXDJH ZDV more impaired than receptive language even after controlling for general intellec-WXDOOHYHO7KHJOREDOGHOD\VZHUHIRXQGWREHGLUHFWO\DVVRFLDWHGZLWKWKHT'6 and could not be explained by physical anomalies or therapeutic interventions such DVFDUGLDFVXUJHU\%HWZHHQWKHDJHRI±\HDUVDQLPSURYHPHQWLQH[SUHVVLYH ODQJXDJH LV W\SLFDOO\ REVHUYHG 6RORW HW DO  ,Q VFKRRODJHG FKLOGUHQ GLI-¿FXOWLHVKDYHEHHQUHSRUWHGLQDQXPEHURIOLQJXLVWLFGRPDLQVLQFOXGLQJV\QWD[ YRFDEXODU\FRQFHSWVZRUG¿QGLQJDEVWUDFWUHDVRQLQJDQGVWRU\UHWHOOLQJ6RORW HWDO3HUVVRQHWDO

Visuomotor integration skills

,QRQHVWXG\WKHSHUFHSWXDODQGYLVXRPRWRUDELOLW\RI\HDUROGFKLOGUHQ ZLWKT'6ZDVDVVHVVHG7KLVVFUHHQLQJWHVWLQFOXGHGWKHFRPSOHWLRQRIIRUP boards, block construction, geometric designs, bilateral integration and tactile dis-FULPLQDWLRQ$OOFKLOGUHQUHJDUGOHVVRIDJHIDLOHGWKHSHUFHSWXDODQGYLVXRPRWRU VFUHHQLQJ WHVW *ROGLQJ.XVKQHU HW DO  ,Q DQRWKHU VPDOOHU VWXG\ RI MXVW QLQHFKLOGUHQWKHPHDQJURXS]VFRUHRQWKH90,9LVXDO0RWRU,QWHJUDWLRQWHVW ZDVZLWKLQWKHZLGHUQRUPDOUDQJHDOWKRXJKRIWKHFKLOGUHQIHOOXQGHU 6'EH-ORZZKDWZRXOGEHH[SHFWHGDFFRUGLQJWRWKHLUDJH6ZLOOHQHWDOE

Executive functions

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Introduction



Areas included in executive function are planning, generation of strategies for DFWLRQDQGPRQLWRULQJRIEHKDYLRXURIUHVSRQVHWRHQYLURQPHQWDOIHHGEDFN([-HFXWLYHG\VIXQFWLRQFDQUHVXOWLQGLI¿FXOW\ZLWKSODQQLQJRUJDQLVDWLRQDQGXVLQJ VWUDWHJLHVZLWKDQLQDELOLW\WRXVHIHHGEDFNUHVXOWLQJLQDULJLGWKRXJKWSURFHVV Planning ability ,PSDLUPHQWVUHJDUGLQJSODQQLQJ7RZHURI/RQGRQZHUHIRXQGLQDJURXSZLWK DGXOWVZLWKT'6FRPSDUHGZLWK,4DJHDQGJHQGHUPDWFKHGFRQWUROV7KH T'6 JURXS ZDV OHVV DFFXUDWH LQ WKHLU SUREOHP VROYLQJ DELOLW\ DQG UHTXLUHG VLJQL¿FDQWO\PRUHPRYHVWRVROYHWKHSUREOHPVWKDQGLGWKHFRQWUROV7KHQXP-EHURIPRYHVUHTXLUHGWRFRPSOHWHWKHWDVNVLQFUHDVHGDVWKHGHJUHHRIGLI¿FXOW\ LQFUHDVHG+HQU\HWDO&RPSDULVRQEHWZHHQWZRJURXSVRIDGXOWVZLWK T'6RQHZLWKVFKL]RSKUHQLDDQGRQHZLWKRXWVKRZHGQRGLIIHUHQFHVPHDQ-LQJ WKDW WKH GLI¿FXOWLHV IRXQG ZHUH DVVRFLDWHG ZLWK T'6 DQG QRW UHODWHG WR VFKL]RSKUHQLDYDQ$PHOVYRRUWHWDO

Attention ability

7KHUHDUHPDQ\QHXURSV\FKRORJLFDODSSURDFKHVWRWKHDQDO\VLVRIYDULRXVDVSHFWV RI DWWHQWLRQ 0LUVN\ 0LUVN\ HW DO  SODFHV ³DWWHQWLRQ´ ZLWKLQ WKH EURDGHU FDWHJRU\RI³LQIRUPDWLRQSURFHVVLQJ´$FFRUGLQJWRWKHPRGHOE\0LUVN\DWWHQ-WLYHSURFHVVLQJLQYROYHVIRXUFRPSRQHQWVVXVWDLQDWWHQWLRQZKLFKUHIHUVWRWKH duration of an individuals response to a task stimulus; 2) focus-execute attention, ZKLFK PHDQV VHOHFWLQJ RU SD\LQJ DWWHQWLRQ WR D FULWLFDO VWLPXOXV  VKLIW DWWHQ-tion is the ability to change focus in an adaptive manner; and 4) encode attenDWWHQ-tion, ZKLFKDSSUR[LPDWHV³ZRUNLQJPHPRU\´0LUVN\HWDO'H¿FLWVLQVXVWDLQ- LQJDWWHQWLRQKDYHEHHQIRXQGLQFKLOGUHQDQG\RXQJDGXOWVZLWKT'6/HYDQ-GRZVN\HWDO7KH7UDLOPDNLQJWHVWZDVXVHGLQDQRWKHUVWXG\RIFKLOGUHQ ZLWKT'67KHUHVXOWVKRZHGDYHUDJHUHVXOWVIRUEULHIIRFXVHGDWWHQWLRQ7UDLO $ZKLOHWKHDELOLW\WRVKLIWDWWHQWLRQDQGFRJQLWLYHÀH[LELOLW\7UDLO%ZDVEHORZ DYHUDJH:RRGLQHWDO

Social and empathy skills

$SDUWIURPWKHUHSRUWHGFRRFFXUUHQFHRI$6'FKLOGUHQZLWKT'6KDYHEHHQ reported to have problems with communication, social interaction initiation and de-FUHDVHGUHSHUWRLUHRIIDFLDOH[SUHVVLRQ)LQHHWDO:RRGLQHWDO(OLH] HWDO([WUHPHVRIEHKDYLRXUKDYHEHHQUHSRUWHGVK\QHVVDQGZLWKGUDZDO DVZHOODVLPSXOVLYLW\DQGGLVLQKLELWLRQ6ZLOOHQHWDO*ROGLQJ.XVKQHUHW DO3UREOHPDWLFSHHUUHODWLRQVKLSVKDYHEHHQUHSRUWHGIURPVFKRRODJHWR DGROHVFHQFH6ZLOOHQHWDOD

