Publications by authors named "Wouter G Staal"

38 Publications

Pivotal Response Treatment for School-Aged Children and Adolescents with Autism Spectrum Disorder: A Randomized Controlled Trial.

J Autism Dev Disord 2021 Feb 9. Epub 2021 Feb 9.

Karakter Child and Adolescent Psychiatry University Centre, Reinier Postlaan 12, 6525 GC, Nijmegen, The Netherlands.

Pivotal Response Treatment (PRT) is promising for children with Autism Spectrum Disorder (ASD), but more methodologically robust designed studies are needed. In this randomized controlled trial, forty-four children with ASD, aged 9-15 years, were randomly allocated to PRT (n = 22) or treatment-as-usual (TAU; n = 22). Measurements were obtained after 12- and 20-weeks treatment, and 2-month follow-up. PRT resulted in significant greater improvements on parent-rated social-communicative skills after 12 weeks treatment (p = .004, partial η = 0.22), compared to TAU. Furthermore, larger gains in PRT compared to TAU were observed on blindly rated global functioning, and parent-rated adaptive socialization skills and attention problems. Implications for clinical practice and suggestions for future research are discussed.
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http://dx.doi.org/10.1007/s10803-021-04886-0DOI Listing
February 2021

Pivotal Response Treatment for School-Aged Children and Adolescents with Autism Spectrum Disorder: A Randomized Controlled Trial.

J Autism Dev Disord 2021 Feb 9. Epub 2021 Feb 9.

Karakter Child and Adolescent Psychiatry University Centre, Reinier Postlaan 12, 6525 GC, Nijmegen, The Netherlands.

Pivotal Response Treatment (PRT) is promising for children with Autism Spectrum Disorder (ASD), but more methodologically robust designed studies are needed. In this randomized controlled trial, forty-four children with ASD, aged 9-15 years, were randomly allocated to PRT (n = 22) or treatment-as-usual (TAU; n = 22). Measurements were obtained after 12- and 20-weeks treatment, and 2-month follow-up. PRT resulted in significant greater improvements on parent-rated social-communicative skills after 12 weeks treatment (p = .004, partial η = 0.22), compared to TAU. Furthermore, larger gains in PRT compared to TAU were observed on blindly rated global functioning, and parent-rated adaptive socialization skills and attention problems. Implications for clinical practice and suggestions for future research are discussed.
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http://dx.doi.org/10.1007/s10803-021-04886-0DOI Listing
February 2021

Self-initiations in young children with autism during Pivotal Response Treatment with and without robot assistance.

Autism 2020 11 30;24(8):2117-2128. Epub 2020 Jul 30.

Karakter Child and Adolescent Psychiatry University Centre, The Netherlands.

Lay Abstract: The initiation of social interaction is often defined as a core deficit of autism spectrum disorder. Optimizing these self-initiations is therefore a key component of Pivotal Response Treatment, an established intervention for children with autism spectrum disorder. However, little is known about the development of self-initiations during intervention and whether this development can be facilitated by robot assistance within Pivotal Response Treatment. The aim of this study was to (1) investigate the effect of Pivotal Response Treatment and robot-assisted Pivotal Response Treatment on self-initiations (functional and social) of young children with autism spectrum disorder over the course of intervention and (2) explore the relation between development in self-initiations and additional gains in general social-communicative skills. Forty-four children with autism spectrum disorder (aged 3-8 years) were included in this study. Self-initiations were assessed during parent-child interaction videos of therapy sessions and coded by raters who did not know which treatment (Pivotal Response Treatment or robot-assisted Pivotal Response Treatment) the child received. General social-communicative skills were assessed before start of the treatment, after 10 and 20 weeks of intervention and 3 months after the treatment was finalized. Results showed that self-initiations increased in both treatment groups, with the largest improvements in functional self-initiations in the group that received robot-assisted Pivotal Response Treatment. Increased self-initiations were related to higher parent-rated social awareness 3 months after finalizing the treatment.
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http://dx.doi.org/10.1177/1362361320935006DOI Listing
November 2020

International Consensus Statement for the Screening, Diagnosis, and Treatment of Adolescents with Concurrent Attention-Deficit/Hyperactivity Disorder and Substance Use Disorder.

Eur Addict Res 2020 7;26(4-5):223-232. Epub 2020 Jul 7.

Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany.

Background: Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance misuse and substance use disorder (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment and is associated with poor treatment outcomes. Research on the effect of treatment of childhood ADHD on the prevention of adolescent SUD is inconclusive, and studies on the diagnosis and treatment of adolescents with ADHD and SUD are scarce. Thus, the available evidence is generally not sufficient to justify robust treatment recommendations.

Objective: The aim of the study was to obtain a consensus statement based on a combination of scientific data and clinical experience.

Method: A modified Delphi study to reach consensus based upon the combination of scientific data and clinical experience with a multidisciplinary group of 55 experts from 17 countries. The experts were asked to rate a set of statements on the effect of treatment of childhood ADHD on adolescent SUD and on the screening, diagnosis, and treatment of adolescents with comorbid ADHD and SUD.

