Behavior Genetics, Vol. 36, No. 3, May 2006 ( 2006) DOI: 10.1007/s10519-006-9048-9
Laterality in Persons with Intellectual Disability. I—Do Patients with Trisomy 21 and Williams–Beuren Syndrome Differ from Typically Developing Persons? Miche`le Carlier,1,2,10 Silvia Stefanini,3 Christine Deruelle,4 Virginia Volterra,5 Anne-Lise Doyen,6 Christine Lamard,1 Ve´ronique de Portzamparc,7 Stefano Vicari,8 and Gene Fisch9 Received 5 Mar. 2005—Final 2 July 2005
Persons with trisomy 21 (T21) and Williams–Beuren syndrome (WBS) have different brain abnormalities which may affect manual laterality. We assessed 45 persons with T21 and 34 with WBS (mean age 13) and 81 typically developing children (TD). Manual laterality was assessed with a fifteen-item task administered two times, and Bishop’s card-reaching task. We found more left-handers in the T21 group compared to the other two groups. Inconsistent laterality was higher in the two groups with genetic diseases than in the TD group. For Bishop’s test, both T21 and WBS participants were less right-oriented than the TD group. They displayed different response patterns in midline crossing when reaching for the cards, but did not display more midline crossing inhibition than the TD group. Is atypical handedness linked to specific genetic syndromes and, more specifically for persons with T21, to the trisomy of some of the genes? KEY WORDS: Genetic diseases; handedness; mental retardation; trisomy 21; Williams–Beuren syndrome.
(abbreviated as T21 and WBS). Persons with T21 and WBS clearly show different psychological profiles, with differences both between the two genetic disease groups and between them and the typically developing (TD) group. Persons with T21 and WBS have specific brain particularities which may in turn affect laterality (see below). To the best of our knowledge, these two groups of patients have never been compared for manual laterality. Previously, it has been shown that mental impairment is linked to atypical laterality (with more non-right handedness or more mixed-handedness in mentally deficient populations) but it is not clear if this atypical laterality is the consequence of the mental impairment or a specific feature of the syndrome itself. To address this question it is necessary ‘‘to distinguish between etiological groups rather than selecting subjects purely on the basis of intellectual level’’, as proposed by Bishop (1990, p. 109, line 12) and later by McManus and Cornish (1997).
INTRODUCTION The present investigation explores manual laterality preference in persons with one of two genetic syndromes: trisomy 21 and Williams–Beuren syndrome UFR PSE, Universite´ de Centre de Recherche PsyCLE, Provence, 13621, Aix en Provence cedex 1, France. 2 University Institute of France, France. 3 Department of Neuroscience, University of Parma, Parma, Italy. 4 Institut de Neurosciences Cognitives de la Me´diterrane´e, CNRS, Marseille, France. 5 Institute of Cognitive Sciences and Technologies, National Research Council (CNR), Roma, Italy. 6 IUFM Orle´ans Tours, Orle´ans, France. 7 Institut Je´roˆme Lejeune, Paris, France. 8 Institute of Research Children Hospital Bambino Gesu´, Santa Marinella and LUMSA University, Rome, Italy. 9 Yeshiva University, and CUNY/Lehman College, New York, USA. 10 To whom correspondence should be addressed at UFR PSE, Universite´ de Provence, 29 Avenue Robert Schuman, 13621, Aix en Provence cedex 1, France. Tel.: +33-442-933-999; Fax: +33442-389-170; e-mail:
[email protected] 1
365 0001-8244/06/0500-0365/0 2006 Springer Science+Business Media, Inc.