22q11DS in Sweden

6LQFHWKHUHKDVEHHQDPXOWLGLVFLSOLQDU\WHDPZLWKDUHPLWWRGLDJQRVHDQG HYDOXDWHWKHSKHQRW\SHRIT'6DWWKH4XHHQ6LOYLD&KLOGUHQ¶V+RVSLWDOSDUWRI 6DKOJUHQVND8QLYHUVLW\+RVSLWDOLQ*|WHERUJ6ZHGHQ7KHDLPKDVEHHQWRDVVHVV WKHVSHFWUXPDQGIUHTXHQF\RIYDULRXVV\PSWRPVDVVRFLDWHGZLWKWKHV\QGURPH Many aspects of the syndrome have been covered, including neuropsychiatric, neurologic, neurodevelopmental, cardiologic, immunologic, speech and language

 DVSHFWVHDUDQGKHDULQJH\HDQGYLVLRQIDFHPRUSKRORJ\DQG RUDOKHDOWK7KH SXUSRVHRIWKLVDVVHVVPHQWLVWRFUHDWHDEURDGNQRZOHGJHEDVLVRIHDFKLQGLYLGXDOV VSHFL¿FVWUHQJWKVDQGGLI¿FXOWLHVVRDVWRSURYLGHDQRSWLPDORSSRUWXQLW\IRUDG-HTXDWHPHGLFDOSV\FKLDWULFSV\FKRORJLFDQGHGXFDWLRQDOLQWHUYHQWLRQVRIYDULRXV NLQGV



AIMS OF THE PRESENT THESIS

7KHDLPVRIWKLVWKHVLVZHUHWR

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 LQYHVWLJDWHWKHJHQHUDOLQWHOOHFWXDOGHYHORSPHQWDODELOLW\DQGSUR¿OHDQG  YLVXRPRWRULQWHJUDWLRQVNLOOVLQT'6

· investigate executive functions, with a particular focus on attention and  SODQQLQJDELOLW\LQT'6DQG

 VWXG\WKHLPSDFWRI$'+'DQG$6'JHQGHUDQGDJHRQLQWHOOHFWXDODELOLW\  DQGSUR¿OHYLVXRPRWRULQWHJUDWLRQVNLOODQGH[HFXWLYHIXQFWLRQVLQWKH

25

METHODS

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Subjects

One hundred individuals were included in each of two of the substudies (II and ,97KHWDUJHWJURXSRIVXEVWXG\,FRQVLVWHGRIWKH¿UVWRIWKHVHLQGLYLGXDOV VHHQDWRXUFOLQLF,QVXEVWXG\,,,DOOFKLOGUHQLQWKHDJHUDQJHWDNHQIURP WKH¿UVWLQGLYLGXDOVVHHQZHUHLQFOXGHG)LJXUH

Table 4. Cases examined in each of the four substudies (I-IV)

Substudy I “Preliminary” II “Neuro-psychiatry” III “Attention” VI “Neuro-psychology” 7LWOHRIVXEVWXG\ ³&KURPR-VRPHT'6 &$7&+ Neuro-SV\FKLDWULF Neuro-psycholgical $VSHFWV´ ³$XWLVP $'+' Learning Disability and Behaviour Problems in ,QGLYLGXDOV ZLWKT'6´ ³$WWHQWLRQ 'H¿FLWVLQ Children with T'6´ ³7KH1HXUR psychology RIT'6 A Clinical 6WXG\RI ,QGLYLGXDOV´ n examined    

Age range years    

)HPDOHsPDOHV    

Paper I (Preliminary)

n=20

Paper III (Attention) n=30

Paper II (Neuropsychiatry)

and IV (Neuropsychology)

n=100

20

80

100

Methods  Substudy I ,QWKLVVXEVWXG\WKHJURXSH[DPLQHGFRPSULVHGWKH¿UVWFRQVHFXWLYHO\UHIHUUHG FDVHVRIT'6UHIHUUHGWRWKH&1&&KLOG1HXURSV\FKLDWU\&OLQLF)LJXUH $OOWRRNSDUWLQDPXOWLGLVFLSOLQDU\DVVHVVPHQWVWXG\DWWKH4XHHQ6LOYLD&KLO-GUHQ¶V+RVSLWDOLQ*|WHERUJ6ZHGHQ7KHDJHUDQJHLQWKLVJURXSZDV\HDUV RIDJHIHPDOHVDQGPDOHV  Substudy II and IV 7KHLQGLYLGXDOVLQFOXGHGLQWKHVHVXEVWXGLHVFRPSULVHGDOOWKH¿UVWFRQVHFXWLYH FDVHVRIT'6UHIHUUHGWRWKH&1&7KLVJURXSLQFOXGHGDOOFDVHVLQ6XEVWXG\ ,DQGDOOFDVHVLQ6XEVWXG\,,,)LJXUH$OOH[FHSWWZRRIWKHVHLQGLYLGXDOV ZLWKT'6WRRNSDUWLQDPXOWLGLVFLSOLQDU\DVVHVVPHQW1LQHW\WZRKDGEHHQ UHIHUUHGWRWKH&1&IURPWKH³T'6WHDP´IRUURXWLQHGHWDLOHGQHXURSV\FKL-DWULFQHXURSV\FKRORJLFDO DVVHVVPHQW ZKLFK FRQVWLWXWHG RQH ODUJH SRUWLRQ RI DOO WKHHYDOXDWLRQVSHUIRUPHGE\WKHT'6WHDPLQHDFKLQGLYLGXDOZLWKD),6+ FRQ¿UPHGGLDJQRVLVRIWKHGLVRUGHU(LJKWLQGLYLGXDOVKDGEHHQUHIHUUHGGLUHFWO\ WRWKH&1&IURPRWKHUVSHFLDOLVWVEHFDXVHRIOHDUQLQJDQGRUEHKDYLRXUSUREOHPV Various aspects of the syndrome were covered, including neurospychiatric, neu-rologic, neurodevelopmental, cardiologic, immunologic, speech and language, ear DQGKHDULQJH\HDQGYLVLRQIDFHPRUSKRORJ\DQGRUDOKHDOWKÏVNDUVGyWWLUHWDO DE3HUVVRQHWDO.OLQJEHUJHWDO )RUW\HLJKWRIWKHLQGLYLGXDOVKDGEHHQUHIHUUHGIURPWKH:HVWHUQ*|WDODQG 5HJLRQLQZHVWHUQ6ZHGHQDQGWKHUHPDLQGHUIURPRWKHUSDUWVRI6ZHGHQ$WWKH WLPHRIWKHVWXG\SDUHQWVPRWKHUDQGIDWKHURIWKHFKLOGUHQ\RXQJDGXOWVZLWK T'6KDGEHHQWHVWHGIRUWKHGHOHWLRQ,Q¿YHRIWKHVHRQHRIWKHSDUHQWVDOO PRWKHUVWHVWHGSRVLWLYH,QWKHXQWHVWHGJURXSWKHUHZHUHLQGLYLGXDOVZKRKDGD SDUHQWZLWKDFOLQLFDOVXVSLFLRQRIT'6