Results: After 3 iterative rounds of rating and adapting 37 statements, consensus was reached on 36 of these statements representing 6 domains: general (n = 4), risk of developing SUD (n = 3), screening and diagnosis (n = 7), psychosocial treatment (n = 5), pharmacological treatment (n = 11), and complementary treatments (n = 7). Routine screening is recommended for ADHD in adolescent patients in substance abuse treatment and for SUD in adolescent patients with ADHD in mental healthcare settings. Long-acting stimulants are recommended as the first-line treatment of ADHD in adolescents with concurrent ADHD and SUD, and pharmacotherapy should preferably be embedded in psychosocial treatment. The only remaining no-consensus statement concerned the requirement of abstinence before starting pharmacological treatment in adolescents with ADHD and concurrent SUD. In contrast to the majority, some experts required full abstinence before starting any pharmacological treatment, some were against the use of stimulants in the treatment of these patients (independent of abstinence), while some were against the alternative use of bupropion.

Conclusion: This international consensus statement can be used by clinicians and patients together in a shared decision-making process to select the best interventions and to reach optimal outcomes in adolescent patients with concurrent ADHD and SUD.
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http://dx.doi.org/10.1159/000508385DOI Listing
July 2020

Adherence and acceptability of a robot-assisted Pivotal Response Treatment protocol for children with autism spectrum disorder.

Sci Rep 2020 05 15;10(1):8110. Epub 2020 May 15.

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, P.O. Box 9104, 6500 HB, Nijmegen, The Netherlands.

The aim of this study is to present a robot-assisted therapy protocol for children with ASD based on the current state-of-the-art in both ASD intervention research and robotics research, and critically evaluate its adherence and acceptability based on child as well as parent ratings. The robot-assisted therapy was designed based on motivational components of Pivotal Response Treatment (PRT), a highly promising and feasible intervention focused at training "pivotal" (key) areas such as motivation for social interaction and self-initiations, with the goal of establishing collateral gains in untargeted areas of functioning and development, affected by autism spectrum disorders. Overall, children (3-8 y) could adhere to the robot-assisted therapy protocol (Mean percentage of treatment adherence 85.5%), showed positive affect ratings after therapy sessions (positive in 86.6% of sessions) and high robot likability scores (high in 79.4% of sessions). Positive likability ratings were mainly given by school-aged children (H(1) = 7.91, p = .005) and related to the movements, speech and game scenarios of the robot. Parent ratings on the added value of the robot were mainly positive (Mean of 84.8 on 0-100 scale), while lower parent ratings were related to inflexibility of robot behaviour.
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http://dx.doi.org/10.1038/s41598-020-65048-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229010PMC
May 2020

Intensive home treatment for adolescents in psychiatric crisis.

BMC Psychiatry 2019 12 19;19(1):412. Epub 2019 Dec 19.

Karakter, Child and Adolescent Psychiatry, University Centre, Reinier Postlaan 12, 6525 GC, Nijmegen, The Netherlands.

Background: Adolescents with acute psychiatric disorders are typically treated with long-term clinical admission. However, long term admission may be associated with a variety of negative outcomes. This pilot study presents a new model of care, that is, the combined application of intensive home treatment and the possibility of short term stay at a psychiatric high & intensive care.

Methods: In total 112 referred adolescents with mixed diagnoses participated in this longitudinal observational design. Clinical outcome was measured by the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) which measures the severity of multiple mental health problems. The HoNOSCA was clinician-rated at intake, after two months and after four months at discharge. Change in HoNOSCA total score was analysed with paired t-tests. Outcome moderators were gender, age, primary diagnosis, clinical admission, home treatment-time, medication and additional therapies. Follow up data were completed for 62 patients after two months and for 53 after four months.

Results: Participants aged between 11 and 18 years (M = 14.8 years, SD = 0.3; 52% female). Mean HoNOSCA total score at intake was 18.8 (SD = 5.2), after two months 13.0 (SD = 5.0); after four months resulting in a score of 9.3 (SD = 5.2). None of the moderators tested showed a significant effect on HoNOSCA scores. However, a control group could not be used because of the severe psychopathology and high risk for suicidality and the lack of an effective treatment intervention for a comparable study group.

Conclusion: With a symptom decrease of over 50% within four months as measured by the HoNOSCA, including less risk for hospitalization, this new model appears promising and of clinical relevance. Nevertheless, further research regarding stability of treatment outcome is warranted and evaluation of long-term effects of this model in follow-up studies is needed.
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http://dx.doi.org/10.1186/s12888-019-2407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924140PMC
December 2019

The effect of patients' feedback on treatment outcome in a child and adolescent psychiatric sample: a randomized controlled trial.

Eur Child Adolesc Psychiatry 2019 Jun 3;28(6):819-834. Epub 2018 Nov 3.

Karakter Child and Adolescent Psychiatry University Centre, Reinier Postlaan 12, 6525 GC, Nijmegen, The Netherlands.

