This article was downloaded by: [University of Auckland Library]On: 05 December 2014, At: 18:00Publisher: RoutledgeInforma Ltd Registered in England and Wales Registered Number: 1072954 Registeredoffice: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

Child Neuropsychology: A Journal onNormal and Abnormal Development inChildhood and AdolescencePublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/ncny20

Neurobehavioral Characteristics ofChildren with Duchenne MuscularDystrophyJacobus Donders a & Chand Taneja aa Psychology Service , Mary Free Bed Rehabilitation Hospital , GrandRapids, Michigan, USAPublished online: 08 Apr 2009.

To cite this article: Jacobus Donders & Chand Taneja (2009) Neurobehavioral Characteristicsof Children with Duchenne Muscular Dystrophy, Child Neuropsychology: A Journal onNormal and Abnormal Development in Childhood and Adolescence, 15:3, 295-304, DOI:10.1080/09297040802665777

To link to this article: http://dx.doi.org/10.1080/09297040802665777

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the“Content”) contained in the publications on our platform. However, Taylor & Francis,our agents, and our licensors make no representations or warranties whatsoever as tothe accuracy, completeness, or suitability for any purpose of the Content. Any opinionsand views expressed in this publication are the opinions and views of the authors,and are not the views of or endorsed by Taylor & Francis. The accuracy of the Contentshould not be relied upon and should be independently verified with primary sourcesof information. Taylor and Francis shall not be liable for any losses, actions, claims,proceedings, demands, costs, expenses, damages, and other liabilities whatsoever orhowsoever caused arising directly or indirectly in connection with, in relation to or arisingout of the use of the Content.

This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

Child Neuropsychology, 15: 295–304, 2009http://www.psypress.com/childneuropsychISSN: 0929-7049 print / 1744-4136 onlineDOI: 10.1080/09297040802665777

© 2009 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business

NEUROBEHAVIORAL CHARACTERISTICS OF CHILDREN WITH DUCHENNE MUSCULAR DYSTROPHY

Jacobus Donders and Chand TanejaPsychology Service, Mary Free Bed Rehabilitation Hospital, Grand Rapids,Michigan, USA

This study investigated cognitive, metacognitive, and psychosocial aspects of neurobehav-ioral functioning in 22 boys with Duchenne muscular dystrophy (DMD) and 18 unaffected sib-lings, all between the ages of 6 and 16 years. Probands and siblings completed the WechslerAbbreviated Scale of Intelligence, as well as selected subtests from the Children’s MemoryScale and from the Delis-Kaplan Executive Function System, while parents completed theChild Behavior Checklist and the Behavior Rating Inventory of Executive Function. Com-pared to siblings, probands demonstrated relative weaknesses on both verbal and nonverbalmeasures of delayed recall and response generation and were rated by parents as havingmore difficulties with social interaction, initiation, and adaptation. It is concluded thatDMD is associated with mild but potentially significant difficulties in a range of neurobe-havioral areas, likely related to deficient dystrophin levels in an integrated brain circuit thatincludes the cerebellum, hippocampus, and association neocortex.

Keywords: Duchenne Muscular Dystrophy; Cognition; Behavior; Children.

INTRODUCTION

Duchenne muscular dystrophy (DMD) is a recessive developmental disorder associ-ated with mutation of a gene at the Xp21 location on the short arm of the X chromosomethat affects about 1 in 3,500 live male births, causing progressive muscle weakness andeventual death in young adulthood. There is evidence for an increased risk for neuro-behavioral impairments in DMD, most likely because the involved gene would typicallydirect the distribution of its protein, dystrophin, to muscles, as well as to the brain (J. L.Anderson, Head, Rae, & Morley, 2002; Mehler, 2000). Previous research has yieldedconflicting results regarding the nature and scope of neurobehavioral deficits in DMD.The current investigation sought further clarification of the associated profile.

Many studies have reported that the median overall intellectual ability of boys withDMD is about one standard deviation below the mean, with Verbal IQ typically moreaffected than Performance IQ; although the latter discrepancy is not universal and when

We would like to thank the families who participated in this study. We also acknowledge the logisticalsupport of neurologists Kip Chillagg, DO, and Steven DeRoos, MD, and especially of Ms. Lois Flaig of theGrand Rapids, MI chapter of the Muscular Dystrophy Association. This research was completed with a grantfrom the Mary Free Bed Guild Fund (project #60) to Dr. Donders.