366 Trisomy 21 is the most common form of genetic mental retardation occurring in about 1 in 700 live births (Lejeune, 1990). In most cases, it is due to the presence of an entire extra copy of chromosome 21. The physical and neuropsychological characteristics have been fully described by Vicari (2006, same issue), and Teipel and Hampel (2006, same issue). Williams–Beuren syndrome (WBS) is a rare genetic syndrome (incidence ranging from 1 in 7500 to 1 in 25,000 live births) resulting from a hemyzigous deletion of genes at the long arm of chromosome 7 at 7q11.23. In 95% of affected persons, the size of the deletion is 1.6 Mb which encompasses at least 24 genes. The specific contributions of most of these deleted genes to the phenotype are not clear. The psychological profile of the WBS phenotype is typified by mental retardation, with aspects of language development relatively intact, while visual–spatial processing ability, counting, planning and implicit learning are severely impaired. This was demonstrated in studies comparing WBS children with T21 children (see inter alia Bellugi et al., 1999; Klein and Mervis, 1999; Mervis et al., 2000; Vicari et al., 2002; Vicari, 2006). Retarded brain development in WBS children is characterized by marked atrophy of the posterior regions of the brain and the basal ganglia. While some authors (Bellugi et al., 1999; Jernigan et al., 1993) have concluded that cerebellar volume is relatively preserved, a more recent study found abnormal cerebellar enlargement in WBS infants and toddlers (Jones et al., 2002). Abnormal development of the corpus callosum (colossal shape and volume of different parts) has also been reported (Schmitt et al., 2001; Tomaiuolo et al., 2002). In contrast, persons with T21 have a lower brain weight with a small cerebellum, frontal and small temporal lobes (Teipel and Hampel, 2006; Vicari, 2006). In a review published in 1988, Pipe concluded that atypical laterality is more frequent in retarded persons. Two-years later, Bishop (1990) published an excellent book on links between handedness and developmental disorders. One of her conclusions stated that ‘‘Findings of excess non-right-handedness are robust for conditions in which there is evidence of underlying neurological damage: mental impairment, infantile autism and, to a lesser extent, epilepsy’’ (p. 163, line 19), in agreement with Pipe (1988). However, in chapter 9 of her book, Bishop (1990) noted that the nature of increases in non-righthandedness in mentally disabled persons was not fully understood. She emphasized the need to distinguish left-handedness from mixed-handedness
Carlier et al. (or ambiguous laterality, i.e. with the preference varying between but not within the tasks) and lack of hand preference (or inconsistent laterality where the preference varies within the tasks; inconsistent laterality may also refer to non-concordance between hand preference and hand skill—McManus and Cornish, 1997). In spite of Bishop’s recommendation, since 1990 relatively few papers have been published on sensory and motor laterality in persons with genetic disorders. An excess of left- or mixedhandedness, assessed using the Edinburgh Handedness Inventory (Oldfield, 1971) was reported in patients according to schizophrenic subtypes (Dollfus et al., 2002), but this excess was not confirmed in a group of children who later developed a schizophrenia spectrum disorder (Schiffman et al., 2005). And in longitudinal studies on offspring of schizophrenic parents by Erlenmeyer-Kimling et al. (2005), no significant differences were observed in the offspring who developed schizophrenic disorders. Umansky et al. (2003) found a left-hand preference of 33% in a group of 145 patients with Rett syndrome. Cornish and McManus (1996) assessed young (3–5 years) and older (11–13 years) children with autism (N=35), 26 children with learning disabilities, and 89 typically developing (TD) children. Hand preference was measured three times using a set of 10 symmetrically presented unimanual preference tasks (e.g. coloring a square and eating with a spoon). Hand skill asymmetry was assessed using the Annett Pegboard (Annett 1970; Annett, 2002; Doyen and Carlier, 2002, for recent references). Left-handedness, which was defined as greater use of the left hand in the preference tasks, was more common in the two groups of disabled children than in the TD group (23% individuals with autism, 11.5% with learning disabilities, and 4% TD). However, the prevalence of left-handedness in the TD group was much lower than the general average. Consistency of handedness calculated across all pairs of replicates for each preference task was highest in the 11– 13 year-old groups (disabled and TD) and higher in the TD group for all ages, compared to the two groups of disabled children. Since 1990, several studies have compared T21 individuals with other groups of disabled children. Lewin et al. (1993) selected adult hospital residents, classifying them in using three diagnostic categories: T21 (N=20), epilepsy (N=20) and autism (N=18). Handedness was established using a 10-item task. The authors did not present any information at all on the criteria used to define right- or left-handers. They
