1. {{A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults With Autism Spectrum Disorder: Erratum}}. {J Clin Psychopharmacol}. 2016; 36(4): 339.
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2. {{Pride in autistic diversity}}. {Lancet}. 2016; 387(10037): 2479.
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3. Ashwood KL, Gillan N, Horder J, Hayward H, Woodhouse E, McEwen FS, Findon J, Eklund H, Spain D, Wilson CE, Cadman T, Young S, Stoencheva V, Murphy CM, Robertson D, Charman T, Bolton P, Glaser K, Asherson P, Simonoff E, Murphy DG. {{Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire}}. {Psychol Med}. 2016: 1-10.
BACKGROUND: Many adults with autism spectrum disorder (ASD) remain undiagnosed. Specialist assessment clinics enable the detection of these cases, but such services are often overstretched. It has been proposed that unnecessary referrals to these services could be reduced by prioritizing individuals who score highly on the Autism-Spectrum Quotient (AQ), a self-report questionnaire measure of autistic traits. However, the ability of the AQ to predict who will go on to receive a diagnosis of ASD in adults is unclear. METHOD: We studied 476 adults, seen consecutively at a national ASD diagnostic referral service for suspected ASD. We tested AQ scores as predictors of ASD diagnosis made by expert clinicians according to International Classification of Diseases (ICD)-10 criteria, informed by the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and Autism Diagnostic Interview-Revised (ADI-R) assessments. RESULTS: Of the participants, 73% received a clinical diagnosis of ASD. Self-report AQ scores did not significantly predict receipt of a diagnosis. While AQ scores provided high sensitivity of 0.77 [95% confidence interval (CI) 0.72-0.82] and positive predictive value of 0.76 (95% CI 0.70-0.80), the specificity of 0.29 (95% CI 0.20-0.38) and negative predictive value of 0.36 (95% CI 0.22-0.40) were low. Thus, 64% of those who scored below the AQ cut-off were ‘false negatives’ who did in fact have ASD. Co-morbidity data revealed that generalized anxiety disorder may ‘mimic’ ASD and inflate AQ scores, leading to false positives. CONCLUSIONS: The AQ’s utility for screening referrals was limited in this sample. Recommendations supporting the AQ’s role in the assessment of adult ASD, e.g. UK NICE guidelines, may need to be reconsidered.
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4. Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, Garcia-Esteban R, Galan IR, Tardon A, Rodriguez-Bernal CL, Iniguez C, Andiarena A, Santa-Marina L, Sunyer J. {{Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms}}. {Int J Epidemiol}. 2016.
BACKGROUND: Acetaminophen is extensively used during pregnancy. But there is a lack of population-representative cohort studies evaluating its effects on a range of neuropsychological and behavioural endpoints. We aimed to assess whether prenatal exposure to acetaminophen is adversely associated with neurodevelopmental outcomes at 1 and 5 years of age. METHODS: This Spanish birth cohort study included 2644 mother-child pairs recruited during pregnancy. The proportion of liveborn participants evaluated at 1 and 5 years was 88.8% and 79.9%, respectively. Use of acetaminophen was evaluated prospectively in two structured interviews. Ever/never use and frequency of use (never, sporadic, persistent) were measured. Main neurodevelopment outcomes were assessed using Childhood Autism Spectrum Test (CAST), Conner’s Kiddie Continuous Performance Test (K-CPT) and ADHD-DSM-IV form list. Regression models were adjusted for social determinants and co-morbidities. RESULTS: Over 40% of mothers reported using acetaminophen. Ever-exposed offspring had higher risks of presenting more hyperactivity/impulsivity symptoms [incidence rate ratio (IRR) = 1.41, 95% confidence interval (CI) 1.01-1.98), K-CPT commission errors (IRR = 1.10, 1.03-1.17), and lower detectability scores (coefficient beta = -0.75, -0.13–0.02). CAST scores were increased in ever-exposed males (beta = 0.63, 0.09-1.18). Increased effect sizes of risks by frequency of use were observed for hyperactivity/impulsivity symptoms (IRR = 2.01, 0.95-4.24) in all children, K-CPT commission errors (IRR = 1.32, 1.05-1.66) and detectability (beta = -0.18, -0.36-0.00) in females, and CAST scores in males (beta = 1.91, 0.44-3.38). CONCLUSIONS: Prenatal acetaminophen exposure was associated with a greater number of autism spectrum symptoms in males and showed adverse effects on attention-related outcomes for both genders. These associations seem to be dependent on the frequency of exposure.