The systematic use of feedback from patients on treatment progress and treatment satisfaction is a promising method to increase treatment effectiveness. The extent to which this also applies to the treatment of children with severe psychiatric problems is not clear. We conducted a Randomized Controlled Trial (RCT) to study the effect of adding Feedback Informed Treatment (FIT) to care as usual in a child psychiatric sample. Quality of Life (QoL) was used as the primary outcome measure and symptom severity as the second. Fifty-one therapists from eight Autism Care Teams in a multi-center facility for Child and Adolescent Psychiatry (Karakter) participated and were cluster randomized to the FIT condition (n = 4 teams) or the Care as Usual (CAU) condition (n = 4 teams). Children aged 6-18 years, mainly with an Autism Spectrum Disorder (ASD) and treated in one of the Autism Care Teams were allocated to the FIT condition (n = 86) or the CAU condition (n = 80). Results indicated that adding FIT leads to an increased QoL [F (2,165) = 3.16, p = 0.045]. No additional effects were observed for symptom severity decrease [F (2,158) = 0.19, p = 0.825]. No interaction with time was found for QoL nor symptom severity. Adding FIT in a child psychiatric setting may increase QoL, but does not appear to decrease symptom severity as compared with CAU. It is suggested that FIT positively changes parents' expectations. Results should be replicated in other child psychiatric samples and with an extended theoretical model.
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http://dx.doi.org/10.1007/s00787-018-1247-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555773PMC
June 2019

Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review.

Eur Child Adolesc Psychiatry 2017 Sep 3;26(9):1093-1103. Epub 2017 Jul 3.

Karakter Child and Adolescent Psychiatry University Center Nijmegen, Reinier Postlaan 12, Nijmegen, The Netherlands.

Somatic disorders occur more often in adult psychiatric patients than in the general adult population. However, in child and adolescent psychiatry this association is unclear, mainly due to a lack of integration of existing data. To address this issue, we here present a systematic review on medical comorbidity in the two major developmental disorders autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) and formulate clinical recommendations. The literature was searched using the PubMed and PsycINFO databases (2000-1 May 2016) with the keywords "[((child and adolescent) AND (Autism OR Attention Deficit Hyperactivity Disorder* OR ADHD)) AND ("Cardiovascular Diseases" [Mesh] OR "Endocrine System Diseases" [Mesh] OR "Immune System Diseases" [Mesh] OR "Neurobehavioral Manifestations" [Mesh] OR "Gastrointestinal Disorders" [Mesh] OR Somatic OR Autoimmune disease OR Nervous system disease OR Infection OR Infectious disease)]. Two raters independently assessed the quality of the eligible studies. The initial search identified 5278 articles. Based on inclusion and exclusion criteria 104 papers were selected and subsequently subjected to a quality control. This quality was assessed according to a standardized and validated set of criteria and yielded 29 studies for inclusion. This thorough literature search provides an overview of relevant articles on medical comorbidity in ADHD and/or ASD, and shows that medical disorders in these children and adolescents appear to be widespread. Those who work with children with ASD and/or ADHD should be well aware of this and actively promote routine medical assessment. Additionally, case-control studies and population-based studies are needed to provide reliable prevalence estimates. Future studies should furthermore focus on a broader evaluation of medical disorders in children and adolescents with ADHD and/or ASD to improve treatment algorithm in this vulnerable group.
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http://dx.doi.org/10.1007/s00787-017-1020-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591355PMC
September 2017

The Context of Symptom Measures: Interpretation and Clinical Diagnosis of Autism Spectrum Disorders in Intellectual Disabilities.

J Am Acad Child Adolesc Psychiatry 2017 07 21;56(7):618-619. Epub 2017 Jun 21.

Karakter Child and Adolescent Psychiatry, University Centre, Nijmegen, The Netherlands; the Donders Institute for Brain, Cognition and Behavior; Centre for Neuroscience, Nijmegen; and Radboud University Medical Center, Nijmegen.

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http://dx.doi.org/10.1016/j.jaac.2017.05.009DOI Listing
July 2017

Sleep Disturbance as a Precursor of Severe Regression in Kleefstra Syndrome Suggests a Need for Firm and Rapid Pharmacological Treatment.

Clin Neuropharmacol 2017 Jul/Aug;40(4):185-188

*Karakter Child and Adolescent Psychiatry, University Center, †Department of Psychiatry, ‡Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, and §Department of Human Genetics, Radboud University Medical Centre; ∥Centers for Molecular Life Sciences and ¶Cognition, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen; #Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray; and **Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands.

Intellectual disability is frequently accompanied by psychiatric symptoms that require pharmacological interventions. Treatment guidelines often provide a general treatment approach for these symptoms in intellectual disability. However, this may not always be the best strategy, as illustrated here in Kleefstra syndrome. We present 3 patients showing severe regression after sleep disturbances. If these are treated with care as usual (eg, behavioral programs and sleep medication) deterioration is likely to follow. It is observed that rapid treatment with relatively high dosages of antipsychotics contributes to restore sleep, halt further regression, and improve daily life functioning.
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http://dx.doi.org/10.1097/WNF.0000000000000226DOI Listing
April 2018

Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities.