Address correspondence to Dr. Jacobus Donders, Psychology Service, Mary Free Bed RehabilitationHospital, 235 Wealthy S.E., Grand Rapids, MI 49503, USA. E-mail: jacobus.donders@maryfreebed.com

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

296 J. DONDERS AND C. TANEJA

present, not consistently of large magnitude (Cotton, Voudouris, & Greenwood, 2001). Inaddition, this discrepancy appears to decline with age, as a consequence of increasingVerbal IQ scores; suggesting delayed maturation, as opposed to a fixed deficiency (Cotton,Voudouris, & Greenwood, 2005).

Hinton and colleagues have proposed that DMD is characterized by a rather selec-tive deficit in immediate or working verbal memory (Hinton, De Vivo, Nereo, Goldstein, &Stern, 2001; Hinton, Fee, Goldstein, & De Vivo, 2007). Delayed acquisition of languagemilestones and related difficulties in reading and narrative abilities have also been described(Billard, Gillet, Barthez, Hommet, & Bertrand, 1998; Cyrulnik, Fee, De Vivo, Goldstein, &Hinton, 2007; Marini et al., 2007). However, several other studies have reported additionaldifficulties in nonverbal abilities (Cotton, Crowe, & Voudouris, 1998; Wicksell, Kihlgren,Melin, & Eeg-Olofsson, 2004). Part of this heterogeneity may have been due to differencesin sample size or comparison group. Yet, some of Hinton et al.’s own findings revealedstatistically significant differences between affected boys and siblings on tasks involvingnonverbal reasoning or facial affect recognition (Hinton, De Vivo, Fee, Goldstein, & Stern,2004; Hinton, Fee, De Vivo, & Goldstein, 2007). Thus, the exact nature of the neurobehav-ioral strengths and weaknesses of children with DMD remains unclear.

There have also been several studies that have found evidence for increased rates ofa wide range of psychosocial adjustment difficulties in boys with DMD, with attentiondeficit / hyperactivity disorder (ADHD) being most common (Hendriksen & Vles, 2008)and some authors suggesting a possible link to Autism Spectrum Disorder (Wu, Kuban,Allred, Shapiro, & Darras, 2005). Hinton, Nereo, Fee, and Cyrulnik (2006) found that,compared to unaffected siblings, boys with DMD showed the greatest degree of deficit onthe Social Problems scale of the Child Behavior Checklist (CBC; Achenbach, 2001), withdifficulties in interpersonal skills more common than mood disorders, and independent ofthe degree of cognitive or mobility impairment. However, these findings have not yet beenreplicated, and previous research has not addressed the daily executive functioning ofchildren with DMD, in terms of behavioral modulation and metacognitive skills (e.g., ini-tiation, self-monitoring). Recent investigations with various conditions have indicated thata standardized rating scale like the Behavior Rating Inventory of Executive Function(BRIEF; Gioia, Isquith, Guy, & Kenworthy, 2000) may provide important insights about achild’s actual functioning in the “real world” that cannot be ascertained from traditionallaboratory-based tests alone (Bodnar, Prahme, Cutting, Denckla, & Mahone, 2007;Vriezen & Piggott, 2002). For all of these reasons, further clarification of the neurobehav-ioral profile of children with DMD was sought in this investigation.

We hypothesized that, compared to unaffected siblings, boys with DMD wouldshow deficits in both verbal and nonverbal cognitive skills, as well as in psychosocialadjustment and daily metacognitive behaviors. We also predicted that, in the probandgroup, the psychosocial and metacognitive deficits would be largely independent of anycognitive impairment.

METHODS

Participants

Following approval from the Institutional Review Board of Mary Free Bed Rehabil-itation Hospital, probands and their siblings were recruited over a period of 18 monthsfrom a regional Muscular Dystrophy clinic. Selection criteria for all participants included

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

DUCHENNE MUSCULAR DYSTROPHY 297

age between 6 and 16 years, English as the primary language, and no concurrent con-founding factors such as a documented history of child abuse.