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5. Boilson AM, Staines A, Ramirez A, Posada M, Sweeney MR. {{Operationalisation of the European Protocol for Autism Prevalence (EPAP) for Autism Spectrum Disorder Prevalence Measurement in Ireland}}. {J Autism Dev Disord}. 2016.
The European Autism Information System project highlighted the lack of systematic and reliable data relating to the prevalence of autism spectrum disorders in Europe. A protocol for the study of ASD prevalence at European level was developed to facilitate a common format for screening and diagnosing children across the EU. This is the first study to operationalise and screen national school children for ASDs using this protocol. National school children 6-11 years (N = 7951) were screened males 54 % (N = 4268) females 46 % (N = 3683). Screening children for ASD implementing the EAIS protocol using the Social Communication Questionnaire (Rutter et al. in Social Communication Questionnaire (SCQ). Western Psychological Services, Los Angeles, ) as a first level screening instrument in a non-clinical setting of Irish national schools was demonstrated.
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6. Bonatto SJ, Kerner M, Merelles S, Ponde MP. {{The prevalence of symptoms of attention-deficit/hyperactivity disorder in parents of children with autism spectrum disorder}}. {Psychiatry Res}. 2016; 240: 1-3.
This study aims to estimate the prevalence of symptoms of attention-deficit/hyperactivity disorder (ADHD) in parents of children with autism spectrum disorder (ASD). This is a cross-sectional study conducted with the parents of 89 children previously diagnosed with ASD. The research instrument used was the 18-item Adult ADHD Self-Report Scale (ASRS). Symptoms of ADHD were present in 10.4% of the mothers of children with a diagnosis of ASD and in 11.3% of the fathers. These results suggest that the prevalence of symptoms of ADHD in the parents of children with autism is higher than that found in the general adult population.
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7. Carther-Krone TA, Shomstein S, Marotta JJ. {{Looking without Perceiving: Impaired Preattentive Perceptual Grouping in Autism Spectrum Disorder}}. {PLoS One}. 2016; 11(6): e0158566.
Before becoming aware of a visual scene, our perceptual system has organized and selected elements in our environment to which attention should be allocated. Part of this process involves grouping perceptual features into a global whole. Individuals with autism spectrum disorders (ASD) rely on a more local processing strategy, which may be driven by difficulties perceptually grouping stimuli. We tested this notion using a line discrimination task in which two horizontal lines were superimposed on a background of black and white dots organized so that, on occasion, the dots induced the Ponzo illusion if perceptually grouped together. Results showed that even though neither group was aware of the illusion, the ASD group was significantly less likely than typically developing group to make perceptual judgments influenced by the illusion, revealing difficulties in preattentive grouping of visual stimuli. This may explain why individuals with ASD rely on local processing strategies, and offers new insight into the mechanism driving perceptual grouping in the typically developing human brain.
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8. Cheak-Zamora NC, Teti M, Maurer-Batjer A, Halloran D. {{Snapshots of Growing Up: Youth with Autism Explore Adulthood Through Photovoice}}. {J Dev Behav Pediatr}. 2016; 37(6): 433-41.
OBJECTIVE: Youth with autism spectrum disorder (ASD) experience significant challenges transitioning to adulthood. We utilized Photovoice to better understand youth’s desires for and perspectives on becoming adults. METHOD: Youth with ASD (N = 11) photographed their life experiences, attended group and individual photo-sharing and discussion sessions, and exhibited their work publicly. Thematic analysis was used to identify salient recurring patterns in the data. RESULTS: Thematic analysis identified important topics in session transcripts and 184 photographs. Youth with ASD expressed many perspectives about their adult lives, which centered around 3 themes: the meaning of adulthood; desire for independent living; and employment goals. CONCLUSION: Findings identified what youth with ASD want and need to achieve adulthood. This study demonstrated the utility of a new methodology to provide opportunities for youth to share their experiences and define their priorities.
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9. Cruchet S, Lucero Y, Cornejo V. {{Truths, Myths and Needs of Special Diets: Attention-Deficit/Hyperactivity Disorder, Autism, Non-Celiac Gluten Sensitivity, and Vegetarianism}}. {Ann Nutr Metab}. 2016; 68 Suppl 1: 43-50.
