The neuropsychology of 22q11 deletion syndrome. A neuropsychiatric study of 100 individuals

Research in Developmental Disabilities 31 (2010) 185–194

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Research in Developmental Disabilities

The neuropsychology of 22q11 deletion syndrome. A neuropsychiatric study of 100 individuals Lena Niklasson a,b,*, Christopher Gillberg a,b a b

Institute of Neuroscience and Physiology, Child and Adolescent Psychiatry, The Sahlgrenska Academy, University of Gothenburg, Go¨teborg, Sweden The Child Neuropsychiatry Clinic, The Queen Silvia Children’s Hospital, Otterha¨llegatan 12A, SE-411 18 Go¨teborg, Sweden

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 August 2009 Accepted 3 September 2009

The primary objective of this study was to study the impact of ASD/ADHD on general intellectual ability and profile, executive functions and visuo-motor skills in children and adults with 22q11 deletion syndrome (22q11DS). A secondary aim was to study if gender, age, heart disease, ASD, ADHD or ASD in combination with ADHD had an impact on general intellectual ability and profile. One hundred consecutively referred individuals aged 1–35 years with 22q11DS were given in-depth neuropsychological assessments. Mean full scale IQ was 71 with a normal distribution around this mean. Higher IQ for females than males, and a negative trend for IQ with higher age were found. Intellectual impairment, as well as visuo-motor dysfunction, was found to be related to 22q11DS per se and not to ASD/ADHD. In the area of executive function, the presence of ASD/ADHD predicted poor planning ability in the children in the study. ß 2009 Elsevier Ltd. All rights reserved.

Keywords: 22q11 deletion syndrome Intellectual ability Executive function ASD ADHD

1. Introduction The 22q11 deletion syndrome (22q11DS) has an estimated rate of approximately 1 in 4000 live births (Devriendt, Fryns, Mortier, van Thienen, & Keymolen, 1998; Oskarsdottir, Vujic, & Fasth, 2004). The diagnosis can be confirmed by Fluorescent In Situ Hybridization (FISH) technique (Driscoll, Budarf, & Emanuel, 1992). The most common physical findings associated with this chromosomal deletion include cardiac defects, palatal anomalies, immunodeficiency, hypoparathyroidism, a variety of minor physical anomalies, and a rather characteristic facial appearance (McDonald-McGinn et al., 1999; Oskarsdottir, Persson, Eriksson, & Fasth, 2005). General intellectual impairment is one of the best documented features of the syndrome. Several studies have shown attention deficits to be common in individuals with 22q11DS. In a recent study of 84 children, 43% were diagnosed with ADHD (Antshel et al., 2006). In another study of 51 patients with the syndrome (Gothelf et al., 2004), 41% were diagnosed with ADHD. In an earlier report (Papolos et al., 1996) (n = 25) 36% were found to meet DSM-IV criteria for ADHD. In a previous study from our group on 32 school age children—all of whom are included in the present study—we found DSM-IV ADHD (mainly inattentive subtype) in 44% (Niklasson, Rasmussen, Oskarsdottir, & Gillberg, 2001). Thus, on the basis of these small to moderate scale studies, ADHD appears to be present in about 40% of all young people with 22q11DS.

* Corresponding author at: The Child Neuropsychiatry Clinic, The Queen Silvia Children’s Hospital, Otterha¨llegatan 12A, SE-411 18 Go¨teborg, Sweden. Fax: +46 31848932. E-mail address: [email protected] (L. Niklasson). 0891-4222/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ridd.2009.09.001