Am J Med Genet A 2017 Jul 12;173(7):1821-1830. Epub 2017 May 12.

Donders Institute for Brain, Cognition and Behavior, Centre for Neuroscience, Nijmegen, The Netherlands.

Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.
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http://dx.doi.org/10.1002/ajmg.a.38280DOI Listing
July 2017

Self-regulation and quality of life in high-functioning young adults with autism.

Autism 2017 10 11;21(7):896-906. Epub 2016 Jul 11.

1 Leiden University, The Netherlands.

Background: Autism is generally associated with poor functional outcome but little is known about predictors of quality of life, especially during early adulthood. This study was conducted to assess subjective quality of life during early adulthood in high-functioning autism spectrum disorder and its relation with self-regulating abilities. Individuals with high-functioning autism spectrum disorder who progressed into post-secondary higher education ( N = 75) were compared to a typical peer control group ( N = 28) based on behavioral self-report questionnaires. The results indicated that individuals with high-functioning autism spectrum disorder reported significantly lower subjective quality of life than typical controls ( p < 0.001, effect size ( d) = 1.84). In addition, individuals with high-functioning autism spectrum disorder reported more problems with emotion processing ( p < 0.05, effect size ( d) = 0.79) and daily executive functioning ( p < 0.001, effect size ( d) = 1.29) than controls. A higher level of executive functioning problems was related to lower quality of life in the high-functioning autism spectrum disorder group, but no significant relation between level of emotion processing and subjective quality of life became apparent in the regression analysis. Our findings show that even in high-functioning young adults with autism, executive functioning, emotion processing, and subjective quality of life are low compared to typically developing peers. Furthermore, these results emphasize the importance of targeting executive functioning problems in individuals with autism to improve subjective quality of life.
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http://dx.doi.org/10.1177/1362361316655525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625847PMC
October 2017

Clinical improvement following vitamin D3 supplementation in Autism Spectrum Disorder.

Nutr Neurosci 2017 Jun 18;20(5):284-290. Epub 2016 Jan 18.

a Department of Pediatric Neurology and Neurorehabilitation , The First Hospital of Jilin University , Changchun 130021 , China.

Objective: High prevalence of vitamin D deficiency was previously reported in children with Autism Spectrum Disorder (ASD), but little is known about the efficacy of vitamin D3 treatment in ASD, although data from pilot studies seem promising. We hypothesized that serum vitamin D levels are reduced in ASD and correlate with the severity of disease. Also, we hypothesized that vitamin D3 treatment may be beneficial for a considerable portion of children with ASD.

Methods: In total, 215 children with ASD and 285 healthy control children were recruited in our study. Thirty seven of 215 ASD children received vitamin D3 treatment. The Autism Behaviour Checklist (ABC) and the Childhood Autism Rating Scale (CARS) were used to assess autism symptoms. High-performance liquid chromatography was used to assess the serum 25-hydroxyvitamin D [25(OH) D] level. Evaluations of ABC, CARS, and serum 25(OH) D levels were performed before and after 3 months of treatment.

Results: Serum levels of 25(OH) D were significantly lower in ASD children than typically developing children. Levels of serum 25(OH) D were negatively correlated with ABC total scores and language subscale scores. After vitamin D3 supplementation, symptom scores were significantly reduced on the CARS and ABC. In addition, the data also suggest that treatment effects were more pronounced in younger children with ASD.

Conclusion: Vitamin D deficiency might contribute to the aetiology of ASD. Supplementation of vitamin D3, which is a safe and cost-effective form of treatment, may significantly improve the outcome of some children with ASD, especially younger children (identifier ChiCTR-CCC-13004498).

Clinical Trial Registration: The trial 'Association of Polymorphisms of Vitamin D Metabolism-Related Genes With Autism and the Treatment of Autism with Vitamin D' has been registered at www.chictr.org/cn/proj/show.aspx? proj=6135 (identifier ChiCTR-CCC-13004498).
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http://dx.doi.org/10.1080/1028415X.2015.1123847DOI Listing
June 2017

Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: a systematic review and meta-analysis.

Eur Child Adolesc Psychiatry 2016 Apr 29;25(4):341-50. Epub 2015 Oct 29.

Department of Pediatric Neurology and Neurorehabilitation, The First Hospital of Jilin University, No. 71, Xinmin Street, Changchun, Jilin, 130021, China.