Different dietary approaches have been attempted for the treatment of attention-deficit/hyperactivity disorder and autism, but only three of them have been subjected to clinical trials: education in healthy nutritional habits, supplementation and elimination diets. On the other hand, for multiple reasons, the number of people who adopt vegetarian and gluten-free diets (GFD) increases daily. More recently, a new entity, non-celiac gluten sensitivity (NCGS), with a still evolving definition and clinical spectrum, has been described. Although, the benefits of GFD are clearly supported in this condition as well as in celiac disease, in the last two decades, GFD has expanded to a wider population. In this review, we will attempt to clarify, according to the existing evidence, which are the myths and facts of these diets.
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10. Fletcher FE, Foster-Owens MD, Conduit R, Rinehart NJ, Riby DM, Cornish KM. {{The development trajectory of parent-report and objective sleep profiles in autism spectrum disorder: Associations with anxiety and bedtime routines}}. {Autism}. 2016.
The present study compared the course of parent-report and actigraphy-derived sleep profiles over a 1-year period, in school-age children with autism spectrum disorder and typically developing children. The Children’s Sleep Habits Questionnaire and 14 nights of actigraphy were used to assess sleep profiles. Parents also completed the Spence Children’s Anxiety Scale, the Social Worries Questionnaire and the Bedtime Routines Questionnaire. Between-group differences in parent-reported sleep problems were less pronounced at follow-up compared to baseline. The course of objective sleep was comparable between groups, with a significant reduction in sleep duration over time in both groups. Children with autism spectrum disorder were further characterised by significantly more night-to-night variability in sleep quality, across both time points. Reductions over time in parent-reported sleep problems were significantly associated with reduced anxiety. Reductions in actigraphy-derived sleep efficiency were associated with an increased frequency of maladaptive activities in the hour before bedtime, in both children with and without autism spectrum disorder.
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11. Garcia D, Dukes C, Brady MP, Scott J, Wilson CL. {{Using modeling and rehearsal to teach fire safety to children with autism}}. {J Appl Behav Anal}. 2016.
We evaluated the efficacy of an instructional procedure to teach young children with autism to evacuate settings and notify an adult during a fire alarm. A multiple baseline design across children showed that an intervention that included modeling, rehearsal, and praise was effective in teaching fire safety skills. Safety skills generalized to novel settings and maintained during a 5-week follow-up in both training and generalization settings.
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12. Gonthier C, Longuepee L, Bouvard M. {{Sensory Processing in Low-Functioning Adults with Autism Spectrum Disorder: Distinct Sensory Profiles and Their Relationships with Behavioral Dysfunction}}. {J Autism Dev Disord}. 2016.
Sensory processing abnormalities are relatively universal in individuals with autism spectrum disorder, and can be very disabling. Surprisingly, very few studies have investigated these abnormalities in low-functioning adults with autism. The goals of the present study were (a) to characterize distinct profiles of sensory dysfunction, and (b) to understand how sensory dysfunction relates to behavioral disorders in this population. Data were collected for a representative sample of inpatients in autism care centers (N = 148) and a non-clinical control group. Results demonstrated that sensory dysfunction (a) is highly prevalent in low-functioning adults with ASD and differentiates at least four sub-profiles of patients, and (b) predicts specific patterns of behavioral disorders. Implications for care are discussed.
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13. Halbach N, Smeets EE, Julu P, Witt-Engerstrom I, Pini G, Bigoni S, Hansen S, Apartopoulos F, Delamont R, van Roozendaal K, Scusa MF, Borelli P, Candel M, Curfs L. {{Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study}}. {Am J Med Genet A}. 2016.