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A high rate of Autism Spectrum Disorders (ASD) in 22q11DS has been documented (Niklasson et al., 2001). Since then, a few more studies have confirmed similarly high rates. In one study the presence of ASD was assessed by caregiver screening measures, followed by Autism Diagnostic Interview-Revised assessment in those with scores indicating significant levels of ASD behaviours. Of the 98 children, 20 exhibited significant levels of autism spectrum symptoms, 14 met criteria for ASD, and 11 of these had autistic disorder (11% of the whole group) (Fine et al., 2005). In another study (n = 60) 50% were found to have ASD (Vorstman et al., 2006). In yet another study the phenotype in two child groups with 22q11DS—17 with and 24 without ASD—was studied. In the subgroup with ASD, 94% had a co-occurring psychiatric disorder compared with 60% in the group with ‘‘22q11DS only’’. Children with 22q11DS + ASD had larger amygdala volumes while all other neuroanatomic regions of interest were statistically similar in the two groups (Antshel et al., 2007). Our own group recently performed a study where the prevalence of neuropsychiatric disorders and learning disability was investigated in the group with 100 individuals with the syndrome referred to in the present paper. In the whole group, only 5% met criteria for typical autistic disorder, but another 18% met criteria for another ASD. Forty-four individuals met criteria for ASD or ADHD or a combination of these diagnoses with or without LD. In this group 14% had ASD ‘‘only’’, 23% ADHD ‘‘only’’ and 9% a combination of ASD and ADHD (Niklasson, Rasmussen, Oskarsdottir, & Gillberg, 2009). A number of studies have looked at neuropsychological functioning in individuals with 22q11DS. The prevalence of Learning Disability/Mental Retardation, LD/MR, is about 50% (Moss et al., 1999; Niklasson, Rasmussen, Oskarsdottir, & Gillberg, 2002; Swillen et al., 1997). Mean IQ has been reported to be lower in those with inherited rather than de novo deletion (Swillen et al., 1997). Sex differences in cognitive function were investigated in children with 22q11DS compared with siblings and controls (Antshel, AbdulSabur, Roizen, Fremont, & Kates, 2005). Boys with 22q11DS were more cognitively affected than girls, and a negative association between age and cognitive functioning was found in the girls but not in boys. Delayed speech and language development is one of the consistent features in 22q11DS. The retelling ability was studied in 19 5- to 8-year-olds with the syndrome (Persson et al., 2006). The vast majority (17/19) had an information score of 1 SD below population mean, and the older the children the more severe the problems. Problems in initiating the story retelling were particularly pronounced. Low grammatical complexity, measured as number of coordinate clauses, was found in about 75% of the children. The phonological process appeared to be delayed rather than deviant. All studies published to date have referred to the low full scale IQ (FSIQ) of children with 22Q11DS. Some studies have reported that children with 22q11DS have higher verbal IQ (VIQ) than performance IQ (PIQ) (Niklasson et al., 2002; Swillen et al., 1997; Woodin et al., 2001). One study (Moss et al., 1999) suggested that a better way of dividing results would be according to the statistically derived factors elaborated by Kaufman: Verbal Comprehension and Perceptual Organization. A highly significant discrepancy between results on these two factors was found: 79.2  14.8 (Verbal Comprehension) versus 68.0  12.3 (Perceptual Organization) (p < 0.001). The contrast between these two factors was larger than the VIQ/PIQ discrepancy. For school aged children (n = 26) the highest mean scores were found on the Information, Comprehension, and Coding subtests, and the lowest scores on the subtests involving visual–perceptual abilities and planning (Picture Completion, Object Assembly, and Picture Arrangement). In one study, 19 adults with 22q11DS were compared with 19 age-, gender-, and IQ-matched controls using a comprehensive neuropsychological battery (Henry et al., 2002). Six individuals with 22q11DS (32%) showed a significant PIQ > VIQ discrepancy (11 points or more) whereas only 3 had a significant VIQ > PIQ discrepancy. Impairments were also found in abstract and social thinking (according to the WAIS-R subtest Comprehension). In another study of children (n = 26; age range 3.5–17 years), perceptual and visuo-motor abilities were assessed. This screening test included the completion of form boards, block construction, geometric designs, bilateral integration and tactile discrimination. All children, regardless of age, failed the perceptual and visuo-motor screening (Golding-Kushner, Weller, & Shprintzen, 1985). In a very small study, VMI (Visual–Motor Integration) test scores were within the normal range, although 6 of the 9 children had scores more than 1 SD below those expected according to age. Problems with visuo-motor integration skills increased with age (Swillen et al., 1999). Executive function impairments—particularly in problem solving and planning (Tower of London test)—were found in a controlled study of adults (Henry et al., 2002). The 22q11DS group was less accurate in problem solving ability, and made significantly more moves to solve the problems than did the age-, gender-, and IQ-matched controls. Also, number of moves increased as the degree of difficulty increased. In another study no differences were found between two adult groups with 22q11S—one with schizophrenia and one without—regarding planning and problem solving ability. The conclusion drawn (van Amelsvoort et al., 2004) was that these difficulties are specific 22q11DS impairments, not related to schizophrenia. In one study (Woodin et al., 2001) the Trail Making test was used in a group of 80 children. Average results were obtained for focused attention (Trail A), while the ability to shift attention, and overall cognitive flexibility (Trail B) were below average. The primary objective of this study was to study the impact of ASD/ADHD on general intellectual ability and profile, executive functions and visuo-motor skills in the 22q11DS. A secondary aim was to study if gender, age, heart disease, ASD ‘‘only’’, ADHD ‘‘only’’ or ASD in combination with ADHD had an impact on general intellectual ability and profile. 2. Material and methods 2.1. Participants One hundred individuals (58 female and 42 male) with 22q11DS were included in the present report. Ninety-eight of these were taking part in a multidisciplinary assessment study at the Queen Silvia Children’s Hospital in Go¨teborg, Sweden.