Diagnosis of DMD was based on clinical documentation of progressive muscleweakness before the age of 5 years, in combination with either muscle biopsy or moleculargenetic testing for mutation of the DMD gene, or both. A total of 22 of 26 eligible boyswith DMD agreed to participate. When possible, one healthy sibling without DMD livingin the same household was then recruited for each proband. If there was more than oneeligible sibling, the one closest in age was used. A total of 18 out of 20 eligible siblings(9 boys, 9 girls) agreed to participate. Informed written consent was obtained from all ofthe participants’ parents for this research and subsequent publication.

We elected not to restrict the sample to children who were free of any other psychi-atric diagnoses because those have been reported to be common in the DMD literature. Inthe complete sample, 4 probands (18%) and 2 controls (11%) had a history of ADHD. Twoprobands (9%) and 1 control (6%) were on psychotropic medications for various adjust-ment difficulties but none had a history of either psychosis or Autism Spectrum Disorder.

Both participant groups were primarily of Caucasian ethnicity (probands: n = 21,95%; siblings: n = 17, 94%). Average ages of probands (M = 11.09 years, SD = 3.01years) and siblings (M = 10.17 years, SD = 2.28 years) were not statistically significantlydifferent, t(38) = 1.18, p = .24. Fifteen probands (68%) used a wheelchair for ambulation,and 11 (50%) of them received at least some special education accommodations. Meanmaternal level of education was 13.33 years (SD = 2.28; range 10–18).

Procedure

Children were evaluated individually by the second author, on an outpatient basis,over a period of approximately 2 hours, during which parents completed standardizedratings scales about them. All participants were awarded $25 for their participation.

Measures

The Wechsler Abbreviated Scale of Intelligence (WASI; Wechsler, 1999) wasselected as the measure of psychometric intelligence because it yields Verbal and Perfor-mance IQ scores (M = 100; SD = 15) that are not confounded by fine motor coordinationor working memory demands. To investigate specific cognitive skills, subtests from theChildren’s Memory Scale (CMS; Cohen, 1997) and the Delis-Kaplan Executive FunctionSystem (D-KEFS; Delis, Kaplan, & Kramer, 2001) were utilized. The CMS includes mea-sures of immediate and 20-minute delayed, verbal (e.g., stories) and nonverbal (e.g.,faces) memory. For the Verbal subtests, measures of multiple-choice recognition memorycan also be obtained after completion of the subtests pertaining to independent delayedrecall. Overall performance on the CMS is expressed in Verbal Immediate, VerbalDelayed, Visual Immediate, Visual Delayed, and Delayed Recognition standard scores(M = 100; SD = 15), with higher scores reflecting better performance. From the D-KEFS,tasks were used that required the oral generation of as many words as possible within 1minute, based on either phonemic (Letter Fluency) or semantic (Category Fluency) cues, orthe drawing of as many different designs as possible within 1 minute (Design Fluency; filleddots version). Performance on these tasks is expressed in scaled scores (M = 10; SD = 3),with higher scores reflecting better performance. D-KEFS norms only extend to age 8, sothis test was not administered to the two probands and two siblings who were younger

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

298 J. DONDERS AND C. TANEJA

than that. From the many tasks that are available on the D-KEFS, Letter, Category, andDesign Fluency were selected because this would allow a contrast of verbal versusnonverbal skills, just like the WASI and CMS.

Parents completed the CBC as well as the BRIEF for both probands and siblings.Numerous scores can be obtained from the CBC, but in order to allow the clearest differ-entiation of adjustment and also to be consistent with previous research (Hinton et al.,2006), we focused on the eight narrow-band scales (Anxious/Depressed, Withdrawn,Somatic Complaints, Social Problems, Thought Problems, Attention Problems, RuleBreaking, and Aggressive Behavior). These scales rate children’s adjustment in age- andgender-based T-scores (M = 50; SD = 10), with higher scores reflecting worse psycho-social functioning.

The BRIEF provides information about the child’s typical daily ability to modulateemotional responses as well as to self-organize from a cognitive point of view. The great-est degree of differentiation is provided by eight narrow-band scales (Inhibit, Shift, Emo-tional Control, Initiate, Working Memory, Plan/Organize, Organization of Materials, andMonitor). These scales rate children’s daily behavior in age- and gender-based T-scores(M = 50; SD = 10), with higher scores reflecting worse executive functioning. The BRIEFalso includes validity checks for unusually (>98th percentile) inconsistent or negativereporting. BRIEF ratings of 3 of the 22 probands were considered invalid according to thiscriterion and were excluded from further analyses.