Many studies have attempted to establish the genotype-phenotype correlation in Rett syndrome (RTT). Cardiorespiratory measurements provide robust objective data, to correlate with each of the different clinical phenotypes. It has important implications for the management and treatment of this syndrome. The aim of this study was to correlate the genotype with the quantitative cardiorespiratory data obtained by neurophysiological measurement combined with a clinical severity score. This international multicenter study was conducted in four European countries from 1999 to 2012. The study cohort consisted of a group of 132 well-defined RTT females aged between 2 and 43 years with extended clinical, molecular, and neurophysiological assessments. Diagnosis of RTT was based on the consensus criteria for RTT and molecular confirmation. Genotype-phenotype analyses of clinical features and cardiorespiratory data were performed after grouping mutations by the same type and localization or having the same putative biological effect on the MeCP2 protein, and subsequently on eight single recurrent mutations. A less severe phenotype was seen in females with CTS, p.R133C, and p.R294X mutations. Autonomic disturbances were present in all females, and not restricted to nor influenced by one specific group or any single recurrent mutation. The objective information from non-invasive neurophysiological evaluation of the disturbed central autonomic control is of great importance in helping to organize the lifelong care for females with RTT. Further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence-based management in RTT. (c) 2016 Wiley Periodicals, Inc.
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14. Ketcheson L, Hauck J, Ulrich D. {{The effects of an early motor skill intervention on motor skills, levels of physical activity, and socialization in young children with autism spectrum disorder: A pilot study}}. {Autism}. 2016.
Despite evidence suggesting one of the earliest indicators of an eventual autism spectrum disorder diagnoses is an early motor delay, there remain very few interventions targeting motor behavior as the primary outcome for young children with autism spectrum disorder. The aim of this pilot study was to measure the efficacy of an intensive motor skill intervention on motor skills (Test of Gross Motor Development-2), physical activity (accelerometers), and socialization (Playground Observation of Peer Engagement) in young children with autism spectrum disorder. A total of 20 children with autism spectrum disorder aged 4-6 years participated. The experimental group (n = 11) participated in an 8-week intervention consisting of motor skill instruction for 4 h/day, 5 days/week. The control group (n = 9) did not receive the intervention. A repeated-measures analysis of covariance revealed statistically significant differences between groups in all three motor outcomes, locomotor (F(1, 14) = 10.07, p < 0.001, partial eta2 = 0.42), object control (F(1, 14) = 12.90, p < 0.001, partial eta2 = 0.48), and gross quotient (F(1, 14) = 15.61, p < 0.01, partial eta2 = 0.53). Findings shed light on the importance of including motor programming as part of the early intervention services delivered to young children with autism spectrum disorder. Lien vers le texte intégral (Open Access ou abonnement)
15. Li C, Liu C, Zhou B, Hu C, Xu X. {{Novel microduplication of CHL1 gene in a patient with autism spectrum disorder: a case report and a brief literature review}}. {Mol Cytogenet}. 2016; 9: 51.
BACKGROUND: The cell adhesion molecule L1-like (CHL1 or CALL) gene is located on chromosome 3p26.3, and it is highly expressed in the central and peripheral nervous systems. The protein encoded by this gene is a member of the L1 family of neural cell adhesion molecules, and it plays a role in nervous system development and synaptic plasticity. Moreover, studies of mice have revealed that CHL1 is a prime candidate gene for a dosage-sensitive autosomal form of mental retardation. To date, four patients with a microdeletion and two with a microduplication of 3p26.3 encompassing only the CHL1 gene have been reported in literature. CASE PRESENTATION: In the present study, we have described a 16-month-old boy with autism spectrum disorder (ASD), developmental delay and minor dysmorphic facial features. This is the first report of a duplication of 3p26.3 including only the CHL1 gene in an ASD patient, and this duplication is the smallest reported to date in this gene. We also reviewed CHL1 gene mutation cases and examined whether this gene has an important role in cognitive function. CONCLUSIONS: We conclude that both CHL1 deletions and duplications are likely responsible for the patient’s impaired cognitive function, and CHL1 may be an intriguing ASD candidate gene.
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16. Matson JL, Cervantes PE, Peters WJ. {{Autism spectrum disorders: management over the lifespan}}. {Expert Rev Neurother}. 2016: 1-10.
INTRODUCTION: For the majority of the autism spectrum disorder (ASD) population, symptoms begin within the first years of life and associated difficulties continue throughout the lifespan. Currently, the research literature focuses more heavily on problems in childhood. However, given that adulthood accounts for the majority of life, more focus should be placed on evidence-based, lifelong treatment and management strategies for ASD. AREAS COVERED: This paper reviews the topic of lifelong ASD management, primarily emphasizing issues in adolescence and adulthood. Among the topics discussed are timing and methods of treatment across the lifespan, and specific intervention targets that emerge or are more relevant to this older cohort. Expert commentary: Several advances have been made in the treatment of adolescent and adult specific issues. However, research should continue to focus on these areas. Greater focus on coordination of care across disciplines and policy regarding ASD management over the lifespan is also required.