Age and gender

7KHPDMRULW\RIWKHSDUWLFLSDQWVZHUHLQWKHVFKRRODJHSHULRG\HDUVRI DJHZKLOHZHUHDJHG\HDUVRUXQGHUDQGZHUH\HDUVRUROGHU7DEOH

Background information regarding the substudy groups II and IV

7KHPRVWFRPPRQUHIHUUDOVRXUFHVWRWKHPXOWLGLVFLSOLQDU\WHDPZHUHVSHHFKSD-WKRORJ\FOHIWSDODWHWHDPSDHGLDWULFFDUGLRORJ\DQGFKLOGQHXURORJ\ 7KHUHPDLQGHUKDGEHHQUHIHUUHGIURPJHQHUDOSDHGLDWULFVFKLOGQHXURSV\FKLDWU\

Table 5. Age range and gender of 100 individuals with 22q11DS

Age range years All n=100 Female n=58 Male n=42 ” 22        22   •    

27

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$ FRQJHQLWDO FDUGLRYDVFXODU DQRPDO\ KDG EHHQ FRQ¿UPHG LQ  LQGLYLGXDOV  IHPDOHVPDOHVDQGRIWKHVHKDGXQGHUJRQHFDUGLDFVXUJHU\&OHIWSDODWHKDG EHHQFRQ¿UPHGLQLQGLYLGXDOV7ZRRIWKHVHKDGFOHIWOLSDQGWZRFOHIWOLSDQG SDODWH9HORSKDU\QJHDOLQVXI¿FLHQF\GXHWRFOHIWSDODWHGHHSSKDU\Q[RUSKD-U\QJHDOK\SRWRQLDZDVIRXQGLQLQGLYLGXDOV7KUHHLQGLYLGXDOVKDG&HUHEUDO 3DOV\DQG¿YHFKLOGUHQKDGKHDULQJLPSDLUPHQWUHTXLULQJKHDULQJDLG Substudy III

7KLUW\ FKLOGUHQ PDUNHG ZLWK x LQ )LJXUH  LQ WKH DJHUDQJH  \HDUV ZHUH LQFOXGHG  IHPDOHV  PDOHV LQ VXEVWXG\ ,,, 7KHVH ZHUH DOO FKLOGUHQ LQ WKDW DJHUDQJHZKHQSDUWLFLSDQWVKDGEHHQLQFOXGHGLQWKHVWXG\

Methods

$ GHWDLOHG QHXURSV\FKLDWULFQHXURSV\FKRORJLFDO HYDOXDWLRQ ZDV SHUIRUPHG LQ RUGHUWRHOXFLGDWHWKHEHKDYLRXUDODQGFRJQLWLYHFKDUDFWHULVWLFVRIT'6$OO H[DPLQDWLRQV ZHUH SHUIRUPHG DW WKH &1& 7KURXJKRXW WKH VWXG\ D SV\FKLDWULVW and a psychologist worked closely together in order to make this evaluation as FRPSUHKHQVLYHDVSRVVLEOH7KHSV\FKRORJLVWVDZWKHFKLOGRUDGXOWVHSDUDWHO\IRU the neuropsychological evaluation or together with the parents (in cases of young FKLOGUHQZKHUHWKHVXSSRUWRIWKHSDUHQWVZDVQHFHVVDU\7KHSV\FKLDWULVWLQWHU-viewed the parents separately and examined the child alone or together with the SDUHQWV,QFDVHVRIDGXOWVLQIRUPDWLRQIURPWKHDGXOWVWKHPVHOYHVZDVFRPELQHG ZLWKLQIRUPDWLRQIURPWKHLUSDUHQWV)LQDOO\WKHSV\FKRORJLVWDQGWKHSV\FKLDWULVW saw the parents and their child together (or - in the case of adult patients - the adults WKHPVHOYHVIRUDSUHVHQWDWLRQRIDOOUHVXOWVIURPWKHGLIIHUHQWH[DPLQDWLRQV,QWKH diagnostic process all information from different examinations was considered important in the clinical evaluation of the individual, although neither the neuro- SV\FKRORJLFDOWHVWUHVXOWVQRUWKHUHVXOWVRQVHYHUDOFROODWHUDOLQIRUPDQWTXHVWLRQ-QDLUHVVHHEHORZZHUHLQFOXGHGLQWKHGLDJQRVWLFSURFHVVRI$6'DQG$'+'

Methods used in all substudies (I-IV)

,QRIWKHFDVHVWKHQHXURSV\FKLDWULFHYDOXDWLRQZDVFDUULHGRXWE\RQHRI two senior, experienced CNC clinicians (Christopher Gillberg and Peder Rasmus-VHQDQGLQWKHUHPDLQLQJE\RQHRIWKUHHSV\FKLDWULVWVIURPWKHVDPHFOLQLF Neuropsychiatric assessment

7KHQHXURSV\FKLDWULFHYDOXDWLRQLQFOXGHGH[WHQVLYHVWUXFWXUHGDQGVHPLVWUXFWXUHG LQWHUYLHZVZLWKWKHSDUHQWV,QWKHDGXOWJURXSERWKWKHSUREDQGVWKHPVHOYHVDQG