Statistical Analyses

Group differences on WASI Full Scale IQ were evaluated with a two-samples t-test,whereas the Verbal Performance discrepancy in each group was evaluated with paired-observations t-tests. Group differences on the CMS and D-KEFS were evaluated with twodifferent multivariate analyses of variance (MANOVA). Follow-up univariate analyses ofcovariance were conducted to determine if the group differences would remain statisti-cally significant after statistically controlling for Full Scale IQ. Covarying for Full ScaleIQ is somewhat controversial because it is likely that this variable is influenced by thesame brain dysfunction that may affect performance on other cognitive tests; thus, oneruns the risk of underestimating true, specific cognitive differences by controlling for FullScale IQ (Miller & Chapman, 2001). However, if boys with DMD would show statisti-cally significant worse performance on any CMS or D-KEFS variable, even after usingFull Scale IQ as a covariate, then that would suggest an especially notable deficit on thatspecific variable.

MANOVA was not considered to be appropriate for the analyses of either CBC orBRIEF because the minimally desirable participant-variable ratio (10:1) would not be met.Instead, we considered univariate contrasts for the variables of each instrument but withalpha set a priori at .01 to balance the relative risk of Type I and Type II errors.

We decided a priori that a minimum univariate effect size (η2) of .10 would berequired for any univariate contrast to be considered potentially meaningful from a clini-cal significance point of view; indicating that at least 10% of the variance in the dependentvariable could be explained by the independent variable. Finally, for those variables onwhich statistically significant group differences were found, Pearson product-momentcorrelations were calculated in the proband group to determine the degree of covariancebetween cognitive, metacognitive, and psychosocial performance levels. The squaredcorrelation coefficient (r2) reflects the amount of variance accounted for. Conventionally,

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

DUCHENNE MUSCULAR DYSTROPHY 299

values of either η2 or r2 between .10 and .24 are considered a medium effect size, andvalues ≥ .25 a large effect size (Murphy & Myors, 2004).

RESULTS

Table 1 presents the WASI IQ data of the proband and control groups. The averageFull Scale IQ of the 22 boys with DMD was statistically significantly worse than that oftheir 18 siblings, t(38) = −2.09, p = .04, η2 = .10. The Verbal-Performance discrepancywas not statistically significant in either the proband group, t(21) = 0.20, p = .84, or thesibling control group, t(17) = 1.07, p = .30. Two of the probands had a Full Scale IQ thatwas more than two SD below the mean. Because of the large variance in the IQ data, wecompared the clinical and sibling groups on the other variables (CMS, D-KEFS, CBC, andBRIEF) both with and without these two possible outliers; we found essentially the samepattern of results. For reasons of clarity, and also in order not to reduce power unnecessar-ily with an already small sample, only findings from comparisons with the completeproband group will be reported here.

Specific neuropsychological test scores are presented in Table 2. The MANOVA forthe five CMS variables yielded a statistically significant main effect of groups, F(5, 34) =3.59, p = .01. Post hoc univariate comparisons indicated that these differences were statis-tically significant for Verbal Delayed Recall, F(1, 38) = 8.84, p = .005, η2 = .19, and

Table 1 WASI IQ Scores.

Test variable

Boys with DMD (n = 22) Sibling controls (n = 18)

M SD range M SD range

Verbal IQ 91.46 17.68 55–118 101.89 16.22 75–130Performance IQ 90.77 16.09 62–119 98.17 10.17 73–109Full Scale IQ* 90.23 16.02 56–116 99.89 12.49 77–118

Note. DMD = Duchenne muscular dystrophy; WASI = Wechsler Abbreviated Scale of Intelligence.*Statistically significant group difference (p < .05).

Table 2 Neuropsychological Test Scores.