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Various aspects of the syndrome were covered in all these individuals, including neuropsychiatric, neurologic, neurodevelopmental, cardiologic, immunologic, speech and language, ear and hearing, eye and vision, face morphology, and oral health (Niklasson et al., 2001; Oskarsdottir, Belfrage, Sandstedt, Viggedal, & Uvebrant, 2005; Oskarsdottir, Persson et al., 2005; Persson, Lohmander, Jonsson, Oskarsdottir, & Soderpalm, 2003; Persson et al., 2006). Forty-eight of the 100 individuals had been referred from the Western Go¨taland Region in western Sweden, and the remainder from other parts of Sweden. Two individuals had only neuropsychiatric and neuropsychological evaluations. The individuals in the present report were the first 100 consecutively referred cases with 22q11DS, confirmed by FISH analysis, undergoing assessment at the Child Neuropsychiatric Clinic (CNC). Ninety-two individuals were referred for neuropsychiatric evaluation from a multidisciplinary team as part of the routine 22q11DS assessment included in the study protocol. The remaining 8 (2 girls and 6 boys) had been referred directly to CNC, from other specialists because of learning and/or behaviour problems. 2.2. Age and gender The age range of the individuals examined was 1–35 years (Table 1). 2.3. Methods 2.3.1. Neuropsychiatric assessment All examinations were performed at the CNC. The neuropsychiatric evaluation was done in 94 cases by one of two senior clinicians who have extensive neuropsychiatric experience, or (n = 6) by one of three other experienced psychiatrists from the same department. The neuropsychiatric evaluation included extensive structured and semistructured interviews with the parent(s). In the adult group both the probands themselves and their parents were interviewed. The interview systematically covered aspects of heredity; medical factors pertaining to pregnancy, parturition, and the neonatal period; child’s early psychomotor and speech-language development and adaptation; physical health problems; behaviour; sustained attention and impulse control; fine and gross motor control; social interaction skills; eating and sleeping habits. Any specific problems suggesting ADHD, ASD, Tourette syndrome, Obsessive–Compulsive Disorder, Oppositional Defiant Disorder (ODD), conduct disorder, or any other DSM-IV psychiatric disorder such as anxiety, specific phobias or psychotic symptoms were specifically asked for covering the appropriate DSM-IV criteria. The evaluation of the child or adult affected included psychiatric assessment, and a general thorough physical examination. 2.3.2. Parent questionnaires Parents completed the Autism Spectrum Screening Questionnaire (Ehlers & Gillberg, 1993; Ehlers, Gillberg, & Wing, 1999; Posserud, Lundervold, & Gillberg, 2006), the Conners Brief Parent Rating Scale (Conners, Sitarenios, Parker, & Epstein, 1998), the Child Behavior Checklist (Achenbach, Howell, Quay, & Conners, 1991), and the Five To Fifteen questionnaire (Kadesjo et al., 2004). Parents were asked to describe the child’s function, according to the statements, during the age period defined in the questionnaire. 2.3.3. Neuropsychiatric diagnostic process ASD and ADHD diagnoses were made by the psychiatrist according to the DSM-IV (American Psychiatric Association, 1994) and Gillberg and Gillberg (1989) criteria, taking the results of the various examinations (interview, medical examinations, observations and those of the Five To Fifteen questionnaire)—but not of neuropsychological tests—into account. ASD comprised autistic disorder, Asperger syndrome and Autistic-Like Condition (ALC)/Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS). LD/MR, DCD, ADHD and autistic disorder were diagnosed strictly in accordance with the DSM-IV. ALC was diagnosed in cases meeting the social criterion (i.e. at least 2 social symptoms) for autistic disorder, and the criteria for at least one more of the other two ‘‘triad’’ areas (communication or repetitive/stereotyped behaviour), plus had a total symptom score for autistic disorder of 4 or more and did not meet criteria for autistic disorder or Asperger syndrome. These criteria are in accordance with the broad criteria of the ICD-10/DSM-IV. However given that these manuals do not supply an exact symptom algorithm, we felt the need to provide a stricter definition so that the present study might be replicated by future students of 22q11DS. The diagnosis of Asperger syndrome was made in accordance with Gillberg and Gillberg (1989) and Gillberg (1991) in cases not meeting criteria for autistic disorder or ALC. ADHD and ASD were not regarded as mutually exclusive diagnoses. In addition to these neuropsychiatric diagnoses, some individuals met criteria for other DSM-IV psychiatric diagnoses. Table 1 Gender and age range of 100 individuals with 22q11DS. Age range (years)

All, n = 100 (100%)

Female, n = 58 (58%)

Male, n = 42 (42%)

p-Value

5 6–11 12–16 17

22 40 22 16

14 22 12 10

8 18 10 6

0.033 0.527 0.670 0.317

(64%) (55%) (55%) (62%)

(36%) (45%) (45%) (38%)