Laterality in Trisomy 21 and Williams–Beuren Syndrome observed a higher prevalence of non-right-handers in the patient groups than in general population, independent of the diagnosis (19% left-handed, 17% mixed-handed). No differences in handedness were observed between groups with severe-to-profound learning disabilities and groups with mild-to-moderate learning disabilities. Cornish et al. (1997) assessed hand preference and hand skill in 27 children with Fragile-X syndrome, 20 children with T21, and 20 who were TD. Laterality assessment followed the protocol described above (Cornish and McManus, 1996). No difference was observed across the three groups for either the proportion of left-handedness nor consistency of handedness. It should be noted that the percentages of left-handers were unusually low in the T21 and TD groups in this study (3.3 and 3.4). Other studies focused only on individuals with T21. Devenny and Silverman (1990) tested 31 adults with T21 in a five-item task (pencil, comb, toothbrush, ball, and scissors). They were classified as right- or left-handed if all five objects were used with the same hand. The others were designated as mixedhanded. With such classification, 48% of participants were right-handed, 13% left-handed and 39% mixedhanded. A summed score of laterality did not correlate to IQ. No group of TD persons was assessed for comparison, which makes it difficult to have any clear interpretation of the data. Vlachos and Karapetsas (1999) used 10 items from the Edinburgh Handedness Inventory to classify children with T21 (7–9-years old) and teenagers with T21 (13–15-years old), comparing them to typically developing persons. Leftand mixed-handedness were more frequent among individuals with T21 than TD individuals. The authors did not include any information on the percentage of left-handers and mixed-handers in their samples. Taken together, the more recent papers do not always confirm earlier studies showing higher prevalence of left- or mixed-handedness in persons with T21 (Batheja and McManus, 1985; Pipe 1987). One of the difficulties in studies of atypical persons is the limited number of participants; this is because of problems recruiting patients. And when the TD group is small, random differences may be expected. Another drawback is the difficulty in assessing manual preference. There is a great deal of literature on this topic, but still no agreement on the best instrument, although some items are almost always chosen. Several inventories are available (see inter alia Annett, 1970, 2002; Delatollas et al., 1988; Oldfield, 1971; Perelle and Ehman, 1994; Stenhuis and Bryden,
367 1989). The prevalence of left-handedness differs according to the items used, and classifications of participants are dependent on the laterality index chosen. This was illustrated by Peters (1992) and more recently by Medland et al. (2004), and summarized by Fagard (2004). The same difficulty arises when performance tests are used, instead of a preference test (Carlier et al., 1993a, 1993b), and the situation is even more complicated by the fact that the structures of manual preference inventories are not the same for right- and left-handers (Peters and Murphy, 1993; Doyen et al., 2001), assuming too that we are able to classify participants in those two categories. From the literature cited above, we can draw at least three conclusions to improve our knowledge on links between manual laterality and mental impairment: (1) information is needed on the cause(s) of the mental impairment; (2) different methods must be used for measuring manual laterality in the same research project; and (3) a distinction must be made between mixed laterality and inconsistent laterality. The manual preference tasks must therefore be administered at least two times.
MATERIALS AND METHOD Participants Data have been collected by three teams based in France, Italy and USA. The participants with T21 and WBS therefore came from different countries. There were 45 persons with T21 (33 from France and 12 from Italy) and 34 persons with WBS (13 from France, 15 from Italy and 6 from the USA). There was no difference in the mean age of the two genetic groups (T21: 13.96±0.88, range: 8–34; WBS: 13.76± 0.76, range: 8–26, t[77]=0.16, p=0.87). All participants were recruited from medical consulting services or parents’ associations. Participants lived with their families who gave their informed consent. The Williams--Beuren syndrome diagnoses had been established by pediatricians and confirmed by molecular analyses (homozygous deletion of the elastin gene, 7q11.2, Mari et al., 1995). Intellectual levels were obtained from psychological records of these patients (mainly on the Stanford-Binet and Wechsler scales). The mean intellectual levels were 47.31±1.56 (range: 30–72) for T21, and 52.70±2.28 (range: 36–93) for WBS. Four individuals were in the borderline to low-normal range, i.e. above 70; one was in the T21 group and 3 in the WBS group.
