Pubmed du 12/06/19

mercredi 12 juin 2019

1. Akobirshoev I, Mitra M, Dembo R, Lauer E. In-hospital mortality among adults with autism spectrum disorder in the United States : A retrospective analysis of US hospital discharge data. Autism ;2019 (Jun 12):1362361319855795.

A retrospective data analysis using 2004-2014 Healthcare Cost and Utilization Project Nationwide Inpatient Sample was conducted to examine in-hospital mortality among adults with autism spectrum disorders in the United States compared to individuals in the general population. We modeled logistic regressions to compare inpatient hospital mortality between adults with autism spectrum disorders (n = 34,237) and age-matched and sex-matched controls (n = 102,711) in a 1:3 ratio. Adults with autism spectrum disorders had higher odds for inpatient hospital mortality than controls (odds ratio = 1.44, 95% confidence interval : 1.29-1.61, p < 0.001). This risk remained high even after adjustment for age, sex, race/ethnicity, income, number of comorbidities, epilepsy and psychiatric comorbidities, hospital bed size, hospital region, and hospitalization year (odds ratio = 1.51, 95% confidence interval : 1.33-1.72, p < 0.001). Adults with autism spectrum disorders who experienced in-hospital mortality had a higher risk for having 10 out of 27 observed Elixhauser-based medical comorbidities at the time of death, including psychoses, other neurological disorders, diabetes, hypothyroidism, rheumatoid arthritis collagen vascular disease, obesity, weight loss, fluid and electrolyte disorders, deficiency anemias, and paralysis. The results from the interaction of sex and autism spectrum disorders status suggest that women with autism spectrum disorders have almost two times higher odds for in-hospital mortality (odds ratio = 1.95, p < 0.001) than men with autism spectrum disorders. The results from the stratified analysis also showed that women with autism spectrum disorders had 3.17 times higher odds (95% confidence interval : 2.50-4.01, p < 0.001) of in-hospital mortality compared to women from the non-autism spectrum disorders matched control group ; this difference persisted even after adjusting for socioeconomic, clinical, and hospital characteristics (odds ratio = 2.75, 95% confidence interval : 2.09-3.64, p < 0.001). Our findings underscore the need for more research to develop better strategies for healthcare and service delivery to people with autism spectrum disorders.

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2. Falk D. More on Asperger’s Career : A Reply to Czech. J Autism Dev Disord ;2019 (Jun 10)

Czech’s claims that my paper abounds with mistranslations, misrepresentations, and factual errors are refuted point-by-point, as is his declaration that the paper contains no relevant or new evidence. Asperger’s statements that Franz Hamburger saved him from the Gestapo are reaffirmed and supported with a personal communication from Asperger’s daughter, Dr. Maria Asperger Felder. Czech’s criticism of anonymous peer reviewers and his call for retraction of my paper are, at best, unconstructive. In light of the current resurgence of authoritarian governments that promote xenophobic and racist ideology in the United States, Europe, and elsewhere, it is essential that details about the Nazi euthanasia program continue to be recalled and deliberated, as they are in this exchange. I stand by my paper.

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3. Flygare O, Andersson E, Ringberg H, Hellstadius AC, Edbacken J, Enander J, Dahl M, Aspvall K, Windh I, Russell A, Mataix-Cols D, Ruck C. Adapted cognitive behavior therapy for obsessive-compulsive disorder with co-occurring autism spectrum disorder : A clinical effectiveness study. Autism ;2019 (Jun 12):1362361319856974.

Obsessive-compulsive disorder and autism spectrum disorder commonly co-occur. Adapted cognitive behavior therapy for obsessive-compulsive disorder in adults with autism spectrum disorder has not previously been evaluated outside the United Kingdom. In this study, 19 adults with obsessive-compulsive disorder and autism spectrum disorder were treated using an adapted cognitive behavior therapy protocol that consisted of 20 sessions focused on exposure with response prevention. The primary outcome was the clinician-rated Yale-Brown Obsessive-Compulsive Scale. Participants were assessed up to 3 months after treatment. There were significant reductions on the Yale-Brown Obsessive-Compulsive Scale at post-treatment (d = 1.5), and improvements were sustained at follow-up (d = 1.2). Self-rated obsessive-compulsive disorder and depressive symptoms showed statistically significant reductions. Improvements in general functioning and quality of life were statistically non-significant. Three participants (16%) were responders at post-treatment and four (21%) were in remission from obsessive-compulsive disorder. At follow-up, three participants (16%) were responders and one (5%) was in full remission. Adapted cognitive behavior therapy for obsessive-compulsive disorder in adults with co-occurring autism spectrum disorder is associated with reductions in obsessive-compulsive symptoms and depressive symptoms. However, outcomes are modest ; few patients were completely symptom free, and treatment engagement was low with few completed exposures and low adherence to homework assignments. We identify and discuss the need for further treatment refinement for this vulnerable group.

