1. Abrahams BS, Arking DE, Campbell DB, Mefford HC, Morrow EM, Weiss LA, Menashe I, Wadkins T, Banerjee-Basu S, Packer A. {{SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)}}. {Molecular autism}. 2013 Oct 3;4(1):36.
New technologies enabling genome-wide interrogation have led to a large and rapidly growing number of ASD candidate genes. Although encouraging, the volume and complexity of these data make it challenging for scientists, particularly non geneticists, to comprehensively evaluate available evidence for individual genes. Described here is the Gene Scoring module within SFARI Gene 2.0 (http://bit.ly/IttMWW), a platform developed to enable systematic community driven assessment of genetic evidence for individual genes with regard to ASD.
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2. Begeer S, Wierda M, Scheeren AM, Teunisse JP, Koot HM, Geurts HM. {{Verbal fluency in children with autism spectrum disorders: Clustering and switching strategies}}. {Autism}. 2013 Oct 3.
This study highlights differences in cognitive strategies in children and adolescents with and without autism spectrum disorders (n = 52) on a verbal fluency task (naming as many words as possible (e.g. animals) within 60 s). The ability to form clusters of words (e.g. farm animals like « cow-horse-goat ») or to switch between unrelated words (e.g. « snake » and « cat ») was analyzed using a coding method that more stringently differentiates between these strategies. Results indicated that children and adolescents with autism spectrum disorders switched less frequently, but produced slightly larger clusters than the comparison group, resulting in equal numbers of total words produced. The currently used measures of cognitive flexibility suggest atypical, but possibly equally efficient, fluency styles used by individuals with autism spectrum disorders.
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3. Campillo C, Herrera G, Remirez de Ganuza C, Cuesta JL, Abellan R, Campos A, Navarro I, Sevilla J, Pardo C, Amati F. {{Using Tic-Tac software to reduce anxiety-related behaviour in adults with autism and learning difficulties during waiting periods: A pilot study}}. {Autism}. 2013 Oct 3.
Deficits in the perception of time and processing of changes across time are commonly observed in individuals with autism. This pilot study evaluated the efficacy of the use of the software tool Tic-Tac, designed to make time visual, in three adults with autism and learning difficulties. This research focused on applying the tool in waiting situations where the participants exhibited anxiety-related behaviour. The intervention followed a baseline and intervention (AB) design, and a partial interval recording procedure was used to code the presence of stereotypes, nervous utterances, wandering or other examples of nervousness during the selected waiting situations. The results showed that the use of Tic-Tac resulted in lower levels of anxiety-related behaviour in all three participants, compared to the baseline, suggesting that this software may be an effective technology for helping people with autism with organisation and predictability during waiting periods. The results are discussed in terms of limitations and implications for further study.
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4. Cridland EK, Jones SC, Magee CA, Caputi P. {{Family-focused autism spectrum disorder research: A review of the utility of family systems approaches}}. {Autism}. 2013 Oct 3.
A family member with an autism spectrum disorder presents pervasive and bidirectional influences on the entire family system, suggesting a need for family-focused autism spectrum disorder research. While there has been increasing interest in this research area, family-focused autism spectrum disorder research can still be considered relatively recent, and there are limitations to the existing literature. The purpose of this article is to provide theoretical and methodological directions for future family-focused autism spectrum disorder research. In particular, this article proposes Family Systems approaches as a common theoretical framework for future family-focused autism spectrum disorder research by considering theoretical concepts such as Boundaries, Ambiguous Loss, Resilience and Traumatic Growth. We discuss reasons why these concepts are important to researching families living with autism spectrum disorder and provide recommendations for future research. The potential for research grounded in Family Systems approaches to influence clinical support services is also discussed.
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5. Grynszpan O, Weiss PL, Perez-Diaz F, Gal E. {{Innovative technology-based interventions for autism spectrum disorders: A meta-analysis}}. {Autism}. 2013 Oct 3.
This article reports the results of a meta-analysis of technology-based intervention studies for children with autism spectrum disorders. We conducted a systematic review of research that used a pre-post design to assess innovative technology interventions, including computer programs, virtual reality, and robotics. The selected studies provided interventions via a desktop computer, interactive DVD, shared active surface, and virtual reality. None employed robotics. The results provide evidence for the overall effectiveness of technology-based training. The overall mean effect size for posttests of controlled studies of children with autism spectrum disorders who received technology-based interventions was significantly different from zero and approached the medium magnitude, d = 0.47 (confidence interval: 0.08-0.86). The influence of age and IQ was not significant. Differences in training procedures are discussed in the light of the negative correlation that was found between the intervention durations and the studies’ effect sizes. The results of this meta-analysis provide support for the continuing development, evaluation, and clinical usage of technology-based intervention for individuals with autism spectrum disorders.