Vitamin D may play an important role in the etiology of Autism Spectrum Disorders (ASD). Vitamin D is regarded as a neuroactive steroid affecting brain development and function. It plays an essential role in myelination, which is important for connectivity in the brain. Studies have shown that decreased vitamin D levels in patients, decreased maternal vitamin D levels during pregnancy, and decreased exposure to solar UVB might increase the risk for ASD. In addition, autism symptoms and global functioning may improve after vitamin D supplementation. Here, we sought to aggregate information from previous publications on vitamin D levels and ASD, in order to achieve a higher statistical power and thereby to determine the validity of vitamin D deficiency as a risk factor for ASD. For this meta-analysis, 11 studies met the inclusion and exclusion criteria, accounting for a total of 870 ASD patients and 782 healthy controls. Levels of serum 25(OH) D in participants with ASD were significantly lower than controls, suggesting that lower vitamin D level might be a risk factor for ASD.
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http://dx.doi.org/10.1007/s00787-015-0786-1DOI Listing
April 2016

A Pilot Study on the Combination of Applied Behavior Analysis and Bumetanide Treatment for Children with Autism.

J Child Adolesc Psychopharmacol 2015 Sep 10;25(7):585-8. Epub 2015 Aug 10.

1 Department of Pediatric Neurology and Neurorehabilitation, The First Hospital of Jilin University , Changchun, China .

Objective: The purpose of this study was to investigate the therapeutic effects of combined bumetanide and applied behavior analysis (ABA) treatment in children with autism.

Methods: Sixty children diagnosed with autism according to the International Classification of Diseases, Tenth Revision (ICD-10) criteria (mean age of 4.5 years) were randomly divided into two groups: A single treatment group (n=28) and a combined treatment group (n=32). The combined treatment group received ABA training combined with oral bumetanide (0.5 mg twice a day). The single treatment group received ABA training only. Autism symptoms were evaluated with the Autism Behavior Checklist (ABC) and the Childhood Autism Rating Scale (CARS), whereas severity of disease (SI) and global improvement (GI) were measured with the Clinical Global Impressions (CGI). Assessment of ABC, CARS, and CGI was performed immediately before and 3 months after initiation of the treatment(s).

Results: Prior to intervention(s) no statistically significant differences in scores on the ABC, CARS, SI, or GI were found between the two groups. Total scores of the ABC, CARS, and SI were decreased in both groups after 3 months (p<0.05) compared with the scores prior to treatment. The total scores of the ABC and the CGI were significantly (p<0.05) lower in the combined treatment group than in the single treatment group. Although the total and item scores of the CARS in the combined treatment group were lower than in the single treatment group after a 3 month intervention, they did not reach statistical significance. No adverse effects of bumetanide were observed.

Conclusions: Treatment with bumetanide combined with ABA training may result in a better outcome in children with autism than ABA training alone.
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http://dx.doi.org/10.1089/cap.2015.0045DOI Listing
September 2015

Stop and change: inhibition and flexibility skills are related to repetitive behavior in children and young adults with autism spectrum disorders.

J Autism Dev Disord 2015 Oct;45(10):3148-58

Department of Child and Adolescent Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Cognitive control dysfunctions, like inhibitory and attentional flexibility deficits are assumed to underlie repetitive behavior in individuals with autism spectrum disorders (ASD). In the present study, prepotent response inhibition and attentional flexibility were examined in 64 high-functioning individuals with ASD and 53 control participants. Performance under different task conditions were tested both in response to visual and auditory information, and requiring a motor or verbal response. Individuals with ASD showed significant more control dysfunctions than typically developing participants on the auditory computer task. Inhibitory control and attentional flexibility predicted RRB in everyday life. Specifically, response inhibition in reaction to visual information and task switching in reaction to auditory information predicted motor and sensory stereotyped behavior.
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http://dx.doi.org/10.1007/s10803-015-2473-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569655PMC
October 2015

DRD3 gene and striatum in autism spectrum disorder.

Br J Psychiatry 2015 May 19;206(5):431-2. Epub 2015 Mar 19.

Wouter G. Staal, MD, PhD, Department of Psychiatry, Radboud University, Nijmegen Medical Centre, Karakter Centre for Child and Adolescent Psychiatry, Nijmegen; Marieke Langen, PhD, Sarai van Dijk, MS, Vincent T. Mensen, MS, Sarah Durston, PhD, NICHE-lab, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.

A single-nucleotide polymorphism (SNP) of the DRD3 gene (rs167771) was recently associated with autism spectrum disorders (ASD). Different polymorphisms of rs167771 corresponded to varying degrees of stereotyped behaviour. As DRD3 receptors are relatively overexpressed in the striatum, we investigated whether striatal volume was related to these polymorphisms in autism. We assessed volumes of caudate nucleus and putamen in 86 participants with ASD (mean age 15.3 years). MANCOVA showed an association between alleles of the rs167771 SNP and the volume of striatal structures. Furthermore, greater caudate nucleus volume correlated with stereotyped behaviour. These findings support a relationship between DRD3 gene SNPs, striatum and stereotyped behaviour in ASD.
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http://dx.doi.org/10.1192/bjp.bp.114.148973DOI Listing
May 2015

Core symptoms of autism improved after vitamin D supplementation.

Pediatrics 2015 Jan 15;135(1):e196-8. Epub 2014 Dec 15.