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4. Ganesan H, Balasubramanian V, Iyer M, Venugopal A, Subramaniam MD, Cho SG, Vellingiri B. mTOR signalling pathway - A root cause for idiopathic autism ?. BMB Rep ;2019 (Jun 12)

Autism spectrum disorder (ASD) is a complex neurodevelopmental monogenic disorder with a strong genetic influence. Idiopathic autism could be defined as a type of autism that does not have a specific causative agent. Among signalling cascades, mTOR signalling pathway plays a pivotal role not only in cell cycle, but also in protein synthesis and regulation of brain homeostasis in ASD patients. The present review highlights, underlying mechanism of mTOR and its role in altered signalling cascades as a triggering factor in the onset of idiopathic autism. Further, this review discusses how distorted mTOR signalling pathway stimulates truncated translation in neuronal cells and leads to downregulation of protein synthesis at dendritic spines of the brain. This review concludes by suggesting downstream regulators such as p70S6K, eIF4B, eIF4E of mTOR signalling pathway as promising therapeutic targets for idiopathic autistic individuals.

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5. Garfunkel D, Anagnostou EA, Aman MG, Handen BL, Sanders KB, Macklin EA, Chan J, Veenstra-VanderWeele J. Pharmacogenetics of Metformin for Medication-Induced Weight Gain in Autism Spectrum Disorder. J Child Adolesc Psychopharmacol ;2019 (Jun 12)

Objectives : We recently found that metformin attenuated weight gain due to mixed dopamine and serotonin receptor antagonists, commonly termed atypical antipsychotics, in children and adolescents with autism spectrum disorder (ASD). Previous studies have found that genetic variation predicts response to metformin in diabetes. In this study, we aimed to assess whether response to metformin for weight gain in this population is associated with variants in five genes previously implicated in metformin response in diabetes. Methods : Youth with ASD who experienced significant weight gain while taking mixed receptor antagonist medications were randomly assigned to metformin or placebo for 16 weeks, followed by open-label metformin treatment for 16 weeks. In the 53 participants with available DNA samples, we used a linear, mixed model analysis to assess response in the first 16 weeks of metformin treatment, whether in the randomized or open-label period, based upon genotypes at polymorphisms in five genes previously associated with metformin response in diabetes : ATM, SLC2A2, MATE1, MATE2, and OCT1. Results : In the primary analysis, both ATM and OCT1 showed significant effects of genotype on change in body mass index z-scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. Conclusion : As has been shown for metformin treatment in diabetes, genetic variation may predict response to metformin for weight gain in youth with ASD treated with mixed receptor antagonists. Further work is needed to replicate these findings and evaluate whether they can be used prospectively to improve outcomes.

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6. Hetzroni O, Agada H, Leikin M. Creativity in Autism : An Examination of General and Mathematical Creative Thinking Among Children with Autism Spectrum Disorder and Children with Typical Development. J Autism Dev Disord ;2019 (Jun 11)

This study investigated creative thinking abilities among two groups of 20 children with autism spectrum disorders (ASD) compared to 20 children with typical development ages 9-11. The study compared performance on two different creativity tests : general creativity (Pictorial Multiple Solutions-PMS) test versus mathematical creativity (Creating Equal Number-CEN) test, and investigated relationships between general and mathematical creative thinking across various cognitive measures including non-verbal IQ, verbal and non-verbal working memory and Attention. Results of the study demonstrate significant correlations among the measures of creativity indicating that the PMS and the CEN tasks represent different skills, or perhaps, different domains of creativity. Findings suggest that creativity can be found among individuals with ASD.

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7. Holyfield C, Light J, McNaughton D, Caron J, Drager K, Pope L. Effect of AAC technology with dynamic text on the single-word recognition of adults with intellectual and developmental disabilities. Int J Speech Lang Pathol ;2019 (Jun 10):1-12.