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2.3.4. ASD, ADHD and other psychiatric diagnoses Forty-four individuals (21 females and 23 males; mean age 12.1 years) met criteria for ASD, ADHD or a combination of these diagnoses (collapsed group referred as ASD/ADHD) with or without LD/MR while there were 56 individuals (37 females and 19 males; mean age 10.8 years) not meeting criteria for ASD/ADHD. Eighteen met criteria for Developmental Coordination Disorder (DCD) (9 females and 9 males; mean age 9.8 years), 10 of whom had a combination of DCD and ADHD, and 8 of whom had DCD ‘‘only’’. One child had ODD, three adults met criteria for Anxiety disorder and one adult for Psychosis. Another three adults had a history of psychotic symptoms, meaning that 25% of those 17 years had a history of or current psychosis compared with none of the 84 individuals 16 years at time of assessment (p < 0.01). 2.3.5. Neuropsychological assessment The neuropsycholgical assessment was carried out by the same neuropsychologist in 99 cases. One individual was tested by another trained neuropsychologist. A neuropsychological test battery was designed so as to provide information concerning intellectual level and profile, visuo-motor development, and executive functions. The wide age range of the probands made it necessary to use different tests for different age groups. A semistructured behavioural observation of all participants was performed during the neuropsychological examinations. This observation covered aspects of attention, activity level and impulse control, social interaction, cooperation, emotion, speech and language. 2.3.6. General intellectual/developmental ability Psychometric assessment of general intellectual/developmental ability was performed in all participants except in two cases in whom the Griffiths’ or the Wechsler scales could not be used due to severe medical problems in combination with low general intellectual function. In these two (with moderate and severe mental retardation according to clinical presentation), parts of the Vineland Adaptive Behavior Scales (Sparrow, Balla, & Cicchette, 1984) were used. These two individuals were excluded from statistical analysis concerning IQ. 2.3.6.1. Griffiths Scales. The Griffiths’ Mental Developmental Scale I or II (Swedish standardization: Ahlin-A˚kerman & Nordberg, 1980) was administered in the youngest children. Scale I consists of five subscales: Motor, Personal–Social, Hearing and Speech, Eye and Hand and Performance. Scale II includes an additional scale, Practical Reasoning. The results are given as developmental age and are transformed into a Developmental Quotient (DQ). 2.3.6.2. Wechsler Scales. Psychometric assessment of general intellectual ability was done for all other participants. The Wechsler Scales—i.e. the Wechsler Primary and Preschool Scale of Intelligence (WPPSI-R; Wechsler, 1989), the Wechsler Intelligence Scale for Children (WISC-III; Wechsler, 1992), or the Wechlser Adult Intelligence Scale-Revised (WAIS-R; Bartfai, Nyman, & Stegman, 1992; Wechsler, 1981)—were used for all individuals in the appropriate chronological or/and mental age group. The three Wechsler Scales yield measures of global intellectual ability—FSIQ, VIQ and PIQ, as well as standard scores on each subtest. On the WISC-III and WAIS-R, statistical factors can also be derived as suggested by Kaufman: Verbal Comprehension (comprising the subtests Information, Vocabulary, Comprehension and Similarities), Perceptual Organization (Picture Completion, Picture Arrangement, Block Design and Object Assembly), Freedom from Distractibility (Arithmetic and Digit Span), and Processing Speed on WISC-III (Coding and Symbol Search) (Kaufman, 1994). On the WAIS-R the subtest Symbol Search is not included which means that the factor Processing Speed cannot be derived. The Kaufman factors are not included in the WPPSI-R. 2.3.7. Visual–Motor Integration skill 2.3.7.1. VMI. To evaluate the visuo-motor ability the Visual–Motor Integration (VMI) test (Beery, 1997) was used. This test consists of geometric forms, in a developmental sequence, to be copied with paper and pencil. 2.3.8. Executive function 2.3.8.1. Planning ability: Tower of London. The planning ability was measured with the Tower of London test (Shallice, 1982). In this test, the child is requested to ‘‘look ahead’’ to determine how to rearrange three pierced coloured beads from an initial position on two upright sticks to a new set of predetermined positions on two or more sticks. The results are given as number of correct trials (converted into a 9-graded scale) and a ‘‘raw score’’, viz. the time taken to correctly complete the pattern reduced by the number of attempts the child needs to achieve the correct configuration (converted into a quotient). For the adults, a mental variant, where the coloured beads are reproduced in a picture, was used. The results are given as number of moves for the two levels, 2–3 and 4–5 moves, and mean reaction times. In the adult group reaction times were registered but not analyzed due to lack of normative data. 2.3.8.2. Attention: Trail Making. The abilities of speed of attention, divide and/or shift attention, were measured by the Trail Making tests A and B (Spreen & Strauss, 1991) where the individuals were asked to connect numbers (Trail A) and numbers and letters (Trail B) with a pencil as quickly as possible.

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Further examination of the attention ability, with special focus on the ability to sustain attention, was measured in the group of school age children with Becker’s Go-No-Go test (Becker, Isaac, & Hynd, 1987). These results have been published in a separate paper (Niklasson, Rasmussen, Oskarsdottir, & Gillberg, 2005). 2.3.9. Statistical methods For variables where age norms are available raw scores have been transformed into z-scores. For comparing groups, paired t-test and 95% confidence interval (CI) were used. Adjustment for multiple comparisons (Tukey’s Studentized Range (HSD) Test) was made. Comparison within groups was made by ANOVA. Linear multiple regression was performed to test the effect of each variable while controlling for the effect of all others. Effect sizes (differences related to pooled SD of the groups) were calculated. 2.3.10. Ethics The study was approved by the Research Ethics Committee at the Faculty of Medicine, Go¨teborg University, Sweden. Informed consent was obtained from parents and from patients depending on age and ability to assent/consent. 3. Results 3.1. Overall findings regarding developmental/IQ tests 3.1.1. General intellectual/developmental level Fifty-one of the 100 individuals in the whole group met criteria for a diagnosis of LD/MR defined as FSIQ/DQ <70 and functional impairment and deficits in social adaptation. Forty-two of these had mild LD (IQ 50–69), 8 moderate LD (IQ 35– 49), and 1 severe LD (IQ < 35). 3.1.1.1. Griffiths. The 14 youngest children (age 1–6 years) were assessed using the Griffiths’ Mental Developmental Scales. They had a mean DQ of 70.1 (range 44–98; girls 74.3 and boys 64.7) (Table 2). There was no significant gender difference in this small group, only a trend for higher DQ among girls compared to boys (p = 0.2; effect size 0.48). The mean differences across all subscales yielded significantly lower result on the subscale Hearing and Speech than on any of the three subscales Eye and Hand, Performance and Personal–Social. 3.1.1.2. Wechsler Scales. 3.1.1.2.1. Intellectual level/profile and diagnostic group effects. The 82 children/adults assessed on one of the Wechsler scales had a mean FSIQ of 70.6 (SD 15.5; range 40–111), VIQ 75.6 (SD 15.9; range 42–108), PIQ 69.8 (SD 15.6; range 46–112). The VIQ–PIQ mean difference was 5.57 (95% CI: 2.86–8.28) (p < 0.01; effect size 0.34). For the whole group the Perceptual Organization factor yielded uniformly poor results. The results on this factor were in the whole group significantly lower than those on the other three factors. The results on Verbal Comprehension factor were significantly better than those on the Perceptual Organization factor (Table 3). Between the two diagnostic groups (No ASD/ADHD and ASD/ADHD) no significant differences, regarding FSIQ, VIQ, PIQ and the Kaufman factors, were found. In both diagnostic groups the result on Verbal Comprehension was significantly higher than that of Perceptual Organization but not for the other two factors (Table 4). No subtest discrepancies were found within the Perceptual Organization factor while such discrepancies were found within the other factors. For the whole group (including the two subgroups), the best and poorest results on the Verbal Comprehension factor, were found for Vocabulary and Information. Differences between these two subtests were significant for the two subgroups. In the group No ASD/ADHD Vocabulary was also superior to Similarities and Comprehension. Comprehension was superior to Information in the No ASD/ADHD group. In the whole group, and in the group ASD/ADHD, Digit Span was superior to Arithmetic. Symbol Search was superior to Coding in the whole group and in the two subgroups.