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6. Holm MB, Baird JM, Kim YJ, Rajora KB, D’Silva D, Podolinsky L, Mazefsky C, Minshew N. {{Therapeutic Horseback Riding Outcomes of Parent-Identified Goals for Children with Autism Spectrum Disorder: An ABA’ Multiple Case Design Examining Dosing and Generalization to the Home and Community}}. {J Autism Dev Disord}. 2013 Oct 4.
We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6-8 years of age participated, and counts of target behaviors were collected in each setting and phase of the study. Compared to Baseline, 70 % of the target behaviors were better during Intervention and improvement was retained in 63 % of the behaviors during Withdrawal. Increased doses of therapeutic riding were significant for magnitude of change, and the effect of the therapeutic riding sessions generalized to home and community.
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7. Ilie A, Weinstein E, Boucher A, McKinney RA, Orlowski J. {{Impaired posttranslational processing and trafficking of an endosomal Na/H exchanger NHE6 mutant (DeltaWST) associated with X-linked intellectual disability and autism}}. {Neurochemistry international}. 2013 Sep 30.
Na+/H+ exchanger NHE6/SLC9A6 is an X-linked gene that is widely expressed and especially abundant in brain, heart and skeletal muscle where it is implicated in endosomal pH homeostasis and trafficking as well as maintenance of cell polarity. Recent genetic studies have identified several mutations in the coding region of NHE6 that are linked with severe intellectual disability, autistic behavior, ataxia and other abnormalities. One such defect consists of an in-frame deletion of three amino acids (370Trp-Ser-Thr372, DeltaWST) that adjoin the predicted ninth transmembrane helix of the exchanger. To better understand the nature of this mutation, a NHE6DeltaWST construct was generated and assessed for its effects on the biochemical and cellular properties of the transporter. In transfected fibroblastic CHO and neuroblastoma SH-SY5Y cells, immunoblot analyses showed that the mutant protein was effectively synthesized, but its subsequent oligosaccharide maturation and overall half-life were dramatically reduced compared to wild-type. These changes correlated with significant accumulation of DeltaWST in the endoplasmic reticulum, with only minor sorting to the plasma membrane and negligible trafficking to recycling endosomes. The diminished accumulation in recycling endosomes was associated with a significant decrease in the rate of endocytosis of cell surface DeltaWST compared to wild-type. Furthermore, while ectopic expression of wild-type NHE6 enhanced the uptake of other vesicular cargo such as transferrin along the clathrin-mediated recycling endosomal pathway, this ability was lost in the DeltaWST mutant. Similarly, in transfected primary mouse hippocampal neurons, wild-type NHE6 was localized in discrete puncta throughout the soma and neurites, whereas the DeltaWST mutant displayed a diffuse reticular pattern. Remarkably, the extensive dendritic arborization observed in neurons expressing wild-type NHE6 was noticeably diminished in DeltaWST-transfectants. These results suggest that deletion of 370Trp-Ser-Thr372 leads to endoplasmic reticulum retention and loss of NHE6 function which potentially impacts the trafficking of other membrane-bound cargo and cell polarity.
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8. Langen M, Bos D, Noordermeer SD, Nederveen H, van Engeland H, Durston S. {{Changes in the Development of Striatum Are Involved in Repetitive Behavior in Autism}}. {Biological psychiatry}. 2013 Sep 30.
BACKGROUND: Repetitive behavior is a core feature of autism and has been linked to differences in striatum. In addition, the brain changes associated with autism appear to vary with age. However, most studies investigating striatal differences in autism are cross-sectional, limiting inferences on development. In this study, we set out to 1) investigate striatal development in autism, using a longitudinal design; and 2) examine the relationship between striatal development and repetitive behavior. METHODS: We acquired longitudinal structural magnetic resonance imaging scans from 86 individuals (49 children with autism, 37 matched control subjects). Each individual was scanned twice, with a mean scan interval time of 2.4 years. Mean age was 9.9 years at time 1 and 12.3 years at time 2. Striatal structures were traced manually with high reliability. Multivariate analyses of variance were used to investigate differences in brain development between diagnostic groups. To examine the relationship with behavior, correlations between changes in brain volumes and clinical measures were calculated. RESULTS: Our results showed an increase in the growth rate of striatal structures for individuals with autism compared with control subjects. The effect was specific to caudate nucleus, where growth rate was doubled. Second, faster striatal growth was correlated with more severe repetitive behavior (insistence on sameness) at the preschool age. CONCLUSIONS: This longitudinal study of brain development in autism confirms the involvement of striatum in repetitive behavior. Furthermore, it underscores the significance of brain development in autism, as the severity of repetitive behavior was related to striatal growth, rather than volume per se.