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368 The difference in IQ between the two groups was statistically significant (t[76]=2.02, p=0.05), with the WBS group having a higher IQ. It should be noted that the difference between the two groups was smaller than previous observations in the literature (5.4 points compared to approximately 10 points). This is because certain persons with T21 with a very low intellectual level were not included in our sample as they were unable to follow the protocol. Our aim was not to match the two groups for their intellectual levels as there is no evidence in the literature of comparisons of samples with mild to moderate intellectual levels showing a correlation between the level of intelligence and laterality (Bradshaw-McAnulty et al., 1984; Devenny and Silverman, 1990; Lewin et al., 1993; Lucas et al., 1989). Both sexes were included (male/ female ratio: 1.05 and 1.27 for the T21 and WBS groups respectively). None of the participants had any obvious physical disability that could influence limb preference. Each participant was tested individually. The comparison group of typically developing persons deserves some comment. Since 1998, we have assessed manual laterality in 492 typically developing persons aged from 3 to 34. One hundred fifty-seven participated in a familial study and had a minimum of two left-handers in each family (Doyen, 2000). As they had been selected for left-handedness, they were not included in our comparison group. Of the remaining 335, 81 were aged 8 or above and they formed the comparison group. Of these 81 children, 24 formed the typically developing group for comparison with the two groups of persons with T21 and WBS when assessing variables measuring inconsistent laterality. The remaining 57 children had been tested before the current study began (Carlier et al., in press), using Annett’s item task and Bishop’s cardreaching test, and had not done the item task a second time, or the four additional items (see below). It was therefore impossible to assess their level of manual inconsistency. The TD group was younger than the T21 and WBS groups (mean age: 8.26±0.05), but laterality in TD persons is fully developed by the age of 8, particularly for the tasks in our study (Carlier, Doyen, Lamard, in press). But this did not preclude a posteriori assessment of an age effect in the two patient groups which has been done here by regression analyses. All the children were seen individually at school and their parents gave informed consent. There was no differential selection of the children as very few parents refused their consent.
Procedure Laterality was assessed with two methods so as to avoid some of the drawbacks discussed in the literature. The testing session lasted approximately 30 min. Item Task The eleven-item task of Annett’s questionnaire was administered: writing, throwing, holding a racket, cutting with scissors, threading a needle, using a broom, shoveling, dealing cards, hammering, using a toothbrush, and unscrewing the lid of a jar (see inter alia, Annett, 1970, 2002; Doyen et al., 2001). The participant performed the action requested and the hand used was recorded. The match-striking item was excluded as children are not allowed to play with matches. For the sub-sample of the 24 TD children and the WBS and T21 groups, four items were added (winding on a reel, combing hair, holding a spoon when eating, and putting a key in a lock), and the item task was administered two times, with the cardreaching test between the two trials. Card-reaching Test We thought it inappropriate to use performance tests on participants known to be slow in movement and frequently awkward (as persons with T21 often are). The card-reaching test proposed by Bishop et al. (1996) was therefore chosen; it provides a behavioral measure of degree and direction of hand preference. In the English adult version, a cardboard template placed in front of the participant is used to mark seven positions, each at a distance of 40 cm from the midpoint of a baseline, at successive 30 degree intervals. Position 4 is the midline. Positions 1, 2 and 3 are situated on the left hand side of the semicircle; positions 5, 6 and 7 are located on the right hand side of the semicircle. Three cards are placed at each of the 7 positions. The participant is seated at a table in front of the cardboard template with his/her hand resting on the table on either side of a box aligned with the midline of the body. He/she is asked by the experimenter to pick up a card at a given position indicated by a number marked just above the card, and to put it in the box (see Fig. 1). The order was random. There are no time limits and the task is easy to perform provided the participant can read the numbers indicating the position of the card and has no serious motor impairment. In a previous research project studying adult populations (Doyen and Carlier, 2002), we changed the original procedure slightly: the
Laterality in Trisomy 21 and Williams–Beuren Syndrome number of cards to be reached for at each position was doubled (6 instead of 3) as longer tests are known to be more reliable; an additional card was placed at each position so that participants did not know the last card had been taken when reaching for the sixth one. Participants with mental impairments were given pictures instead of numbers (from left to right: boat, flower, rabbit, car, bird, plane, and lion). Before starting the task, the experimenter checked that the participant could recognize each figure. Only 3 cards were set for each position, as in Bishop’s original procedure (Bishop et al., 1996), as it is difficult for mentally disabled persons to maintain their attention for long periods of time. The box in Bishop’s original procedure, where the child puts the card, was not used as we had observed that certain children had problems placing the card in the box. The distance between the midpoint of the baseline and the cards was shorter (25 cm). In a previous experiment (Carlier and Lamard, unpublished) studying 47 typically developing children (6–8-years old), we showed that the large cardboard template with numbers and the short cardboard template with pictures correlated well with the laterality index (LATB, defined below) (r[44]=0.83, pWBS (0.042) 0.021 T21>TD (0.005)
TD (TD (TD (0.007) 0.045 T21>TD (0.013) n.s. n.s. n.s. 0.001 T21>TD (0.000) T21>WBS (0.085) 0.042 T21>TD (0.012) n.s. 0.097 T21>TD (0.036)
Levels of significance for the comparison of the three groups and summary of partial comparisons are given. TD: 81 typically developing participants, T21: 45 participants with trisomy 21, WBS: 34 participants with Williams–Beuren syndrome. For the T21 and WBS groups, only the first trial was considered, as the TD group had been assessed with only one trial (see text).