Table 2 Griffiths’ Mental Developmental Scale results. Variable

Developmental Quotient Motor Personal–Social Hearing and Speech Eye and Hand Performance Practical Reasoning a

Mean followed by 95% CI.

All

Females

Males

Meana

n

Meana

n

Meana

n

70.1 73.8 74.8 57.4 73.6 77.2 66.8

14 13 14 14 14 14 6

74.3 74.1 78.0 63.0 77.8 82.3 72.3

8 8 8 8 8 8 3

64.7 73.4 70.5 49.8 68.2 70.5 61.3

6 5 6 6 6 6 3

(60.6–79.7) (61.8–85.9) (63.8–85.8) (47.5–67.3) (61.4–85.9) (63.9–90.5) (56.5–77.2)

(59.2–89.3) (54.0–94.3) (60.5–95.5) (47.2–78.8) (60.1–95.4) (64.1–100.4) (42.3–102.4)

(50.2–79.1) (57.3–89.5) (52.5–88.5) (37.2–62.5) (45.0–91.4) (44.4–96.6) (56.2–66.5)

190

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Table 3 Wechsler scales results by gender and for the whole group. Variable

All

Females

Mean

a

a

Males a

n

Females:males p-value

Females:males effect size

n

Mean

n

Mean

FSIQ VIQ PIQ

70.6 (67.2–74.0) 75.6 (72.1–79.2) 69.8 (66.4–73.2)

82 82 84

75.3 (70.6–80.0) 80.3 (75.6–85.0) 73.4 (66.6–78.1)

46 46 46

64.6 (60.3–68.9) 69.7 (64.9–74.5) 65.0 (60.5–69.5)

36 36 36

0.002 0.002 0.014

0.71 0.68 0.55

Verbal Comprehension Vocabulary Similarities Comprehension Information

78.7 6.8 6.0 5.9 5.1

(75.1–82.3) (6.1–7.5) (5.3–6.7) (5.1–6.7) (4.5–5.8)

68

83.3 7.7 6.7 7.0 5.8

(78.0–88.1) (6.6–8.8) (5.8–7.5) (5.7–8.2) (4.7–6.9)

38

72.8 5.8 5.0 5.0 4.3

(67.8–77.9) (4.6–7.0) (4.0–6.2) (3.9–6.1) (3.4–5.3)

30

0.003 0.017 0.022 0.020 0.047

0.71 0.56 0.58 0.57 0.47

Perceptual Organization Picture Completion Object Assembly Block Design Picture Arrangement

72.0 5.9 5.6 5.1 5.0

(68.2–75.9) (5.1–6.7) (4.9–6.4) (4.3–5.9) (4.3–5.7)

68

75.9 5.8 5.8 5.8 5.0

(70.5–81.3) (4.7–6.9) (4.6–7.0) (4.6–7.1) (4.0–6.1)

38

67.2 4.5 3.8 4.2 4.9

(62.0–72.3) (3.2–5.7) (2.9–4.8) (2.8–5.6) (3.8–6.0)

30

0.022 0.123 0.014 0.084 0.835

0.55 0.38 0.59 0.40 0.03

Freedom from Distractibility Digit Span Arithmetic

75.8 (72.8–78.9) 6.1 (5.5–6.7) 5.5 (4.9–6.1)

68

79.6 (76.0–83.2) 6.8 (6.0–7.7) 5.9 (5.0–6.7)

38

70.9 (66.3–75.5) 5.2 (4.3–6.2) 4.7 (3.7–5.7)

30

0.003 0.010 0.074

0.72 0.57 0.45

Processing Speed Symbol Search Coding

75.6 (71.5–79.8) 6.0 (5.1–6.9) 4.7 (3.9–5.6)

54

81.5 (76.3–86.8) 7.2 (6.0–8.3) 5.7 (4.6–6.8)

29

68.8 (62.9–74.6) 4.6 (3.4–5.9) 3.6 (2.5–4.8)

25

0.002 0.004 0.001

0.87 0.82 0.69

84 cases tested with WPPSI-R, WISC-III and WAIS-R. For Kaufman factors only 68 cases (not included on WPPSI-R) and processing speed only 54 cases (only included on WISC-III). a Mean followed by 95% CI.