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9. Levitt ES, Hunnicutt BJ, Knopp SJ, Williams JT, Bissonnette JM. {{A selective 5-HT 1a receptor agonist improves respiration in a mouse model of Rett syndrome}}. {Journal of applied physiology (Bethesda, Md : 1985)}. 2013 Oct 10.
Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular inter-breath cycle. 8-Hydroxy-2-dipropylaminotetralin (8-OH-DPAT) has been shown to positively modulate these disturbances (Abdala et al, PNAS 107:18208, 2010) but the mode of action is not understood. Here we show that the selective 5-HT1a biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methy l}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity. In whole-cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current which reversed at the potassium equilibrium potential and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1a receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK) In contrast, F15599 did not activate 5-HT 1b/d receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus, F15599 activated somatodendritic 5-HT1a autoreceptors, but not axonal 5-HT 1b/d receptors. In unanaesthetized methyl-CpG-binding protein 2 (Mecp2) deficient heterozygous female mice F15599 reduced apnea in a dose dependent manner with maximal effect of 74.5 +/- 6.9 % at 0.1 mg/Kg and improved irregularity. Similarly in Mecp2 null male mice apnea was reduced by 62 +/- 6.6 % at 0.25 mg/Kg and breathing became more regular. The results indicate respiration is improved with a 5-HT1a agonist that activates GIRK channels without affecting neurotransmitter release.
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10. Luca R, Averna M, Zalfa F, Vecchi M, Bianchi F, Fata GL, Del Nonno F, Nardacci R, Bianchi M, Nuciforo P, Munck S, Parrella P, Moura R, Signori E, Alston R, Kuchnio A, Farace MG, Fazio VM, Piacentini M, De Strooper B, Achsel T, Neri G, Neven P, Evans DG, Carmeliet P, Mazzone M, Bagni C. {{The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formation}}. {EMBO molecular medicine}. 2013 Oct;5(10):1523-36.
The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression.
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11. Mazurek MO. {{Loneliness, friendship, and well-being in adults with autism spectrum disorders}}. {Autism}. 2013 Oct 3.
This study examined the relations among loneliness, friendship, and emotional functioning in adults (N = 108) with autism spectrum disorders. Participants completed self-report measures of symptoms of autism spectrum disorders, loneliness, number and nature of friendships, depression, anxiety, life satisfaction, and self-esteem. The results indicated that loneliness was associated with increased depression and anxiety and decreased life satisfaction and self-esteem, even after controlling for symptoms of autism spectrum disorders. In addition, greater quantity and quality of friendships were associated with decreased loneliness among adults with autism spectrum disorders. Multivariate models indicated that friendship did not moderate the relationship between loneliness and well-being; however, number of friends provided unique independent effects in predicting self-esteem, depression, and anxiety above and beyond the effects of loneliness. This was the first study to examine the relations among these aspects of social and emotional functioning in adults with autism spectrum disorders, and the results indicate that this topic warrants further clinical and research attention.
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12. McGonigle JJ, Migyanka JM, Glor-Scheib SJ, Cramer R, Fratangeli JJ, Hegde GG, Shang J, Venkat A. {{Development and Evaluation of Educational Materials for Pre-hospital and Emergency Department Personnel on the Care of Patients with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2013 Oct 4.
With the rising prevalence of patients with autism spectrum disorder (ASD), there has been an increase in the acute presentation of these individuals to the general health care system. Emergency medical services and emergency department personnel commonly address the health care needs of patients with ASD at times of crisis. Unfortunately, there is little education provided to front-line emergency medical technicians, paramedics and emergency nurses on the characteristics of ASD and how these characteristics can create challenges for individuals with ASD and their health care providers in the pre-hospital and emergency department settings. This paper describes the development of educational materials on ASD and the results of training of emergency medical services and emergency department personnel.
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13. Nielsen JA, Zielinski BA, Fletcher PT, Alexander AL, Lange N, Bigler ED, Lainhart JE, Anderson JS. {{Multisite functional connectivity MRI classification of autism: ABIDE results}}. {Frontiers in human neuroscience}. 2013;7:599.