Department of Pediatric Neurology and Neurorehabilitation, The First Hospital of Jilin University, Changchun, China;

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by a complex interaction between genetic and environmental risk factors. Among the environmental factors, vitamin D3 (cholecaliferol) seems to play a significant role in the etiology of ASD because this vitamin is important for brain development. Lower concentrations of vitamin D3 may lead to increased brain size, altered brain shape, and enlarged ventricles, which have been observed in patients with ASD. Vitamin D3 is converted into 25-hydroxyvitamin D3 in the liver. Higher serum concentrations of this steroid may reduce the risk of autism. Importantly, children with ASD are at an increased risk of vitamin D deficiency, possibly due to environmental factors. It has also been suggested that vitamin D3 deficiency may cause ASD symptoms. Here, we report on a 32-month-old boy with ASD and vitamin D3 deficiency. His core symptoms of autism improved significantly after vitamin D3 supplementation. This case suggests that vitamin D3 may play an important role in the etiology of ASD, stressing the importance of clinical assessment of vitamin D3 deficiency and the need for vitamin D3 supplementation in case of deficiency.
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http://dx.doi.org/10.1542/peds.2014-2121DOI Listing
January 2015

Autism, DRD3 and repetitive and stereotyped behavior, an overview of the current knowledge.

Authors:
Wouter G Staal

Eur Neuropsychopharmacol 2015 Sep 1;25(9):1421-6. Epub 2014 Sep 1.

Department of Psychiatry RadboudUMC, Nijmegen, The Netherlands; Donders Centre for Neuroscience, Reinier Postlaan 12, 6525 GC Nijmegen, The Netherlands; Karakter, Centre for Child & Adolescent Psychiatry, Nijmegen, The Netherlands. Electronic address:

The SNP rs167771 of the dopamine-3-receptor gene (DRD3) has been associated with autism spectrum disorder (ASD) in samples from the United Kingdom, The Netherlands and Spain. The DRD3 polymorphisms of rs167771 are significantly associated with a specific type of repetitive and stereotyped behavior, called sameness. Repetitive and stereotyped behavior occurs in several neuropsychiatric disorders and the combined picture across these disorders strongly suggests the involvement of the basal ganglia - frontal lobe circuitry. In autism, abnormalities of the basal ganglia, in particular the caudate nucleus, are the best replicated findings in neuroimaging studies. Interestingly, the DRD3 gene is highly expressed in the basal ganglia, most notably the caudate nucleus. The rs167771 SNP was recently also found to be related to risperidone-induced extra-pyramidal side effects (EPS) in patients with autism, which is important since risperidone is approved for the treatment of aggression, irritability and rigid behavior in ASD. To conclude, striatum abnormalities in autism are associated with repetitive and stereotyped behavior in autism and may be related to DRD3 polymorphisms.
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http://dx.doi.org/10.1016/j.euroneuro.2014.08.011DOI Listing
September 2015

Differences in body mass index z-scores and weight status in a Dutch pediatric psychiatric population with and without use of second-generation antipsychotics.

J Child Adolesc Psychopharmacol 2012 Apr;22(2):166-73

Faculty of Pharmaceutical Sciences, University of Utrecht, The Netherlands.

Objective: Weight gain and metabolic adverse effects of second-generation antipsychotics (SGAs) have become a major concern, particularly in youth. However, the specific contribution of SGAs versus other medications or the underlying illness is unclear.

Methods: In a chart review study of psychiatric outpatients aged ≤ 18 years treated with SGAs and psychiatric controls without lifetime SGA, use body mass index (BMI) z-scores between patients and controls were compared in the entire sample, patients without co-medications, diagnostic subgroups, and age subgroups. In patients with follow-up data, weight z-score change was calculated.

Results: Altogether, 592 Caucasian patients aged 4-18 (mean: 10.0) years with a psychiatric diagnosis were included. BMI z-scores in 96 youth treated with SGAs for 9.0 ± 6.1 months were significantly higher than in 496 patients without lifetime SGA use (0.81 ± 1.1 vs. 0.05 ± 1.2; p<0.0001). BMI z-score differences remained significant in all age groups <16 years old. In sub-analyses, results remained the same after eliminating patients on any co-medication (0.82 ± 1.2 vs. 0.23 ± 1.2; p<0.0001) and in patients with (0.75 ± 1.2 vs. 0.17 ± 1.1, p<0.0001) or without autism spectrum disorders (1.1 ± 1.0 vs. -0.02 ± 1.2, p<0.0001). Significantly more SGA-treated youth were obese (27.1% vs. 9.5%, odds ratio [OR]: 3.55, 95% confidence interval [CI]:2.07-6.08) or overweight (21.9% vs. 8.3%, OR: 3.11, 95%CI: 1.75-5.52). In 24 patients (92.3% antipsychotic-naïve) with 6.6 months follow-up, weight z-score increased significantly from -0.17 ± 1.5 to 0.25 ± 1.4 (p<0.0001) with 12.5% transitioning to overweight or obese status.