Number of crossings + SEM
Laterality in Trisomy 21 and Williams–Beuren Syndrome 3 2.5 TD ( 81) 2 T21 (45) 1.5 WBS (34) 1 Far
Middle Position from the midline
Near
Fig. 2. Mean number of times the reaches crossed the midline (and standard errors of means). Far: positions 1 and 7 of the semicircle; Middle: positions 2 and 6; Near: positions 3 and 5. TD: Typically developing participants; T21: participants with trisomy 21; WBS: participants with Williams–Beuren syndrome. In brackets, number of participants.
comparisons did not, however, reveal any differences at any position between the three groups. DISCUSSION Participants with T21 and WBS syndromes were compared to typically developing persons for hand laterality in two tasks. Differences between the genetic disorder groups and the typically developing group were often significant, with the effect sizes ranging from medium (@5%) to large (>15%). For the first task, they were asked to execute fifteen actions, and the test was administered two times. For the second task, they were required to reach cards situated either in the body midline position, or in a semicircle to the left or right of the midline. Participants were classified into two categories using the item task (right- or left-handedness); the proportion of left-handedness was higher in the T21 group than in the other two groups. Participants were also classified into three categories (RR, mixed and LL) and the three groups of participants differed, with the highest percentage of mixed-handedness recorded for the T21 group. Left-handedness and mixed-handedness have been reported in populations of mentally retarded individuals (see Introduction), and particularly in T21 samples. In our study, these features are more characteristic of persons with T21 than WBS. Hand inconsistency was observed in the two groups of patients, but was very rare in the group of typically developing children aged 8 years and more. Results from the card-reaching task provided a different picture: the three groups of participants differed in the percentage of left-handers, but only when classified into three groups of handedness
373 (RR, mixed, and LL), with fewer left-handed individuals being in the TD group; there was no difference between the T21 and WBS groups. The results obtained with the LATB variable confirmed the observation that the TD group was more right lateralized, and, to a certain extent, corroborate the relevance of Bishop’s task for discriminating typically developing persons and persons with developmental disorders (Bishop, 2005; Hill and Bishop, 1998). Independent of hand preference, for the total number of midline crossings the two groups of patients did not differ from typically developing children aged 8 and above, but did differ in their response patterns when comparisons of the reaching were made according to the position of the object to reach (from furthest to nearest in relation to the midline). It is generally acknowledged that midline crossing inhibition disappears by the age of 8 or 9 (Cermak et al., 1980; confirmed by Carlier et al., in press). Developmental delays with midline crossing inhibition have been reported in children and adults with mental retardation (see Surburg and Eason 1999, for a brief review). Our data partially tally with previously published studies and the discrepancy may be explained by at least two factors. First, our samples were selected for their genetic disorders and not for general cognitive characteristics such as the level of retardation. Second, the card-reaching task assesses a relatively simple motor movement and the accuracy of the movement was not assessed, nor was the time required to perform it. It is unlikely that differences between manual preference profiles of persons with T21 and WBS which we observed in the item task (more left- and mixed-hand preference) can be attributed to the 5.4 IQ score difference. In the T21 group which had a higher proportion of left-handers, the mean IQ scores of left- and right-handers could be compared and were almost identical (47), and for any of the classification criteria chosen (item task or card-reaching task). This supports the hypothesis that atypical laterality occurs more frequently below a certain IQ threshold. The second main finding is the lower level of consistency in handedness (i.e. more hand changes in the T21 and WBS groups). In the field of cross-cultural studies, we have found no investigations of consistency in handedness, but it has been shown that this consistency typically follows a developmental curve, with older children having more consistency than young children (Carlier and Doyen, unpublished; Cornish and McManus 1996). Low levels of