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17. Mazurek MO, Engelhardt CR, Hilgard J, Sohl K. {{Bedtime Electronic Media Use and Sleep in Children with Autism Spectrum Disorder}}. {J Dev Behav Pediatr}. 2016.
OBJECTIVES: The purpose of this study was to better understand the use of screen-based media at bedtime among children with autism spectrum disorder (ASD). The study specifically examined whether the presence of media devices in the child’s bedroom, the use of media as part of the bedtime routine, and exposure to media with violent content just before bedtime were associated with sleep difficulties. METHODS: Parents of 101 children with ASD completed questionnaires assessing their children’s sleep habits, bedroom media access (including television, video game devices, and computers), and patterns of nighttime media use (including timing of media exposure and violent media content). RESULTS: Children with ASD who used media as part of the bedtime routine showed significantly greater sleep onset latency than those who did not (39.8 vs 16.0 minutes). Similarly, children who were exposed to media with violent content within the 30-minute period before bedtime experienced significantly greater sleep onset delays and shorter overall sleep duration. In contrast, the mere presence of bedroom media was not associated with either sleep onset latency or sleep duration. CONCLUSION: Overall, these findings indicate that incorporating television and video games into the bedtime routine is associated with sleep onset difficulties among children with ASD. Exposure to violent media before bed is also associated with poor sleep. Families of children with ASD should be encouraged to regulate and monitor the timing and content of television and video game use, whether or not such devices are physically present in the child’s bedroom.
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18. Merrick AD, Grieve A, Cogan N. {{Psychological impacts of challenging behaviour and motivational orientation in staff supporting individuals with autistic spectrum conditions}}. {Autism}. 2016.
Despite increased risk of experiencing challenging behaviour, psychological impacts on community and residential staff supporting adults with autistic spectrum conditions are under-explored. Studies examining related roles indicate protective psychological factors may help maintain staff well-being. This study investigated relationships between motivational orientation (eudaimonic or hedonic), challenging behaviour frequency and type (physical, verbal or self-injurious) and psychological impacts (anxiety, depression and life satisfaction). Participants (N = 99) were recruited from six organisations providing autism-specific adult services within Scotland. A series of binary logistic regressions demonstrated weekly challenging behaviour exposure (compared to monthly or daily) significantly increased the likelihood of anxiety caseness. Increased eudaimonic motivation significantly reduced the likelihood of anxiety caseness while also predicting higher life satisfaction. Furthermore, having high levels of eudaimonic motivation appeared to moderate the impact of weekly challenging behaviour exposure on anxiety. No motivational orientation or challenging behaviour factor significantly predicted depression. This sample also demonstrated higher anxiety, lower depression and equivalent life satisfaction levels compared with general population norms. The results highlight the need for considering staff’s motivational orientations, their frequency of exposure to challenging behaviour, and both positive and negative psychological outcomes, if seeking to accurately quantify or improve well-being in this staff population.
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19. Mussap M, Noto A, Fanos V. {{Metabolomics of autism spectrum disorders: early insights regarding mammalian-microbial cometabolites}}. {Expert Rev Mol Diagn}. 2016: 1-13.
INTRODUCTION: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders consisting of delayed or impaired language development and difficulties in social interactions. The very high degree of phenotypic heterogeneity in ASD originates from the interaction between environmental risk factors and susceptible genetic loci, leading to epigenetic DNA methylation. Advances in system biology are becoming strategic for implementing knowledge on the ASD aetiology and for the early diagnosis of the disease after birth. AREAS COVERED: We overhauled the value of either targeted or untargeted metabolomics studies in autism for identifying the most relevant metabolic pathways and key metabolites implicated in the disease, with special emphasis to mammalian-microbial metabolites. The most discriminant metabolites in ASD belong to amino acid metabolism, antioxidant status, nicotinic acid metabolism, and mitochondrial metabolism. Expert commentary: Most published studies point out the role of metabolites derived from the gut microbiota: they can modulate the behavioral phenotype of the autistic children, greatly influencing host metabolic pathways and the immune system, shaping the individual susceptibility to the disease. Pitfalls and caveats in metabolomics results across studies have been additionally recognized and discussed leading to the conclusion that metabolomics studies in ASD are far to be definitive and univocal.