3.1.1.2.2. The effect of gender, age, heart malformation, ASD, ADHD and ASD + ADHD on intellectual level and profile. Females (n = 46) had higher mean Wechsler FSIQ (75.3; SD 19.9) than males (64.6; SD 12.8) (p < 0.002). There was higher VIQ than PIQ with a significant discrepancy for both females and males (p < 0.01). A significant discrepancy between FSIQ (including the 4 Kaufman factors) for females–males was found (p < 0.002). Gender differences were found for all subtests within the factors Verbal Comprehension and Processing Speed, for one subtest (Object Assembly) within Perceptual Organization, and one subtest (Digit Span) within Freedom from Distractibility (Table 3). Within this group of 82 individuals, a negative correlation between FSIQ and age was found (p < 0.002) with no effect of gender. The effect of each variable (gender, age, heart malformation, ASD ‘‘only’’, ADHD ‘‘only’’ and ADHD + ASD) controlling for the effect of all others, was tested (Table 5). Gender, (females performing better than males), had an effect on FSIQ and on the four Kaufman factors, while age had a negative effect on FSIQ and the factor Processing Speed. No effects of heart malformation, ASD ‘‘only’’, ADHD ‘‘only’’ or ASD + ADHD were found on FSIQ or any of the four factors. 3.2. Other tests used 3.2.1. Visual–motor ability 3.2.1.1. VMI. For the group tested with the VMI (n = 56) the mean quotient was 64.3 (95% CI: 59.7–68.9) which was rather low given a mean PIQ of 68.8 (95% CI: 64.9–72.8) (p < 0.008) and an FSIQ of 69.5 (95% CI: 65.5–73.5) (p < 0.001; effect size 0.32). FSIQ was higher than VMI also in the two subgroups (p < 0.02, respectively). Variation in VMI is explained by FSIQ in 61.7% (p < 0.01) and by PIQ in 51.1% (p < 0.001). In the subgroup No ASD/ADHD 65.1% of the variation can be explained by FSIQ compared to 48% in the subgroup ASD/ADHD. Females (n = 30) had a mean score of 70.3 (95% CI: 63.7–77.0) which was better than 57.4 (95% CI: 51.7–63.1) for the males (n = 26) (p = 0.004; effect size 0.76). No significant differences between the result on VMI and the two subgroups were found. 3.2.2. Executive function—children 3.2.2.1. Planning: Tower of London. Forty-five children performed the Tower of London test, 30 of whom were in the age range of the normative group (6–13 years). The total score for the whole group of 30 was 91.7 (95% CI: 85.5–97.9) and the stanine value for correct solutions was 4.1 (95% CI: 3.3–4.8). The mean FSIQ 74.7 (95% CI: 66.7–79.8) was lower than the TOL quotient (p < 0.001: effect size 1.06). No gender differences were found. In the group No ASD/ADHD (n = 17) the mean quotient was 99.1 (95% CI: 92.1–106.2) and the mean correct solutions 4.9 (95% CI: 3.9–5.9). The mean FSIQ in this group was 77.2 (95% CI: 68.9–85.4), significantly lower than TOL quotient (p < 0.001; effect size 1.37). In the group ASD/ADHD the mean quotient was 82.0 (95% CI: 72.8–91.2) and the mean correct solutions 3.0 (95% CI: 2.1–3.9). The subgroup ASD/ADHD had

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Table 4 Wechsler scales results by ASD/ADHD in 84 cases with 22q11DS tested. Variable

No ASD/ADHD Mean

ASD/ADHD

a

n

Meana

n

FSIQ Verbal IQ Performance IQ

72.3 (67.5–77.1) 77.2 (72.2–82.1) 71.4 (66.6–76.1)

47 47 47

68.3 (63.6–73.1) 73.6 (68.5–78.7) 67.8 (62.9–72.7)

35 35 37

Verbal Comprehension Vocabulary Similarities Comprehension Information

78.9 6.8 5.8 6.0 5.0

(73.9–83.8) (5.6–8.0)b,c,d (4.8–6.7)e (4.8–7.2)f (4.0–6.1)

38

78.5 6.9 6.2 6.2 5.3

(73.0–84.0) (5.8–8.0)b (5.1–7.3)e (4.8–7.6) (4.2–6.4)

30

Perceptual Organization Picture Completion Object Assembly Block Design Picture Arrangement

73.0 5.5 5.1 5.1 5.1

(67.6–78.4) (4.4–6.6) (4.2–6.0) (3.9–6.3) (3.9–6.2)

38

70.8 4.8 4.9 5.1 4.8

(65.1–76.5) (3.5–6.1) (3.7–6.1) (3.6–6.6) (3.6–6.0)

30

Freedom from Distractibility Digit Span Arithmetic

76.5 (72.1–80.9) 6.1 (5.2–7.0) 5.7 (4.8–6.7)

38

74.8 (70.8–78.9) 6.2 (5.3–7.1)g 5.0 (4.1–5.8)