Methods

28

WKHLUSDUHQWVZHUHLQWHUYLHZHG7KHLQWHUYLHZV\VWHPDWLFDOO\FRYHUHGDVSHFWVRI heredity; medical factors pertaining to pregnancy, parturition, and the neonatal period; child’s early psychomotor and speech-language development and adapta-tion; physical health problems; behaviour; sustained attention and impulse control; ¿QHDQGJURVVPRWRUFRQWUROVRFLDOLQWHUDFWLRQVNLOOVHDWLQJDQGVOHHSLQJKDELWV $Q\VSHFL¿FSUREOHPVVXJJHVWLQJ$'+'$6'7RXUHWWHV\QGURPH2EVHVVLYH &RPSXOVLYH'LVRUGHU2&'2SSRVLWLRQDO'H¿DQWGLVRUGHU2''FRQGXFWGLVRU-GHURUDQ\RWKHU'60,9SV\FKLDWULFGLVRUGHUZHUHVSHFL¿FDOO\DVNHGIRUFRYHULQJ WKHDSSURSULDWH'60,9FULWHULDXVLQJD'60,9FKHFNOLVW7KHHYDOXDWLRQRIWKH child or adult affected included psychiatric assessment, a general thorough physi-FDOH[DPLQDWLRQDQGDFOLQLFDOQHXURORJLFDODJHDSSURSULDWHH[DPLQDWLRQ Questionnaires used 3DUHQWVFRPSOHWHGWKH$XWLVP6SHFWUXP6FUHHQLQJ4XHVWLRQQDLUH$664(KOHUV DQG*LOOEHUJ(KOHUV*LOOEHUJDQG:LQJ3RVVHUXGHWDOWKH &RQQHUV%ULHI3DUHQW5DWLQJ6FDOH%356&RQQHUVWKH&KLOG%HKDYLRU &KHFNOLVW&%&/$FKHQEDFKDQGWKH)LYH7R)LIWHHQ)7)TXHVWLRQQDLUH .DGHVM|HWDO2IWKHVHRQO\WKH)7)ZDVXVHGLQWKHGLDJQRVWLFSURFHVV ASSQ

7KH $664 LWHP VFDOH XVHG IURP  \HDUV RI DJH \LHOGV D UDQJH RI SRVVLEOH VFRUHVRIKLJKHUVFRUHVRIDERXWDQGDERYHRQWKHSDUHQW$664LQGLFDW-LQJDKLJKSUREDELOLW\RIDQ$6'(KOHUVHWDO Conners BPRS 7KH&RQQHUVLWHPVFDOHXVHGIURP\HDUVRIDJH\LHOGVDUDQJHRISRVVLEOH VFRUHVRI6FRUHVRIRUPRUHDUHVRPHWLPHVWDNHQDVDQLQGLFDWLRQWKDW DGLDJQRVLVRI$'+'VKRXOGEHFRQVLGHUHG&RQQHUV CBCL 7KH&%&/LWHPVFDOHXVHGIRUWKHDJHJURXS\HDUVFRPSULVHVVWDWHPHQWV UHODWHGWREHKDYLRXUDOHPRWLRQDOSUREOHPVGLYLGHGLQWRGRPDLQVZLWKGUDZQVR-matic complaints, anxious, social problems, thought problems, attention problems, GHOLQTXHQWEHKDYLRXUDJJUHVVLYHEHKDYLRXU7KUHHRIWKHVHGRPDLQVZLWKGUDZQ VRPDWLFFRPSODLQWVDQGDQ[LRXVDUHLQFOXGHGLQWKH,QWHUQDOL]LQJEHKDYLRXUVFDOH DQGWZRGHOLQTXHQWEHKDYLRXUDQGDJJUHVVLYHEHKDYLRXUDUHLQFOXGHGLQ([WHU-QDOL]LQJ EHKDYLRXU VFDOH 7KH 6ZHGLVK JHQHUDO SRSXODWLRQ PHDQ WRWDO VFRUHV IRU FKLOGUHQH[DPLQHGDERXW\HDUVDJRZDV6'IRUWKHQRUPJURXS \HDUVRIDJH/DUVVRQDQG)ULVN

)7)

7KH )7) TXHVWLRQQDLUH IRU WKH DJH JURXS  \HDUV FRPSULVHV  VWDWHPHQWV related to behavioural or developmental problems, yields a range of possible mean VFRUHVRIRQHDFKLWHPIURPHLJKWGRPDLQVPRWRUH[HFXWLYHIXQFWLRQVSHU-FHSWLRQPHPRU\ODQJXDJHOHDUQLQJVRFLDODQGHPRWLRQDOSUREOHPV.DGHVM|HW DO7KHQRUPVDUHUHODWHGWRJHQGHUDQGWRWKUHHGLIIHUHQWDJHEDQGV \HDUV\HDUVDQG\HDUV

 Neuropsychological assessment 7KHQHXURSV\FKRORJLFDODVVHVVPHQWZDVFDUULHGRXWE\WKHVDPHQHXURSV\FKROR-JLVW/1LQRIWKHFDVHV$QHXURSV\FKRORJLFDOWHVWEDWWHU\ZDVGHVLJQHGWR SURYLGHLQIRUPDWLRQFRQFHUQLQJLQWHOOHFWXDOOHYHODQGSUR¿OHYLVXRPRWRUGHYHO-RSPHQWH[HFXWLYHIXQFWLRQVDQGPHQWDOLVDWLRQVNLOOV'LIIHUHQWWHVWVZHUHFKRVHQ DFFRUGLQJWRWKHDJHRIWKHSDUWLFLSDQWV

A semistructured behavioural observation of all participants was performed dur- LQJWKHQHXURSV\FKRORJLFDOH[DPLQDWLRQV7KLVREVHUYDWLRQFRYHUHGDVSHFWVRIDW-tention, activity level and impulse control, social interaction, cooperation, emo-WLRQVSHHFKDQGODQJXDJH