Test variable

Boys with DMD (n = 22) Sibling controls (n = 18)

M SD range M SD range

CMS Verbal Immediate 92.91 19.69 50–115 100.11 14.39 63–128CMS Verbal Delayed* 83.86 22.09 50–115 102.17 15.33 63–137CMS Visual Immediate 96.91 19.58 54–128 105.17 10.93 82–121CMS Visual Delayed* 92.86 16.15 60–121 105.89 11.36 78–121CMS Delayed Recognition 101.86 21.19 50–128 108.94 13.64 84–131D-KEFS Letter Fluency 7.35 3.66 1–15 9.25 3.07 5–15D-KEFS Category Fluency* 6.85 2.89 1–12 9.25 2.24 6–13D-KEFS Design Fluency* 8.20 2.09 3–11 10.28 2.34 6–15

Note. CMS = Children’s Memory Scale; D-KEFS = Delis-Kaplan Executive Function System.*Statistically significant univariate group contrast (p < .01).

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

300 J. DONDERS AND C. TANEJA

Visual Delayed Recall, F(1, 38) = 8.33, p = .006, η2 = .18. The MANOVA for the three D-KEFS variables also yielded a statistically significant main effect of groups, F(3, 32) =4.38, p = .01. Post hoc comparisons indicated that these differences were statisticallysignificant for Category Fluency, F(1, 34) = 7.45, p = .01, η2 = .18, and Design Fluency,F(1, 34) = 8.67, p = .006, η2 = .20. When Full Scale IQ was used as a covariate, a statisti-cally significant group difference remained only for CMS Verbal Delayed Recall (F =4.18, p = .05) whereas the group differences on the other variables were reduced tostatistically nonsignificant trends. The degree of improvement in verbal recall under a rec-ognition format in the proband group was evaluated with a t-test for paired observations,yielding a statistically significant effect, t(21) = −5.05, p < .0001.

The group profiles on the CBC and on the BRIEF are presented in, respectively,Figure 1 and Figure 2. As can be seen in Figure 1, probands received worse average rat-ings from their parents on all CBC variables than siblings. These differences were statisti-cally significant only for Withdrawn, F(1, 38) = 8.42, p = .006, η2 = .18, and SocialProblems, F(1, 38) = 7.82, p = .008, η2 = .17. Inspection of Figure 2 suggests thatprobands were also given worse average parental ratings on most BRIEF variables thantheir siblings. Group differences were statistically significant only for Shift, F(1, 35) =7.70, p = .009, η2 = .18, and Initiate, F(1, 35) = 7.22, p = .01, η2 = .17.

Because group averages can obscure the prevalence of individual parental ratingsthat can be considered clinically significant, we also computed the odds of children in bothgroups of receiving a T-score rating > 65, which has been identified as the cutoff point forratings to be in the “clinical” range (Achenbach, 2001; Gioia et al., 2000). Compared tosiblings, probands were especially more likely to have ratings in this clinically significant

Figure 1 Child Behavior Checklist (T-scores). Note. DMD = Duchenne muscular dystrophy.

Figure 2 Behavior Rating Inventory of Executive Function (T-scores). Note. DMD = Duchenne musculardystrophy.

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

DUCHENNE MUSCULAR DYSTROPHY 301

range on CBC Social Problems (Odds Ratio = 6.38; 90% confidence interval 0.99–41.23)and BRIEF Initiation (Odds Ratio = 6.07; 90% confidence interval 0.91–40.48), but this wastrue only to a lesser extent on CBC Withdrawn (Odds Ratio = 3.78; 90% confidence interval0.55–25.80) and BRIEF Shift (Odds Ratio = 2.13; 90% confidence interval 0.46–9.97).

Finally, we evaluated in the proband group, the correlations between those variableson which that group had demonstrated statistically significant worse performance than thesibling group. None of the WASI, CMS, or D-KEFS measures had a statistically significantcorrelation with either of the two CBC scales or either of the two BRIEF scales (p > .15 forall variables). The only statistically significant correlation was between the CBC With-drawn scale and the BRIEF Shift scale (r = .51, p = .03).

DISCUSSION

The purpose of this investigation was to examine the degree to which boys withDMD would demonstrate differences in neurobehavioral abilities compared to theirunaffected siblings. The results indicate that, consistent with our original hypothesis, theprobands displayed difficulties in both verbal and nonverbal cognitive domains, mani-fested in delayed recall of new information as well as fluid response generation. Further-more, although parental ratings did not suggest the presence of pervasive mood disordersin the probands, they did demonstrate relative difficulties in selected aspects of interper-sonal and metacognitive skills. As we had predicted, the latter difficulties were largelyindependent of the degree of cognitive impairment.