30

Processing Speed Symbol Search Coding

77.8 (71.8–83.8) 6.3 (4.9–7.6)h 5.1 (4.0–6.1)

31

72.7 (58.8–69.1) 5.7 (4.5–6.8)i 4.4 (3.2–5.1)

23

84 cases tested with WPPSI-R. WISC-III and WAIS-R. For Kaufman factors only 68 cases (not included on WPPSI-R) and Processing Speed only 54 cases (only included on WISC-III). a Mean followed by 95% CI. b p < 0.01, Vocabulary versus Information. c p < 0.01, Vocabulary versus Similarities. d p < 0.05, Vocabulary versus Comprehension. e p < 0.05, Similarities versus Information. f p < 0.01, Similarities versus Information. g p < 0.05, Digit Span versus Arithmetic. h p < 0.05, Symbol Search versus Coding. i p < 0.01, Symbol Search versus Coding.

Table 5 P-values for the effect of gender, age, heart malformation, ASD, ADHD and ASD + ADHD on FSIQ and the four Kaufman factors. Significant effects (p < 0.01) in bold. Variable

FSIQ sign.a

Verbal Comprehension sign.aPercept. Organization sign.aFreedom from Distractibility sign.aProcessing Speed sign.a

Gender 0.002 (0.345) 0.003 Age 0.001 ( 0.346)0.159 Heart malformation0.700 (0.041) 0.480 ASD only 0.063 ( 0.195)0.450 ADHD only 0.140 (0.146) 0.213 ASD + ADHD 0.268 (0.115) 0.698 a

(0.355) ( 0.163) ( 0.083) ( 0.761) (0.144) ( 0.048)

0.022 0.089 0.926 0.116 0.173 0.469

(0.276) ( 0.202) (0.011) ( 0.187) (0.162) ( 0.091)

0.003 0.085 0.928 0.520 0.771 0.883

(0.356) ( 0.191) ( 0.011) ( 0.075) (0.034) (0.018)

0.003 0.000 0.431 0.093 0.736 0.097

(0.357) ( 0.487) (0.098) ( 0.204) (0.041) ( 0.202)

p-Value followed by (B-coefficient).

significantly lower TOL quotient (p < 0.01) as well as number of correct solutions (p = 0.01) compared to the subgroup No ASD/ADHD. The variation in TOL quotient can in the whole group be explained by FSIQ in 28%, in the subgroup No ASD/ADHD be explained by FSIQ in 50.3% while no such correlation can be find in the ASD/ADHD group. 3.2.2.2. Attention: Trail Making A and B. For the whole group of 22 children who were in the age range for the normative group (7–15 years) the mean z-score was 2.3 (95% CI: 1.6 to 3.1) on Trail A and 2.8 (95% CI: 1.8 to 3.9) on Trail B. Both of these were significantly lower than for the normative group. No differences were found between the results on Trail A and Trail B and there were no differences regarding gender. No differences between the two groups No ASD/ADHD (n = 13) and the group ASD/ADHD (n = 9), were found. 3.2.3. Executive function—adults The number of adults was too low for meaningful comparison across diagnostic subgroups.

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3.2.3.1. Planning: Tower of London. Ten individuals performed the adult version of the Tower of London test. The total score, mean correct solutions, was 9.2 (95% CI: 8.1–10.3) for the whole test (12 items) and corresponding scores for the six test items included in level 1 was 5.5 (95% CI: 5.0–6.0) and 3.7 (95% CI: 2.7–4.7) for the six test items in level 2. The total number of correct solutions was lower than for normative group (p = 0.05). The total mean response time was 16.4 s (SD 6.8), level 1 7.3 (SD 5.1) and for level 2 27.9 (SD 11.6). 3.2.3.2. Attention: Trail Making A and B. Seven individuals performed the adult version of the Trail Making test. The mean zscore for Trail A was 2.5 (95% CI: 1.4–3.5) and for Trail B 5.7 (95% CI: 1.4–3.5). For both Trail A and Trail B significantly lower mean z-score was found and a tendency (p = 0.06) for lower mean z-score on Trail B compared to Trail A.