'HYHORSPHQWDODELOLW\DQGSUR¿OH

7KH *ULI¿WKV 0HQWDO 'HYHORSPHQWDO 6FDOHV , DQG ,, ZDV DGPLQLVWHUHG WR WKH \RXQJHVWFKLOGUHQ6FDOH,FRQVLVWVRI¿YHVXEVFDOHV0RWRU3HUVRQDO6RFLDO+HDU- LQJDQG6SHHFK(\HDQG+DQGDQG3HUIRUPDQFH*ULI¿WKV,QVFDOH,,DQ-RWKHU VFDOH 3UDFWLFDO 5HDVRQLQJ LV LQFOXGHG DV ZHOO 6ZHGLVK QRUPV ZHUH XVHG $OLQcNHUPDQ%DQG1RUGEHUJ/7KHUHVXOWVDUHJLYHQLQGHYHORSPHQWDO DJHDQGDUHWUDQVIRUPHGLQWR'HYHORSPHQWDO4XRWLHQW'4 ,QWHOOHFWXDODELOLW\DQGSUR¿OH 7KHZLGHDJHUDQJHRIWKHSUREDQGVPDGHLWQHFHVVDU\WRXVHGLIIHUHQWWHVWV3V\FKR-PHWULFDVVHVVPHQWRIJHQHUDOLQWHOOHFWXDODELOLW\ZDVSHUIRUPHGLQDOOSDUWLFLSDQWV 7KH:HFKVOHU3ULPDU\DQG3UHVFKRRO6FDOHRI,QWHOOLJHQFH:336,5:HFKVOHU WKH:HFKVOHU,QWHOOLJHQFH6FDOHIRU&KLOGUHQ:,6&,,,:HFKVOHU WKH:HFKVOHU$GXOW,QWHOOLJHQFH6FDOH5HYLVHG:$,65:HFKVOHU%DUWIDL WKH9LQHODQG$GDSWLYH%HKDYLRXU6FDOHV6SDUURZHWDOZHUHXVHG DVFRQVLGHUHGDSSURSULDWHGHSHQGLQJRQWKHLQGLYLGXDOVDJHDQGLQWHOOHFWXDOIXQF-WLRQLQJ7KHWKUHH:HFKVOHU6FDOHVSURYLGHVPHDVXUHVRIJOREDOLQWHOOHFWXDODELOLW\ ±)XOOVFDOH,4)6,49HUEDO,49,4DQG3HUIRUPDQFH,43,4VXEVFRUHVDV ZHOODVLQGLYLGXDOVFRUHVRQHDFKVXEWHVW2QWKH:,6&,,,DQG:$,65IRXUDQG WKUHH UHVSHFWLYHO\ VWDWLVWLFDO IDFWRUV FDQ EH GHULYHG DV VXJJHVWHG E\ .DXIPDQ Verbal Comprehension (comprising the subtests Information, Vocabulary, Com-prehension and Similarities), Perceptual Organisation (Picture Completion, Pic-WXUH$UUDQJHPHQW%ORFN'HVLJQDQG2EMHFW$VVHPEO\)UHHGRPIURP Distract-ibility (Arithmetic and Digit Span), and Processing Speed on WISC-III (Coding DQG6\PERO6HDUFK.DXIPDQ2QWKH:$,65WKHVXEWHVW6\PERO6HDUFK LVQRWLQFOXGHGZKLFKPHDQVWKDWWKHIDFWRU3URFHVVLQJ6SHHGFDQQRWEHGHULYHG 7KH.DXIPDQIDFWRUVDUHQRWLQFOXGHGLQWKH:336,5

In two cases FSIQ could not be established due to severe medical problems in FRPELQDWLRQZLWKODFNRIODQJXDJH,QWKHVHWZRLQGLYLGXDOVZLWKFOLQLFDOPRGHU-ate and severe mental retardation, respectively), parts of the Vineland Adaptive %HKDYLRXUVFDOHVZHUHXVHG7KHVHWZRLQGLYLGXDOVZHUHH[FOXGHGIURPVWDWLVWLFDO DQDO\VLVFRQFHUQLQJ)6,4

Visuomotor integration skill

Methods



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Methods used in some substudies

Executive function

$WWHQWLRQIRFXVHQFRGHDWWHQWLRQ (III)

Four of the WISC-III subtests are considered to measure the focus and encode FRPSRQHQWRIDWWHQWLRQ0LUVN\HWDO7KHVHDUH$ULWKPHWLFDQG'LJLW6SDQ (included in the Kaufman factor Freedom from Distractibility) and Coding and 6\PERO6HDUFKLQFOXGHGLQWKH3URFHVVLQJ6SHHGIDFWRU

$WWHQWLRQIXQFWLRQVXVWDLQ (III)

Attention, with special focus on the ability to sustain attention, was measured by XVLQJWKH%HFNHU*R1R*RDQG&RQÀLFWWHVW%HFNHUHWDO7KLVWHVWEH-ORQJVWRWKHJURXSFRQWLQXRXVSHUIRUPDQFHWHVWV,QWKH*R1R*RFRQGLWLRQWKH FKLOG LV UHTXHVWHG WR UHVSRQG RQFH HYHU\ WLPH WZR VWLPXOL DUH SUHVHQWHG ,Q WKH &RQÀLFWFRQGLWLRQWKHFKLOGLVUHTXLUHGWRUHVSRQGFRQÀLFWLQJO\WZLFHZKHQRQH VWLPXOXV LV SUHVHQWHG DQG RQFH ZKHQ WZR VWLPXOL DUH SUHVHQWHG 7KHUH DUH WZR conditions (visual and auditory) and in both conditions reaction times, omissions DQGFRPPLVVLRQVDUHUHFRUGHG(DFKFKLOG¶VYDOXHLVFRPSDUHGSDLUZLVHZLWKWKH FRUUHVSRQGLQJDJHPDWFKHGQRUPDWLYHJURXS

$WWHQWLRQIXQFWLRQVSHHGDQGVKLIW (IV)

7KHVSHHGDQGDELOLW\WRVKLIWDWWHQWLRQZDVPHDVXUHGE\7UDLO0DNLQJ7HVW$DQG %6SUHHQ 6WUDXVVZKHUHWKHLQGLYLGXDOVZHUHDVNHGWRFRQQHFWQXPEHUV DQG OHWWHUV ZLWK D SHQFLO DV TXLFNO\ DV SRVVLEOH 7UDLO $ LV UHJDUGHG DV D PRUH VWUDLJKWIRUZDUGVSDWLDODUUDQJHPHQWWDVNZKLOH7UDLO%DOVRLQYROYHVGLYLGLQJDQG RUVKLIWLQJDWWHQWLRQ/H]DN

Planning ability (I and IV)