The current findings do not clearly support the possibility of a selective deficit inverbal skills, as has been previously suggested by some authors (Hinton et al., 2001;Hinton, Fee, Goldstein., 2007). Instead, the mild cognitive dysfunction of boys with DMDappears to extend to visual memory and nonverbal executive functioning; consistent withthe findings from Wicksell et al. (2004). However, unlike the latter authors, we found thatit was delayed memory on which the most striking group contrasts were evident. This maybe due to the fact that we used sibling controls instead of unrelated healthy peers. It shouldalso be noted that when Hinton and colleagues investigated both verbal and nonverbalmemory, they only evaluated immediate and not delayed recall (Hinton et al., 2001). Wecannot completely rule out the possibility of fatigue or motor slowing contributing to theD-KEFS tasks that were timed, but this would not explain the memory test scores, whichdid not make significant demands on fine motor skills or speed of processing.

We did find that CMS Verbal Delayed Recall was the only cognitive variable onwhich group differences remained statistically significant, even after covarying for FullScale IQ. Thus, although verbal-based skills may not necessarily be selectively impairedin children with DMD, the current findings suggest the possibility that they may bedisproportionately affected. However, this is a preliminary finding that will require repli-cation in an independent and especially larger sample because a clear limitation of thisinvestigation is that our sample size was somewhat modest. At the same time, the findingthat the performance of the proband group normalized on Delayed Recognition (which iscomposed of verbal tasks only) suggests that the underlying problem was not one ofencoding or consolidation but rather one of retrieval.

We also found group differences on some standardized ratings of children’s dailypsychosocial (CBC) and executive skills (BRIEF). Consistent with previous research(Hinton et al., 2006), children with DMD were viewed by their parents as having rela-tively greater difficulties with social integration. The finding that probands did not seem to

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

302 J. DONDERS AND C. TANEJA

have an unusual degree of somatic concerns makes it unlikely that their social problemsare the result of their motor limitations. Recent findings that have revealed some mild dif-ficulties in matching facial affects may be more relevant in this regard and point to thepossibility that children with DMD may lack the subtle social perception skills that areimportant for optimal interpersonal integration (Hinton, Fee, De Vivo, et al., 2007).

This is the first study of DMD to incorporate data from the BRIEF. The findingssuggest that, compared to their unaffected siblings, boys with DMD have relative difficul-ties with initiating social interactions and with efficiently adjusting to changes in socialcircumstances. These findings appear to be complimentary to, but not redundant with,those from the CBC. Specifically, the fact that the BRIEF Initiate scale did not correlatestrongly with either of the two CBC scales on which group differences were found sug-gests that the interpersonal inefficiencies of children with DMD are not just perceptive orreactive in nature; they may also lack the drive to “make the first move” during opportuni-ties for social interaction. The fact that the BRIEF did not correlate strongly with theWASI, CMS, or D–KEFS variables is consistent with the literature that suggests that thisparent rating of real-life behavior often provides incremental information, above andbeyond laboratory-based tests (V. A. Anderson, Anderson, Northam, Jacobs, & Mikiewicz,2002; Vriezen & Pigott, 2002).

The findings from this investigation suggest that the psychosocial and metacogni-tive difficulties of children with DMD cannot be fully explained by their cognitive dys-function because the WASI, CMS, and D-KEFS variables did not correlate significantlywith the CBC and BRIEF variables. This is consistent with previous research (Hintonet al., 2006). The consequences of DMD are likely multifactorial in nature, which raisesthe possibility of subtypes of neurobehavioral functioning. A much larger sample wouldbe needed to explore that with the appropriate statistical (e.g., cluster) analyses.

It should be noted that the cognitive and psychosocial difficulties noted in theprobands were not extreme, and that they were not universal. Furthermore, we did notconduct longitudinal tracking of these difficulties. With those reservations in mind, weconclude that children with DMD are at increased risk for a range of mild but potentiallysignificant neurobehavioral impairments, affecting verbal and nonverbal cognitivedomains, as well as some aspects of psychosocial and metacognitive abilities. Neuropsy-chological assessment, with inclusion of standardized rating scales of daily functioning,can help to identify those children who show early signs of either cognitive dysfunction orsocial adjustment difficulties, so that academic support and behavioral counseling servicescan be initiated in expedient manner as secondary and tertiary preventive interventions.Further research is needed to determine the exact reasons why children with DMD havespecific neurobehavioral impairments, and why some are more affected than others.