4. Discussion In this study of 100 individuals with 22q11DS, the majority of whom were children, our main findings were that (1) females had higher FSIQ, VIQ and PIQ than males, (2) there was a negative correlation between FSIQ and age for both females and males, (3) the presence of ASD/ADHD did not affect general intellectual ability or profile, (4) ASD/ADHD negatively affected planning ability, (5) the poorest neuropsychological test results were demonstrated for the Perceptual Organization factor, and (6) the best results were found on the Verbal Comprehension factor (but subtest results within this factor varied greatly with Vocabulary standing out as the main strength). Females were superior to males in all subtests within the two factors Verbal Comprehension and Processing Speed. This superiority was found only for one subtest each (Object Assembly and Digit Span) within the other two factors. Most previous 22q11DS research reports have failed to document sex differences in cognitive functioning. However, one recent study showed boys to be more cognitively affected than girls (Antshel et al., 2005). In that study, sex differences in frontal lobe volume between girls and boys were the same as those seen in the general population (boys > girls). The authors of the paper suggested that girls have a higher threshold than boys for the level of liability needed to manifest dysfunction. In another recent study (De Smedt et al., 2007) similar FSIQ levels in girls and boys with 22q1DS were found. Interestingly, when we divided our sample into two diagnostic groups we found an even sex distribution in the subgroup ASD/ADHD and it was only in the group with No ASD/ADHD that the overrepresentation of females was very pronounced. We found a negative correlation between FSIQ and age with no mediating effect of gender. However, given that our data were cross-sectional, follow-up is needed to determine whether or not there might be a prospective longitudinal decline of FSIQ in 22q11DS over time or not. Our result contrasts with that of Antshel et al. (2005) who found a negative age-IQ-effect in girls but not in boys. We found, that females generally had a better visuo-motor skill than males while there were no gender differences regarding executive functions. One of our aims in this study was to assess intellectual ability/profile in relation to neuropsychiatric diagnoses. It appeared that the cognitive impairment found in 22q11DS is related to the syndrome and not to the coexistence of ASD or ADHD. The poorest result was found on the factor Perceptual Organization. We found no subtest discrepancies within this factor which supports the notion that the major neuropsychological deficit in 22q11DS lies in the integration of visual stimuli, non-verbal reasoning as well as visual–spatial and visual–motor skills. Verbal Comprehension was superior to Perceptual Organization which was in accordance with previous findings by Moss et al. (1999). However, the quite large subtest discrepancies within Verbal Comprehension makes the result of this factor less solid and the result must therefore be interpreted with caution. It could be that the only relative verbal strength of young people with 22q11DS is that of generally rather good Vocabulary. The relatively high result on the Verbal Comprehension factor is in contrast with the result for the youngest children, assessed with the Griffiths’ scales, where the significantly lowest result were found on the verbal subscale ‘‘Hearing and Speech’’. These results could be taken to mean that, in spite of delayed speech and language development in early childhood, children with 22q11DS thereafter have positive development resulting, at school age, in high scores on the Verbal Comprehension factor. Analysing the subtests included in this factor, the highest score was found for Vocabulary and the lowest score for Information for all four subgroups, which is interesting given that these two subtests are regarded (Kaufman, 1994) to have a high correlation in typically developed populations. This discrepancy could be explained by a quite good ability to define words while the ability to respond to questions about common events, objects, places and people is weak. One possible underlying explanation for this difference could be a deficit in language use. This would be in accordance with previous findings from our own group demonstrating (in 22q11DS) difficulties in retelling, which is considered to be a more complex language skill (Persson et al., 2006). Their initiation difficulties and general lack of energy probably also have a negative impact on communication. These findings may partly explain the clinical observation that the relative ‘‘verbal strength’’ of children with 22q11DS is often not recognized by teachers or parents. The lowest result, of all factors, was found for Perceptual Organization demonstrating deficits in visual–perceptual abilities. Initiation difficulties might have had a negative impact on the results of the three subtests, within the factor Perceptual Organization, where time (given bonus points for fast solution) is included. Difficulties in integrating visual and motor abilities were also found according to the results of the VMI. According to Beery (1997) in ‘‘normally’’ developed children there is a correlation between PIQ and VMI (r = 0.06). In our group the variation of VMI can be explained by PIQ in one half of the group and we found lower result on VMI comparing to PIQ. One explanation for this result could be that VMI requires better fine motor skills, than do most of the

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subtests included in PIQ. The coexistence of ASD/ADHD had no impact no visuo-motor integration skill. In about 60% the variation on VMI can be explained by FSIQ. Interestingly, the result on the factor Processing Speed was not particularly poor even though the clinical impression was that the individuals with 22q11DS had initiation difficulties, and that such difficulties contributed to the impression that they work quite slowly with different tasks. These initiation difficulties are obvious from clinical experience, but it seems as though that when affected individuals know what to do and receive some help getting started (as is the case in the practise test for Symbol Search), one of two subtests of the Processing Speed factor, their processing speed can be on par with the results on the other factors. A significant discrepancy between the two subtests Coding and Symbol Search was found with scores significantly higher on Symbol Search than on Coding. A possible explanation for this finding could be that the Coding test requires more of a fine motor skill than does the Symbol Search subtest. In the area of executive functions the planning ability of children with 22q11DS was found to be on an average level. Interestingly, superior result for the group No ASD/ADHD compared with the group ASD/ADHD, was found. This finding shows, regarding the planning ability, that the coexistence of ASD/ADHD has a negative impact. The variation in TOL can in the subgroup No ASD/ADHD be explained by FSIQ in half the group while no such correlation were found in the ASD/ADHD group. However, no such differences were found in the area of attention. Among the children, all groups had difficulties and there were no differences between the results on Trail A and Trail B. A possible explanation could be that these difficulties are more related to problems with speed of attention than with shifting attention. In the small group of adults a tendency to more specific problems with shifting attention was found. Our group (Niklasson et al., 2005) has previously showed difficulties with sustaining attention but not focusing attention. Obviously then, there are different types of attention deficits in individuals with 22q11DS. 5. Limitations One limitation in this study is that no comparison group was used. However we had major problems defining what would constitute a reasonable ‘‘control group’’. For instance, it would be very difficult, if not impossible, to find an IQ-matched non22q11 deletion syndrome comparison group that would not include a large subgroup with a heterogeneous mixture of other genetic syndromes. Further, the small number of adults included in this study had a negative impact on the possibilities of more detailed analysis of the results for this age group. 6. 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