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20. Olexova L, Stefanik P, Krskova L. {{Increased anxiety-like behaviour and altered GABAergic system in the amygdala and cerebellum of VPA rats-An animal model of autism}}. {Neurosci Lett}. 2016.
Anxiety is one of the associated symptoms of autism spectrum disorder. According to the literature, increases in anxiety are accompanied by GABAergic system deregulation. The aim of our study, performed using an animal model of autism in the form of rats prenatally treated with valproic acid (VPA rats), was to investigate changes in anxiety-like behaviour and the gene expression of molecules that control levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Anxiety-like behaviours were investigated using zone preferences in the open field test. The levels of the 65 and 67kDa enzymes of L-glutamic acid decarboxylase (GAD) mRNAs and type 1 GABA transporter (GAT1) were evaluated in the amygdala, as well as GABA producing enzymes in the cortex layer of the cerebellum. Our research showed that adult VPA rats spent less time in the inner zone of the testing chamber and more time in the outer zone of the testing chamber in the open field test. We also found that adult VPA rats had increased expression of GAT1 in the amygdala, as well as decreased levels of GAD65 and GAD67 mRNA in the cerebellum compared to control animals. These findings support the existence of a relationship between increased anxiety-like behaviour and changes in the regulation of the GABAergic system in VPA rats.
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21. Schweitzer J, James C, Jenkins W, Reiff MI, Stein MT. {{Acute Agitation and Self-Injury in a 5-Year Old with Autism}}. {J Dev Behav Pediatr}. 2016.
CASE: A 5-year-old nonverbal child with autism spectrum disorder (ASD) was admitted to inpatient pediatrics with new onset agitation and self-injurious behavior. His parents described him as a pleasant child without previous episodes of self-injury. Four days before admission, the parents noted new irritability followed by 2 days of self-injury to the face without clear precipitant. His hitting intensified with closed fist to face, and he required parental physical restraint to prevent further injury. Car rides and ibuprofen provided only temporary relief. He consumed minimal liquid and ate no solid food for 2 days. The parents denied any changes to the environment or routine and denied recent travel, sick contacts, fevers, cough, otalgia, vomiting, diarrhea, and constipation. The patient had been diagnosed with ASD at age 18 months old but had no other significant medical history.On examination, the child was alert but distressed and restless, wearing padded mitts as his parents attempted to calm him by pushing him in a stroller. He had multiple areas of severe bruising and facial swelling in the right periorbital area, cheek, and jaw. The rest of the physical examination was unremarkable. Laboratory results included a leukocytosis with left shift, a normal metabolic panel, and an elevated creatine kinase. Other investigations included a normal lumber puncture, chest radiograph, head and face computerized tomography without contrast, and brain magnetic resonance imaging. A dentist consultant examined him and noted an erupting molar but no decay or abscesses. A psychiatric evaluation was requested as there was no clear medical source for the patient’s distress.
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22. Tager-Flusberg H, Plesa Skwerer D, Joseph RM, Brukilacchio B, Decker J, Eggleston B, Meyer S, Yoder A. {{Conducting research with minimally verbal participants with autism spectrum disorder}}. {Autism}. 2016.
A growing number of research groups are now including older minimally verbal individuals with autism spectrum disorder in their studies to encompass the full range of heterogeneity in the population. There are numerous barriers that prevent researchers from collecting high-quality data from these individuals, in part because of the challenging behaviors with which they present alongside their very limited means for communication. In this article, we summarize the practices that we have developed, based on applied behavioral analysis techniques, and have used in our ongoing research on behavioral, eye-tracking, and electrophysiological studies of minimally verbal children and adolescents with autism spectrum disorder. Our goal is to provide the field with useful guidelines that will promote the inclusion of the entire spectrum of individuals with autism spectrum disorder in future research investigations.
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23. Turner AH, Greenspan KS, van Erp TG. {{Pallidum and lateral ventricle volume enlargement in autism spectrum disorder}}. {Psychiatry Res}. 2016; 252: 40-5.