Background: Systematic differences in functional connectivity MRI metrics have been consistently observed in autism, with predominantly decreased cortico-cortical connectivity. Previous attempts at single subject classification in high-functioning autism using whole brain point-to-point functional connectivity have yielded about 80% accurate classification of autism vs. control subjects across a wide age range. We attempted to replicate the method and results using the Autism Brain Imaging Data Exchange (ABIDE) including resting state fMRI data obtained from 964 subjects and 16 separate international sites. Methods: For each of 964 subjects, we obtained pairwise functional connectivity measurements from a lattice of 7266 regions of interest covering the gray matter (26.4 million « connections ») after preprocessing that included motion and slice timing correction, coregistration to an anatomic image, normalization to standard space, and voxelwise removal by regression of motion parameters, soft tissue, CSF, and white matter signals. Connections were grouped into multiple bins, and a leave-one-out classifier was evaluated on connections comprising each set of bins. Age, age-squared, gender, handedness, and site were included as covariates for the classifier. Results: Classification accuracy significantly outperformed chance but was much lower for multisite prediction than for previous single site results. As high as 60% accuracy was obtained for whole brain classification, with the best accuracy from connections involving regions of the default mode network, parahippocampaland fusiform gyri, insula, Wernicke Area, and intraparietal sulcus. The classifier score was related to symptom severity, social function, daily living skills, and verbal IQ. Classification accuracy was significantly higher for sites with longer BOLD imaging times. Conclusions: Multisite functional connectivity classification of autism outperformed chance using a simple leave-one-out classifier, but exhibited poorer accuracy than for single site results. Attempts to use multisite classifiers will likely require improved classification algorithms, longer BOLD imaging times, and standardized acquisition parameters for possible future clinical utility.
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14. Piven J, Vieland VJ, Parlier M, Thompson A, I OC, Woodbury-Smith M, Huang Y, Walters K, Fernandez B, Szatmari P. {{A molecular genetic study of autism and related phenotypes in extended pedigrees}}. {Journal of neurodevelopmental disorders}. 2013 Oct 5;5(1):30.
BACKGROUND: Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD. METHODS: We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior. RESULTS: Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas ‘repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study. CONCLUSIONS: These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD.
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15. Scott O, Richer L, Forbes K, Sonnenberg L, Currie A, Eliyashevska M, Goez HR. {{Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: An Unusual Cause of Autistic Regression in a Toddler}}. {Journal of child neurology}. 2013 Oct 3.
Anti N-methyl-d-aspartate (NMDA) receptor encephalitis in children is associated with psychiatric changes, seizures, and dyskinesias. We present the first report of autistic regression in a toddler caused by this entity. A 33-month-old boy presented with decreased appetite, irritability, and insomnia following an upper respiratory tract infection. Over the next few weeks he lost language and social skills, and abnormal movements of his hand developed. Within a month, this patient came to fit the diagnostic criteria for autistic spectrum disorder. Upon investigation, anti-NMDA receptor antibodies were found in the boy’s cerebrospinal fluid. He was treated with intravenous immunoglobulins and steroids, resulting in reacquisition of language and social skills and resolution of movements. Our case emphasizes the significance of suspecting anti-NMDA receptor encephalitis as the cause of autistic regression, even in an age group where the diagnosis of autistic spectrum disorder is typically made, and especially when presentation follows a febrile illness.
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16. Sharma S, Woolfson LM, Hunter SC. {{Maladaptive cognitive appraisals in children with high-functioning autism: Associations with fear, anxiety and theory of mind}}. {Autism}. 2013 Oct 3.
Despite the well-documented success of cognitive restructuring techniques in the treatment of anxiety disorders, there is still little clarity on which cognitions underpin fear and anxiety in children with high-functioning autism spectrum disorder. This study examined whether certain cognitive appraisals, known to be associated with fear and anxiety in typically developing groups, may help explain these emotions in children with high-functioning autism spectrum disorder. It also investigated relations between these cognitive appraisals and theory of mind. Appraisals, fear and anxiety were assessed using a vignette approach in 22 children with high-functioning autism spectrum disorders and 22 typically developing children. The two groups differed significantly on all four appraisal types. Anxiety was negatively correlated with future expectancy and positively with problem-focused coping potential in the high-functioning autism spectrum disorder group but was not correlated with appraisals in the typically developing group. The two appraisals associated with fear were emotion-focused coping potential (in the high-functioning autism spectrum disorder group only) and self-accountability (in the typically developing group only). Linear regression analysis found that appraisals of emotion-focused coping potential, problem-focused coping potential and future expectancy were significant predictors of theory-of-mind ability in the high-functioning autism spectrum disorders group. These findings indicate that specific, problematic patterns of appraisal may characterise children with high-functioning autism spectrum disorders.