The neurobehavioral difficulties of children with DMD are likely related to deple-tion of brain dystrophin with associated dysfunction in a network that includes neocorticalassociation cortex and the hippocampal regions, with a potentially crucial mediating rolefor the cerebellum (Cyrulnik & Hinton, 2008; Lee et al., 2002). The cerebellum andhippocampus are part of an integrated network that includes connections to the cerebralcortex (Cotterill, 2001). Normally, dystrophin isoforms Dp427-C and Dp427-P would bedistributed to the hippocampus and Purkinje cells in the cerebellum, respectively, contrib-uting to greater postsynaptic density (Culligan & Ohlendieck, 2002). However, both dis-tributions are decreased in DMD, which is associated with altered postsynaptic plasticitythat may hinder efficient learning and memory (Vaillend, Billard, & Laroche, 2004). Moreadvanced structural (e.g., diffusion tensor tractography) as well as functional (e.g., fMRI)

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

DUCHENNE MUSCULAR DYSTROPHY 303

neuroimaging studies will be needed to address this possibility and to clarify why somechildren with DMD seem to have dysfunction in various domains whereas others appearto be largely unaffected. Therapies aimed at remediation of the observed neurobehavioraldifficulties in DMD will also need further exploration, preferably through randomizedclinical trials.

Original manuscript received September 15, 2008Revised manuscript accepted November 29, 2008

First published online January 22, 2009

REFERENCES

Achenbach, T. (2001). Child Behavior Checklist for ages 6–18. Burlington, VT: University ofVermont.

Anderson, V. A., Anderson, P., Northam, E., Jacobs, R., & Mikiewicz, O. (2002). Relationshipsbetween cognitive and behavioral measures of executive function in children with braindisease. Child Neuropsychology, 8, 231–240.

Anderson, J. L., Head, S. I., Rae, C., & Morley, J. W. (2002). Brain function in Duchenne musculardystrophy. Brain, 125, 4–13.

Billard, C., Gillet, P., Barthez, M. A., Hommet, C., & Bertrand P. (1998). Reading ability andprocessing in Duchenne muscular dystrophy and spinal muscular atrophy. DevelopmentalMedicine and Child Neurology, 40, 12–20.

Bodnar, L. E., Prahme, M. C., Cutting, L. E., Denckla, M. B., & Mahone, E. M. (2007). Constructvalidity of parent ratings of inhibitory control. Child Neuropsychology, 13, 345–362.

Cohen, M. J. (1997). Children’s Memory Scale. San Antonio, TX: Psychological Corporation.Cotterill, R. M. (2001). Cooperation of the basal ganglia, cerebellum, sensory cerebrum and

hippocampus: Possible implications for cognition, consciousness, intelligence and creativity.Progress in Neurobiology, 64, 1–33.

Cotton, S., Crowe, S. F., & Voudouris, N. (1998). Neuropsychological profile of Duchennemuscular dystrophy. Child Neuropsychology, 4, 110–117.

Cotton, S., Voudouris, N. J., & Greenwood, K. M. (2001). Intelligence and Duchenne musculardystrophy: Full-Scale, Verbal, and Performance intelligence quotients. DevelopmentalMedicine and Child Neurology, 43, 497–501.

Cotton, S. M., Voudouris, N. J., & Greenwood, K. M. (2005). Association between intellectualfunctioning and age in children and young adults with Duchenne muscular dystrophy:Further results from a meta-analysis. Developmental Medicine and Child Neurology, 47,257–265.

Culligan, K., & Ohlendieck, K. (2002). Diversity of the brain dystrophin-glycoprotein complex.Journal of Biomedicine and Biotechnology, 2, 31–36 .

Cyrulnik, S. E., Fee, R. J., De Vivo, D. C., Goldstein, E., & Hinton V. J. (2007). Delayed develop-mental milestones in children with Duchenne muscular dystrophy. Journal of Pediatrics, 150,474–478.

Cyrulnik, S. E., & Hinton, V. J. (2008). Duchenne muscular dystrophy: A cerebellar disorder?Neuroscience and Biobehavioral Reviews, 32, 486–496.