Studies on structural brain abnormalities in individuals with autism spectrum disorders (ASD) have been of limited size and many findings have not been replicated. In the largest ASD brain morphology study to date, we compared subcortical, total brain (TBV), and intracranial (ICV) volumes between 472 subjects with DSM-IV ASD diagnoses and 538 healthy volunteers (age range: 6-64 years), obtained from high-resolution structural brain scans provided by the Autism Brain Imaging Data Exchange (ABIDE). Compared to healthy volunteers, we found significantly larger pallidum (Cohen’s d=0.15) and lateral ventricle volumes (Cohen’s d=0.18) in ASD. These enlargements were independent of total brain volume and IQ, passed FDR correction for multiple comparisons, and were observed in overall, male-only, and medication-free subjects. In addition, intracranial, hippocampal, and caudate volumes were enlarged in ASD at a nominal statistical threshold of p<0.05. This study provides the first robust evidence for pallidum enlargement in ASD independent from TBV and encourages further study of the functional role of the pallidum in individuals with autism spectrum disorder. Lien vers le texte intégral (Open Access ou abonnement)
24. Veeraragavan S, Wan YW, Connolly DR, Hamilton SM, Ward CS, Soriano S, Pitcher MR, McGraw CM, Huang SG, Green JR, Yuva LA, Liang AJ, Neul JL, Yasui DH, LaSalle JM, Liu Z, Paylor R, Samaco RC. {{Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome}}. {Hum Mol Genet}. 2016.
Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modeling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioral feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures.
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25. Yang Y, Kucukkal TG, Li J, Alexov E, Cao W. {{Binding Analysis of Methyl-CpG Binding Domain of MeCP2 and Rett Syndrome Mutations}}. {ACS Chem Biol}. 2016.
Methyl-CpG binding protein 2 (MeCP2) binds to methylated cytosine in CpG island through its methyl-CpG binding domain (MBD). Here, the effects of the Rett syndrome-causing missense mutations on binding affinity of MBD to cytosine (C), methylcytosine (mC), hydroxymethylcytosine (hmC), formylcytosine (fC) and carboxylcytosine (caC) in CpG dinucleotide are investigated. MeCP2-MBD binds to mC-containing variants of double stranded CpG stronger than any other cytosine modified CpG with strongest affinity to mC/mC. Thirteen MBD missense mutations show reduced binding affinity for mC/mC ranging with 2-fold decrease for T158M to 88-fold for R111G. The binding affinities of these mutants to C/C are also reduced to various degrees except for T158M. Consistent with free energy perturbation analysis, correlation of binding affinity with protein unfolding allows for grouping mutations into three clusters. Correlation of the first cluster includes mutations that have a higher tendency to unfold and have lesser affinity to mC/mC and C/C. Mutations in the second cluster have similar structural stability but various affinity to mC/mC and C/C. R111G and A140V belong to the third cluster in which the loss of protein flexibility may underlie their reduction in binding affinity to mC/mC and C/C. Most notably, R111 emerges as the key structural element that modulates the specific contacts with mCpG. Implications of the results for the mCpG binding mechanism of MeCP2-MBD are discussed. These analyses provide new insights on the structure and function relationships in MeCP2-MBD and offer new clues to their roles in the pathology of Rett syndrome.
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26. Yoo MH, Kim TY, Yoon YH, Koh JY. {{Autism phenotypes in ZnT3 null mice: Involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation}}. {Sci Rep}. 2016; 6: 28548.
To investigate the role of synaptic zinc in the ASD pathogenesis, we examined zinc transporter 3 (ZnT3) null mice. At 4-5 weeks of age, male but not female ZnT3 null mice exhibited autistic-like behaviors. Cortical volume and neurite density were significantly greater in male ZnT3 null mice than in WT mice. In male ZnT3 null mice, consistent with enhanced neurotrophic stimuli, the level of BDNF as well as activity of MMP-9 was increased. Consistent with known roles for MMPs in BDNF upregulation, 2.5-week treatment with minocycline, an MMP inhibitor, significantly attenuated BDNF levels as well as megalencephaly and autistic-like behaviors. Although the ZnT3 null state removed synaptic zinc, it rather increased free zinc in the cytosol of brain cells, which appeared to increase MMP-9 activity and BDNF levels. The present results suggest that zinc dyshomeostasis during the critical period of brain development may be a possible contributing mechanism for ASD.