3ODQQLQJDELOLW\ZDVPHDVXUHGZLWKWKH7RZHURI/RQGRQ7HVW6KDOOLFH,Q WKLVWHVWWKHFKLOGLVUHTXHVWHGWR³ORRNDKHDG´WRGHWHUPLQHKRZWRUHDUUDQJHWKUHH pierced coloured beads from an initial position on two upright sticks to a new set of SUHGHWHUPLQHGSRVLWLRQVRQWZRRUPRUHVWLFNV7KHUHVXOWVDUHJLYHQDVQXPEHURI WULDOVFRUUHFWDQGD³UDZVFRUH´YL]WKHWLPHWDNHQWRFRUUHFWO\FRPSOHWHWKHSDW-WHUQFRQYHUWHGLQWRDJUDGHGVFDOHUHGXFHGE\WKHQXPEHURIDWWHPSWVWKHFKLOG QHHGVWRDFKLHYHWKHFRUUHFWFRQ¿JXUDWLRQ)RUWKHDGXOWVDPHQWDOYDULDQWZKHUH WKHFRORXUHGEHDGVDUHUHSURGXFHGLQDSLFWXUHZDVXVHG7KHUHVXOWVZHUHJLYHQLQ DQXPEHURIPRYHVIRUWKHWZRSDUWVDQGPRYHVDQGPHDQUHDFWLRQWLPHV IRUUHVSHFWLYHO\SDUWV

7KHRU\RIPLQG (I and II)

,QDVXEJURXSQ RIWKHLQGLYLGXDOVLQFOXGHGLQWKHVWXG\GLIIHUHQWWHVWVRI ³WKHRU\RIPLQG´DVDSSURSULDWHIRUDJHDQGGHYHORSPHQWZHUHXVHGWKH6PDUWLHV DQG6DOO\$QQHWDVNV)ULWK6WUDQJH6WRULHV+DSSp1RQPHQWDODQG 0HQWDO&DUWRRQV+DSSpHWDO,QWKHDJHUDQJH\HDUVIRXURI¿YHLQ-cluded children performed the Baron-Cohen Picture arrangement test and one the



6PDUWLHVDQG6DOO\$QQHWDVN,QWKHDJHUDQJH\HDUVHLJKWRIHOHYHQFKLOGUHQ performed the Strange Stories and three, due to low mental age, the Baron Cohen 3LFWXUH$UUDQJHPHQWWHVW)RXULQGLYLGXDOVZHUHLQWKHDJHRIRUDERYHWKUHHRI these performed Non-mental and Mental Cartoons and one was given the Strange 6WRULHVWHVW

:HDOVRXVHGWKH$XWLVP'LDJQRVWLF2EVHUYDWLRQ6FKHGXOH$'26/RUGHWDO LQDVXEJURXSEXWWKHUHVXOWVIURPWKRVHDVVHVVPHQWVZLOOEHUHSRUWHGVHSDUDWHO\

Neuropsychiatric diagnostic process

ASD and AD/HD diagnoses

&RPSUHKHQVLYHQHXURSV\FKLDWULFGLDJQRVHV$6'DQG$'+'ZHUHPDGHE\WKH SV\FKLDWULVWDFFRUGLQJWRWKH'60,9$PHULFDQ3V\FKLDWULF$VVRFLDWLRQ taking the results of the various examinations (interview, medical examinations, REVHUYDWLRQVDQGWKRVHRIRQHRIWKHSDUHQWTXHVWLRQQDLUHVVHHEHORZLQWRDF-FRXQW $6' FRPSULVHG DXWLVWLF GLVRUGHU $VSHUJHU V\QGURPH DQG $XWLVWLF/LNH &RQGLWLRQ $/& /'05 '&' $'+' DQG DXWLVWLF GLVRUGHU ZHUH GLDJQRVHG VWULFWO\LQDFFRUGDQFHZLWKWKH'60,9$/&ZDVGLDJQRVHGLQFDVHVPHHWLQJWKH VRFLDOFULWHULRQLHDWOHDVWVRFLDOV\PSWRPVIRUDXWLVWLFGLVRUGHUDQGWKHFULWHULD IRUDWOHDVWRQHPRUHRIWKHRWKHUWZR³WULDG´DUHDVFRPPXQLFDWLRQRUUHSHWLWLYH stereotyped behaviour) and had a total symptom score for autistic disorder of 4 or PRUHDQGGLGQRWPHHWFULWHULDIRUDXWLVWLFGLVRUGHURU$VSHUJHUV\QGURPH7KHVH FULWHULDDUHLQDFFRUGDQFHZLWKWKHEURDGFULWHULDRIWKH,&''60,9+RZHYHU given that these manuals do not supply an exact symptom algorithm, we felt the QHHGWRSURYLGHDVWULFWHUGH¿QLWLRQVRWKDWWKHSUHVHQWVWXG\PLJKWEHUHSOLFDWHGE\ IXWXUHVWXGHQWVRIT'6,QRXUVWXG\$'+'DQG$6'ZHUHQRWUHJDUGHGDV PXWXDOO\H[FOXVLYHGLDJQRVHV LD/MR diagnosis 'LDJQRVLVRI/'05ZDVGH¿QHGDVWKHFRPELQDWLRQRI)6,4'4and func-WLRQDOLPSDLUPHQWDQGGH¿FLWVLQVRFLDODGDSWDWLRQ:LWKLQWKLVJURXSRI/'05 FDVHVPLOG/'ZDVGH¿QHGDV,4PRGHUDWH/',4DQGVHYHUH/' IQ Ethics 7KHVWXG\ZDVDSSURYHGE\WKH5HVHDUFK(WKLFV&RPPLWWHHDWWKH)DFXOW\RI0HGL-FLQH*|WHERUJ8QLYHUVLW\6ZHGHQ,QIRUPHGFRQVHQWZDVREWDLQHGIURPSDUHQWV DQGIURPSDWLHQWVGHSHQGLQJRQDJHDQGDELOLW\WRDVVHQWFRQVHQW Statistical methods 7KHVWDWLVWLFDOPHWKRGVXVHGLQWKHGLIIHUHQWVXEVWXGLHVDUHGHWDLOHGEHORZXQGHU WKH 5RPDQ QXPHUDO RI HDFK VXEVWXG\ 7KH DQDO\VHV ZHUH SHUIRUPHG ZLWK 6$6 6WDWLVWLFDO$QDO\VHV6\VWHPRUZLWK6366