Conclusion: These data show robust and significant differences in sex- and age-adjusted body weight and weight status in young pediatric Caucasian samples with and without use of SGAs independent of Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000 ) diagnosis and nonantipsychotic medications. Weight status and metabolic effects of SGAs require careful attention, especially in youth.
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http://dx.doi.org/10.1089/cap.2011.0079DOI Listing
April 2012

Social Responsiveness Scale-aided analysis of the clinical impact of copy number variations in autism.

Neurogenetics 2011 Nov 12;12(4):315-23. Epub 2011 Aug 12.

Department of Child and Adolescent Psychiatry, University Medical Centre, Utrecht, The Netherlands.

Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient's phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders.
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http://dx.doi.org/10.1007/s10048-011-0297-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215885PMC
November 2011

Brief report: the dopamine-3-receptor gene (DRD3) is associated with specific repetitive behavior in autism spectrum disorder (ASD).

J Autism Dev Disord 2012 May;42(5):885-8

Karakter, Radboud University Nijmegen Medical Centre (Cognitive Neuroscience), Reinierpostlaan 12, 6525 CG Nijmegen, The Netherlands.

Recently the DRD3 gene has been associated with ASD in two independent samples. Follow up analysis of the risk allele of the SNP rs167771 in 91 subjects revealed a significant association with a specific type of repetitive behavior: the factor "insistence on sameness" (IS) derived from the Autism Diagnostic Interview. This risk allele was associated with a decreased risk for IS, but not with any other symptomatology. Further study and replication of this finding is necessary, bearing in mind that these results would not be statistically significant if corrected for multiple testing.
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http://dx.doi.org/10.1007/s10803-011-1312-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324694PMC
May 2012

Paternal age and psychiatric disorders: findings from a Dutch population registry.

Schizophr Res 2011 Jul 12;129(2-3):128-32. Epub 2011 Apr 12.

Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Background: We measured the association between paternal age and schizophrenia (SCZ), autism spectrum disorders (ASD), major depressive disorder (MDD), and bipolar disorder (BPD) in the Dutch population.

Methods: In total, 14231 patients and 56924 matched controls were collected and analyzed for an association with paternal age by logistic regression.

Results: ASD is significantly associated with increased paternal age: Older fathers >40 years of age have a 3.3 times increased odds of having a child with ASD compared to young fathers <20 years of age. SCZ has significant associations for fathers aged >35 years (OR=1.27, 95% Confidence Interval: 1.05 and 1.53). For MDD, both younger and older fathers have increased odds. No association was found for BPD.

Conclusions: The effects of paternal age as a risk factor are different for ASD and SCZ on one hand, and the affective disorders on the other hand. Different types of association might indicate different biological or psychosocial mechanisms. Late paternity (associated with predispositions to psychiatric disorders) seems the most probable explanation for the association with paternal age.
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http://dx.doi.org/10.1016/j.schres.2011.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110532PMC
July 2011

Morphological features in children with autism spectrum disorders: a matched case-control study.

J Autism Dev Disord 2011 Jan;41(1):23-31

Department of Child and Adolescent Psychiatry, University Medical Center, Utrecht, The Netherlands.

This study was designed to examine morphological features in a large group of children with autism spectrum disorder versus normal controls. Amongst 421 patients and 1,007 controls, 224 matched pairs were created. Prevalence rates and odds ratios were analyzed by conditional regression analysis, McNemar test or paired t-test matched pairs. Morphological abnormalities were significantly more prevalent in patients with autism than in the normal control group and 48 morphological features distinguished patients from controls. Our findings show that morphological features are associated with autism. Exploring potential underlying genetic mechanisms of this association might lead to a better understanding of autism.
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http://dx.doi.org/10.1007/s10803-010-1018-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005119PMC
January 2011

Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia.

Biol Psychiatry 2010 Aug 26;68(4):320-8. Epub 2010 Mar 26.

The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Background: Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral deficits and complex genetic etiology. A recent study of 517 ASD families implicated DOCK4 by single nucleotide polymorphism (SNP) association and a microdeletion in an affected sibling pair.

Methods: The DOCK4 microdeletion on 7q31.1 was further characterized in this family using QuantiSNP analysis of 1M SNP array data and reverse transcription polymerase chain reaction. Extended family members were tested by polymerase chain reaction amplification of junction fragments. DOCK4 dosage was measured in additional samples using SNP arrays. Since QuantiSNP analysis identified a novel CNTNAP5 microdeletion in the same affected sibling pair, this gene was sequenced in 143 additional ASD families. Further polymerase chain reaction-restriction fragment length polymorphism analysis included 380 ASD cases and suitable control subjects.