Delis, D. C., Kaplan, E., & Kramer, J. H. (2001). Delis-Kaplan Executive Function System.San Antonio, TX: Psychological Corporation.

Gioia, G. A., Isquith, P. K., Guy, S. C., & Kenworthy, L. (2000). Behavior Rating Inventory ofExecutive Function. Odessa, FL: Psychological Assessment Resources.

Hendriksen, J. G., & Vles, J. S. (2008). Neuropsychiatric disorders in males with Duchennemuscular dystrophy: Frequency rate of attention-deficit hyperactivity disorder (ADHD),autism spectrum disorder, and obsessive-compulsive disorder. Journal of Child Neurology,23, 477–481.

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014

304 J. DONDERS AND C. TANEJA

Hinton, V. J., De Vivo, D. C., Fee, R., Goldstein, E., & Stern, Y. (2004). Investigation of poor aca-demic achievement in children with Duchenne muscular dystrophy. Learning DisabilitiesResearch and Practice, 19, 146–154.

Hinton, V. J., De Vivo, D. C., Nereo, N. E., Goldstein, E., & Stern, Y. (2001). Selective deficits inverbal working memory associated with a known genetic etiology: The neuropsychologicalprofile of Duchenne muscular dystrophy. Journal of the International NeuropsychologicalSociety, 7, 45–54.

Hinton, V. J., Fee, R. J., De Vivo, D. C., & Goldstein, E. (2007). Poor facial affect recognitionamong boys with Duchenne muscular dystrophy. Journal of Autism and DevelopmentalDisorders, 37, 1925–1933.

Hinton, V. J., Fee, R. J., Goldstein, E. M., & De Vivo, D. C. (2007). Verbal and memory skills inmales with Duchenne muscular dystrophy. Developmental Medicine and Child Neurology, 49,123–128.

Hinton, V. J., Nereo, N. E., Fee, R. J., & Cyrulnik, S. E. (2006). Social behavior problems in boyswith Duchenne muscular dystrophy. Journal of Developmental and Behavioral Pediatrics, 27,470–476.

Lee, J. S., Pfund, Z., Juhasz, C., Bohen, M. E., Muzik, O., Chugani, D. C., et al. (2002). Alteredregional glucose metabolism in Duchenne muscular dystrophy: A PET study. Muscle andNerve, 26, 506–512.

Marini, A., Lorusso, M. L., D’Angelo, M. G., Civati, F., Turconi, A. C., Fabbro, F., et al. (2007).Evaluation of narrative abilities in patients suffering from Duchenne muscular dystrophy. Brainand Language, 102, 1–12.

Mehler, M. F. (2000). Brain dystrophin, neurogenetics and mental retardation. Brain ResearchReviews, 32, 277–307.

Miller, G. A., & Chapman, J. P. (2001). Misunderstanding analysis of covariance. Journal ofAbnormal Psychology, 110, 40–48.

Murphy, K. R., & Myors, B. (2004). Statistical power analysis (2nd ed.). Mahwah, NJ: Erlbaum.Vaillend, C., Billard, J. M., & Laroche, S. (2004). Impaired long-term spatial and recognition

memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient DMD(mdx) mouse.Neurobiological of Disease, 17, 10–20.

Vriezen, E. R., & Piggott, S. E. (2002). The relationship between parental report on the BRIEF andperformance-based measures of executive function in children with moderate to severetraumatic brain injury. Child Neuropsychology, 8, 296–303.

Wechsler, D. (1999). Wechsler Abbreviated Scale of Intelligence. San Antonio, TX: PsychologicalCorporation.

Wicksell, R. K., Kihlgren, M., Melin, L., & Eeg-Olofsson, O. (2004). Specific cognitive deficits arecommon in children with Duchenne muscular dystrophy. Developmental Medicine and ChildNeurology, 46, 154–159.

Wu, J. Y., Kuban, K. C. K., Allred, E., Shapiro, F., & Darras, B. T. (2005). Association of Duchennemuscular dystrophy with autism spectrum disorder. Journal of Child Neurology, 20, 790–795.

Dow

nloa

ded

by [

Uni

vers

ity o

f A

uckl

and

Lib

rary

] at

18:

00 0

5 D

ecem

ber

2014