, 6WDWLVWLFDO DQDO\VHV ZHUH SHUIRUPHG XVLQJ QRQSDUDPHWULF WHVWV :LOFR[RQV UDQNVXPWHVW6SHDUPDQVUDQNFRUUHODWLRQWHVWDQGFRQ¿GHQFHLQWHUYDOVRU WWHVWLIGDWDZHUHIRXQGWREHQRUPDOO\GLVWULEXWHG

Methods



,,,QGHSHQGHQWJURXSVZHUHFRPSDUHGXVLQJ6WXGHQWVWWHVWDQG&KLVTXDUHWHVW :LOFR[RQQRQSDUDPHWULFWHVWZDVXVHGIRUFRPSDULVRQRIUDZVFRUHV)RUWHVWLQJ LQWHUDFWLRQEHWZHHQYDULDEOHV$129$ZHUHXVHG

(III) For variables where age norms are available raw scores have been trans-IRUPHGLQWR]VFRUHV:LOFR[RQQRQSDUDPHWULFWHVWZDVXVHGIRUFRPSDULVRQRI UDZVFRUHV

(IV) For variables where age norms are available raw scores were transformed into ]VFRUHV)RUFRPSDULQJLQWUD-LQGLYLGXDOUHVXOWVSDLUHGWWHVWDQGFRQ¿GHQFH LQWHUYDO ZHUH XVHG  $GMXVWPHQW IRU PXOWLSOH FRPSDULVRQ 7XNH\V 6WXGHQWL]HG 5DQJH+6'7HVWZDVPDGH



RESULTS

Neuropsychiatric and neuropsychologic aspects in the preliminary

study (I)

As can be seen under the results reported for substudies II and IV, it is clear that the ¿UVWDQGSUHOLPLQDU\UHVXOWVWKDWZHSXEOLVKHGLQWKHHDUO\\HDUVRIWKHst _century

IURPWKH¿UVWFKLOGUHQRIWKHFRKRUWZHUHTXLWHVLPLODUWRWKRVHWKDWZHUHSRUWHG DIWHUKDYLQJFRPSOHWHGRXUDVVHVVPHQWVRIWKHZKROHFRKRUWRIFDVHV

ASD/AD/HD and other psychiatric diagnoses

,QWKH¿UVWFRKRUWRIWKHLQGLYLGXDOVPHWFULWHULDIRU$6'$'+'RUD FRPELQDWLRQRIWKHVHGLDJQRVHV(OHYHQLQGLYLGXDOVKDG$'+'$'+' LQDWWHQWLYHVXEW\SHDQGFRPELQHGVXEW\SH2QHFKLOGKDGDXWLVWLFGLVRUGHU DQGVL[KDG$/&)LYHLQGLYLGXDOVKDGDFRPELQDWLRQRI$6'DQG $'+'$OOWKUHHDGXOWVLQWKLVVXEVWXG\KDGDSV\FKLDWULFGLVRUGHUZLWKDQ[LHW\ DVWKHLUPDLQFRPSODLQW7ZRRIWKHPPHWFULWHULDIRUDQ[LHW\GLVRUGHUDQGDOOWKUHH KDGDKLVWRU\RIRQHRUPRUHHSLVRGHVRIGHSUHVVLRQ7KUHHFKLOGUHQVKRZHGDYHU\ PDUNHGWHQGHQF\WRKDYHLQDSSURSULDWHDQ[LHW\UHDFWLRQV

Behaviour according to questionnaires

7KHWRWDOSUREOHPPHDQVFRUHRI&%&/ZDV6'ZKLFKZDVVLJQL¿FDQWO\ KLJKHUWKDQIRUWKHQRUPDWLYHJURXSPHDQ6'S7KHKLJKHVW problem scores were found in the clusters Attention problems, Aggressive behav-LRXUDQG6RFLDOSUREOHPV

7KH$664ZDVFRPSOHWHGLQFDVHV,QWKLVJURXSLQGLYLGXDOVKDGVFRUHVRI RUPRUHLQGLYLGXDOVZLWK$6'RQHZLWK$'+'³RQO\´DQGRQHZLWKQR QHXURSV\FKLDWULF GLDJQRVLV 1R FRUUHODWLRQ EHWZHHQ )6,4 DQG WKH $664 VFRUH ZDVIRXQG Intellectual ability IQdZDVIRXQGLQRIWKHLQGLYLGXDOV7KHPDMRULW\ZHUHLQWKH ,4UDQJHRIDQGRQO\ZHUHLQWKHUDQJHRI1RUPDO,4RUORZ QRUPDOLQWHOOHFWXDOOHYHO,4ZDVVHHQLQ¿YHLQGLYLGXDOVHDFK9,4ZDV VLJQL¿FDQWO\KLJKHUWKDQ3,4EXWWKHUHZHUHQRVLJQL¿FDQWGLVFUHSDQFLHVDFURVVWKH .DXIPDQIDFWRUV)LJXUH

Correlations between FSIQ and neuropsychiatric diagnoses, age and gender

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Results



Visuomotor integration skill

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Schooling

)LYH RI WKH HLJKW FKLOGUHQ RI VFKRRO DJH KDG DQ ,4   ZHUH LQ VSHFLDO FODVVHV IRUFKLOGUHQZLWKLQWHOOHFWXDOGLVDELOLWLHV$QRWKHU¿YHZLWKQRUPDORUORZQRUPDO LQWHOOLJHQFHKDGPDUNHGOHDUQLQJDQGRUEHKDYLRXUDOGLI¿FXOWLHVLQVFKRRO7KHVH children needed at least part-time support by an assistant or to attend a small group ZLWKH[WUDUHVRXUFHV

“Theory of Mind” test

,QWKHPDMRULW\LQGLYLGXDOVWKHUHVXOWVRIWKHVHWHVWVLPSOLHGVRPHGH¿FLWVZLWK-LQWKLVDUHD7KHUHZHUHWKUHHFKLOGUHQLQWKHDJHJURXS\HDUVRQHLQWKHDJH JURXSDQGRQHDGXOWZKRVXFFHHGHGLQVROYLQJWKHVHWHVWV+RZHYHUWKHZLGH DJHDQGGHYHORSPHQWDOOHYHOUDQJHPHDQWKDWWKLV¿QGLQJVPXVWEHDQDO\VHGZLWK FDXWLRQ

Figure 2. Distribution with regard to difference between Verbal IQ (VIQ) and

35

Autism, AD/HD and LD in the larger 100 cohort: “neuropsychiatry” (II)