Results: The maternally inherited microdeletion encompassed chr7:110,663,978-111,257,682 and led to a DOCK4-IMMP2L fusion transcript. It was also detected in five extended family members with no ASD. However, six of nine individuals with this microdeletion had poor reading ability, which prompted us to screen 606 other dyslexia cases. This led to the identification of a second DOCK4 microdeletion co-segregating with dyslexia. Assessment of genomic background in the original ASD family detected a paternal 2q14.3 microdeletion disrupting CNTNAP5 that was also transmitted to both affected siblings. Analysis of other ASD cohorts revealed four additional rare missense changes in CNTNAP5. No exonic deletions of DOCK4 or CNTNAP5 were seen in 2091 control subjects.

Conclusions: This study highlights two new risk factors for ASD and dyslexia and demonstrates the importance of performing a high-resolution assessment of genomic background, even after detection of a rare and likely damaging microdeletion using a targeted approach.
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http://dx.doi.org/10.1016/j.biopsych.2010.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941017PMC
August 2010

The neurobiology of repetitive behavior: of mice….

Neurosci Biobehav Rev 2011 Jan 13;35(3):345-55. Epub 2010 Feb 13.

Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.

Repetitive and stereotyped behavior is a prominent element of both animal and human behavior. Similar behavior is seen across species, in diverse neuropsychiatric disorders and in key phases of typical development. This raises the question whether these similar classes of behavior are caused by similar neurobiological mechanisms or whether they are neurobiologically unique? In this paper we discuss fundamental animal research and translational models. Imbalances in corticostriatal function often result in repetitive behavior, where different classes of behavior appear to be supported by similar neural mechanisms. Although the exact nature of these imbalances are not yet fully understood, synthesizing the literature in this area provides a framework for studying the neurobiological systems involved in repetitive behavior.
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http://dx.doi.org/10.1016/j.neubiorev.2010.02.004DOI Listing
January 2011

The neurobiology of repetitive behavior: …and men.

Neurosci Biobehav Rev 2011 Jan 12;35(3):356-65. Epub 2010 Feb 12.

Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.

In young, typically developing children, repetitive behavior similar to that in certain neuropsychiatric syndromes is common. Whereas this behavior is adaptive in typical development, in many disorders it forms a core component of symptoms and causes prominent impairment in the daily life of affected individuals. Understanding the neurobiological mechanisms involved repetitive behavior will improve our understanding of the pathogenesis of developmental neuropsychiatric disorders, stimulating novel approaches to these conditions. However, studies on the neurobiology of human repetitive behavior have often been limited to distinct conditions and generalization has been hindered by inconsistent terminology. In this paper, we synthesize the 'disorder-driven' literature, building on findings from fundamental animal research and translational models. These findings suggest a model for classifying repetitive behavior by its neuroanatomical correlates.
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http://dx.doi.org/10.1016/j.neubiorev.2010.02.005DOI Listing
January 2011

A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder.

Am J Med Genet B Neuropsychiatr Genet 2010 Jun;153B(4):960-6

Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht, The Netherlands.

High resolution genomic copy-number analysis has shown that inherited and de novo copy-number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR analysis revealed over 70% increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94% in patients vs. 0.42% controls, P = 0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale.
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http://dx.doi.org/10.1002/ajmg.b.31055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933514PMC
June 2010

Systematic genotype-phenotype analysis of autism susceptibility loci implicates additional symptoms to co-occur with autism.

Eur J Hum Genet 2010 May 25;18(5):588-95. Epub 2009 Nov 25.

Rudolf Magnus Institute of Neurosciences, Department of Psychiatry, University Medical Centre, Heidelberglaan, Utrecht, The Netherlands.

Many genetic studies in autism have been performed, resulting in the identification of multiple linkage regions and cytogenetic aberrations, but little unequivocal evidence for the involvement of specific genes exists. By identifying novel symptoms in these patients, enhanced phenotyping of autistic individuals not only improves understanding and diagnosis but also helps to define biologically more homogeneous groups of patients, improving the potential to detect causative genes. Supported by recent copy number variation findings in autism, we hypothesized that for some susceptibility loci, autism resembles a contiguous gene syndrome, caused by aberrations within multiple (contiguous) genes, which jointly increases autism susceptibility. This would result in various different clinical manifestations that might be rather atypical, but that also co-occur with autism. To test this hypothesis, 13 susceptibility loci, identified through genetic linkage and cytogenetic analyses, were systematically analyzed. The Online Mendelian Inheritance in Man database was used to identify syndromes caused by mutations in the genes residing in each of these loci. Subsequent analysis of the symptoms expressed within these disorders allowed us to identify 33 symptoms (significantly more than expected, P=0.037) that were over-represented in previous reports mapping to these loci. Some of these symptoms, including seizures and craniofacial abnormalities, support our hypothesis as they are already known to co-occur with autism. These symptoms, together with ones that have not previously been described to co-occur with autism, might be considered for use as inclusion or exclusion criteria toward defining etiologically more homogeneous groups for molecular genetic studies of autism.
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http://dx.doi.org/10.1038/ejhg.2009.206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987310PMC
May 2010

Gene-network analysis identifies susceptibility genes related to glycobiology in autism.

PLoS One 2009 May 28;4(5):e5324. Epub 2009 May 28.

Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005324PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683930PMC
May 2009