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374 consistency in handedness have been reported in adults with severe and profound mental retardation (Soper et al., 1987), and in children with autism and learning disabilities (Cornish and McManus, 1996). Is this inconsistent handedness a pathological subtype of handedness found only in ‘‘clinical’’ populations, as proposed by Soper et al. (1987), or is it linked to motor immaturity, as suggested by Bishop (1990)? With T21 and WBS populations, either hypothesis could apply. One limitation of our study was the heterogeneous origin of the participants, living in three different countries. Geographical variations in human handedness have been reported, with differences in the prevalence of left-handers in certain countries which may be due to differential culture pressures on certain tasks (Fagard and Dahmen, 2004; Mandal et al., 1999; Perelle and Ehrman, 1994; Raymond and Pontier, 2004; Salmaso and Longoni, 1985). If very large variations are found between Italy, France and the US, our data may be biased. It is impossible to establish the absolute percentage of left-handers in a given population, but published data suggest that the proportion of left-handers in the USA is about 10%, although this may be a slight underestimate (Gilbert and Wysocki, 1992; Medland et al., 2004; Perelle, 2005, personal communication; Perelle and Ehrman, 1994). The percentage may be lower in Italian communities (about 8%, Viggiano et al., 2001). In typically developing children studied here, we found 12.3% left-handers, a figure similar to the prevalence for the US participants, but which may be high for typically developing Italian children. The possibility of not detecting a significant difference between the groups with genetic diseases and the typically developing individuals may be increased by this, but it does not affect the possibility of detecting a falsely significant difference. We are therefore safe in concluding that the percentage of left-handers was higher in the T21 group, as there was a similar proportion of left-handers for the Italian and French participants. A second limitation is that body lateralities, other than manual laterality (foot, eye, and ear), were not evaluated. This aspect of our research is currently under way with a larger sample of persons with T21 and typically developing individuals. A third limitation is that the individuals were not studied developmentally. We do not know how manual laterality evolves in children with T21 and WBS. Given the rarity of Williams–Beuren syndrome, it is difficult to collect developmental data on
this population; it may be easier to investigate T21 children from this perspective. We have presented the initial data on manual laterality in persons with Williams–Beuren syndrome. Atypical manual laterality seems to occur more frequently among individuals with trisomy 21 and Williams–Beuren syndrome, compared to typically developing individuals. However, manual laterality is not the same for the two genetic diseases. The relationship often quoted in the literature between left- or mixed-handedness and mental retardation is probably more complex than previously thought, and more data covering other genetic diseases should be collected to distinguish between non-syndromic and syndromic atypical laterality. The differences between the two groups of patients, both presenting mental retardation, suggest that atypical laterality does not result from ‘‘amplified development instability’’ (Antonarakis et al., 2004) but from dosage effect: atypical laterality could be due to genes carried by HSA 21 (Roubertoux et al., 2005), and HSA7, among others.
ACKNOWLEDGMENTS This research project was supported by the Fondation Je´roˆme Lejeune, the University of Provence, the University Institute of France, FIRB/ MIUR ‘‘Action and Perception in the construction of the cognitive world’’ (RBNE01SZB4), ESF EUROCORES program ‘‘The Origin of Man, Language and Languages’’ (Italy). In Italy the research was conducted through the special agreement between ISTC-CNR, the Italian Williams Syndrome Association and ASL No. 8, Regione Sardegna. We wish to express our gratitude to all the participants in the study and their families, and to Samantha Bellucci and Franc¸oise Be´tourne´ for their help in the assessment of the participants. We wish to thank the Institut Je´roˆme Lejeune (France) for the support provided and in particular Dr. Henri Ble´haut.
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