Overall prevalence of ASD and AD/HD and overlap of ASD/AD/HD

Sixty-seven individuals had either ASD, AD/HD, LD or a combination of these diagnoses while the remainder (33 individuals) did not meet criteria for any of these diagnoses. There were 23 individuals with LD without ASD/AD/HD mean-ing that 44 individuals met criteria for ASD, AD/HD or a combination of the two with or without LD. Thirty individuals met criteria for AD/HD, 23 for ASD and 9 individuals had a combination of those two diagnoses. In the group with AD/HD 16 individuals had AD/HD the inattentive subtype while 14 individuals had the combined type. Five children had autistic disorder, 17 autistic-like condition and one Asperger syndrome of the group with ASD. In the ASD group two individuals with Autistic disorder and 7 with autistic-like condition also had AD/HD. In the group of 9 individuals with ASD+AD/HD 8 had AD/HD combined type and only RQH$'+'WKHLQDWWHQWLYHVXEW\SH¿JXUH7KHUDWHRI$6'$'+'ZDVQRW DIIHFWHGE\WKHH[LVWHQFHRIFDUGLRYDVFXODUDQRPDO\YHORSKDU\QJHDOLQVXI¿FLHQF\ or hearing impairment.

Fifty-one individuals had LD. The majority had mild LD, 8 moderate LD, and 1 severe LD (IQ<35). Mean IQ, for the 82 individuals assessed with the Wechsler scales, was 71 (SD 15). ADHD+ASD n=9 ADHD only n=21 ASD only n=14 ADHD/AD n=15 n=1 ADHD/HD n=6 n=8 Autistic disorder n=3 n=2 Autistic-like condition n=10 n=7 Asperger syndrome n=1 n=0

Figure 3. ASD, AD/HD and the overlap of these diagnoses All shaded areas indicate AD/HD in combination with ASD.

AD/HD/AD=AD/HD inattentive subtype AD/HD/HD=AD/HD combined subtype

Results



ASD diagnosis related to referral source

7KHUDWHRI$6'ZDV20LQWKHJURXSUHIHUUHGURXWLQHO\DVSDUWRIWKHPXO-WLGLVFLSOLQDU\DVVHVVPHQWZKLOHWKH$6'UDWHZDVLQWKHVPDOOVXEJURXS UHIHUUHGGLUHFWO\WR&1&GXHWREHKDYLRXUDQGRUOHDUQLQJSUREOHPV

ASD, AD/HD, and LD related to age

7KHUDWHRI$6'$'+'ZDVVLPLODULQWKHVXEJURXSVRIDGXOWV!\HDUVDQG FKLOGUHQ\HDUVRU\RXQJHU7KHGLDJQRVLVRI$'+'ZDVPRVWFRPPRQLQWKH DJHJURXS\HDUVRIDJH7DEOH

ASD/AD/HD and LD in relation to gender

7KHUHZHUHIHPDOHVRIWKHIHPDOHJURXSDQGPDOHV3RIWKHPDOH JURXSLQWKHJURXSRILQGLYLGXDOVZKRKDGHLWKHU$6'$' +'/'RUDFRPEL-QDWLRQRIWKHVHGLDJQRVHV,QWKHZKROHFRKRUW$6'³RQO\´ZDVIRXQGLQIHPDOHV DQGLQPDOHV$'+'³RQO\´ZDVIRXQGLQIHPDOHVDQG PDOHVDQGWKHFRPELQDWLRQRI$6'DQG$'+'LQIHPDOHVDQG PDOHV 7KHIHPDOHPDOHUDWLRVZLWKLQWKH$6'JURXSZDVDXWLVWLFGLVRUGHU$/& DQG$VSHUJHUV\QGURPH:LWKLQWKHJURXSZLWK$'+'WKHIHPDOHPDOHUDWLR ZDV$'+'PDLQO\LQDWWHQWLRQVXEW\SHDQG$'+'FRPELQHGVXEW\SH /'ZDVIRXQGLQIHPDOHVDQGLQPDOHV,QWKHJURXSZLWK $6'WKHUHZHUHIHPDOHDQGPDOHVZLWKRXW/'DQGLQWKH$'+'JURXSWKHUH ZHUHIHPDOHVDQGPDOHV RIZKRPKDGDFRPELQDWLRQZLWK$6'ZLWKRXW/'

Other psychiatric/neurodevelopmental diagnoses related to age

0RVWRIWKHGLDJQRVHVZHUHIRXQGDPRQJWKHDGXOWV7KUHHDGXOWVKDGDQ[LHW\GLV-RUGHURQHDGXOWSV\FKRVLVDQRWKHUWKUHHKDGDKLVWRU\RISV\FKRWLFV\PSWRPV2QH adult met criteria for depression but another 4 had a history of medication treated

Diagnosis All n=100 Age range ”\HDUV n=22 Age range 6-11 years n=40 Age range 12-16 years n=22 Age range •\HDUV n=16 $'+'³RQO\´  2   4 $6'³RQO\´   4 4  $'+'$6'  2 5   Autistic disorder 5     Autistic-Like Condition  4  4  Asperger syndrome      Mild MR 42    8 Moderate MR 8  2 5  Severe MR     

Table 6. ASD, AD/HD, and LD related to age



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DSM-IV triad domains (Autistic disorder) in 23 individuals with ASD

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DSM-IV symptom cluster domains (AD/HD) in 30 individuals with AD/HD

,QDWWHQWLYH V\PSWRPV PHDQ  6' ) were much more commonly endorsed WKDQ K\SHUDFWLYH V\PSWRPV PHDQ  6'  DQG LPSXOVLYH V\PSWRPV PHDQ 6'

Overall clinical impression

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7KHPHDQ&RQQHUV%356WRWDOVFRUHZDV6'Q ). Forty-four individuals KDGVFRUHVRIRUEHORZKDGVFRUHVLQWKHUDQJHRIDQGKDGVFRUHV t7ZHQW\HLJKWRIWKHLQGLYLGXDOVZLWK$'+'KDGFRPSOHWHGWKH&RQQHUV %356,QWKLVJURXSDVFRUHRIRUDERYHZDVIRXQGLQLQGLYLGXDOVZKLOH KDGVFRUHVEHORZWKLVOHYHO:LWKDFXWRIIVFRUHVRILQGLYLGXDOVKDGVFRUHV