Purpose : Single-word recognition can support participation in life, including engagement in leisure activities, navigation through the community, and vocational opportunities. Given the limited reading skills of many adults with intellectual and developmental disabilities (IDD) and limited speech, the current study evaluated the effects of using an augmentative and alternative communication (AAC) app, featuring dynamic text and speech output embedded in visual scene displays, on the single-word recognition performance of six adults with IDD who demonstrated limited speech. Method : A multiple baseline across participants single-subject design was used. Ten target sight words for each participant were selected on an individual basis, based on participant interest. Intervention consisted solely of interactions between investigators and individual participants using the app. Result : In the absence of any formal instruction and solely through the use of the AAC app interaction, three of the six participants demonstrated increased accuracy in single-word recognition. Conclusion : Results from the study were mixed, but suggest that AAC apps which provide the dynamic display of text in conjunction with voice output can assist some adults with IDD in achieving gains in single-word reading.

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8. Parlade MV, Weinstein A, Garcia D, Rowley AM, Ginn NC, Jent JF. Parent-Child Interaction Therapy for children with autism spectrum disorder and a matched case-control sample. Autism ;2019 (Jun 12):1362361319855851.

Parent-Child Interaction Therapy is an empirically based, behavioral parent training program for young children exhibiting disruptive behaviors. Parent-Child Interaction Therapy shows promise for treating disruptive behaviors in children with autism spectrum disorder. Treatment processes (i.e. treatment length and homework compliance), parenting skills, parenting stress, and behavioral outcomes (i.e. disruptive and externalizing behaviors and executive functioning) were compared in 16 children with autism spectrum disorder and 16 children without autism spectrum disorder matched on gender, age, and initial intensity of disruptive behaviors. Samples were statistically similar in terms of child receptive language, child race and ethnicity, parent age, gender and education, and number of two-parent families in treatment. Families received standard, mastery-based Parent-Child Interaction Therapy. Both groups demonstrated significant and clinically meaningful improvements in child disruptive and externalizing behavior and executive functioning, parenting skills, and parenting stress. Length of treatment, homework compliance, and parent and child outcomes did not differ significantly between groups. A subset of children with autism spectrum disorder also showed significant improvements in social responsiveness, adaptive skills, and restricted/repetitive behaviors. This study replicates and extends prior research by demonstrating that children with and without autism spectrum disorder experience similar benefits following Parent-Child Interaction Therapy. Findings may expand the availability and dissemination of time-limited, evidence-based interventions for autism spectrum disorder and comorbid disruptive behaviors.

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9. Patel SP, Kim JH, Larson CR, Losh M. Mechanisms of voice control related to prosody in autism spectrum disorder and first-degree relatives. Autism Res ;2019 (Jun 12)

Differences in prosody (e.g., intonation, rhythm) are among the most obvious language-related impairments in autism spectrum disorder (ASD), and significantly impact communication. Subtle prosodic differences have also been identified in a subset of clinically unaffected first-degree relatives of individuals with ASD, and may reflect genetic liability to ASD. This study investigated the neural basis of prosodic differences in ASD and first-degree relatives through analysis of feedforward and feedback control involved in the planning, production, self-monitoring, and self-correction of speech by using a pitch-perturbed auditory feedback paradigm during sustained vowel and speech production. Results revealed larger vocal response magnitudes to pitch-perturbed auditory feedback across tasks in ASD and ASD parent groups, with differences in sustained vowel production driven by parents who displayed subclinical personality and language features associated with ASD (i.e., broad autism phenotype). Both ASD and ASD parent groups exhibited increased response onset latencies during sustained vowel production, while the ASD parent group exhibited decreased response onset latencies during speech production. Vocal response magnitudes across tasks were associated with prosodic atypicalities in both individuals with ASD and their parents. Exploratory event-related potential (ERP) analyses in a subgroup of participants during the sustained vowel task revealed reduced P1 ERP amplitudes in the ASD group, with similar trends observed in parents. Overall, results suggest underdeveloped feedforward systems and neural attenuation in detecting audio-vocal feedback may contribute to ASD-related prosodic atypicalities. Importantly, results implicate atypical audio-vocal integration as a marker of genetic risk to ASD, evident in ASD and among clinically unaffected relatives. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Previous research has identified atypicalities in prosody (e.g., intonation) in individuals with ASD and a subset of their first-degree relatives. In order to better understand the mechanisms underlying prosodic differences in ASD, this study examined how individuals with ASD and their parents responded to unexpected differences in what they heard themselves say to modify control of their voice (i.e., audio-vocal integration). Results suggest that disruptions to audio-vocal integration in individuals with ASD contribute to ASD-related prosodic atypicalities, and the more subtle differences observed in parents could reflect underlying genetic liability to ASD.

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10. Quartier A, Courraud J, Thi Ha T, McGillivray G, Isidor B, Rose K, Drouot N, Savidan MA, Feger C, Jagline H, Chelly J, Shaw M, Laumonnier F, Gecz J, Mandel JL, Piton A. Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment. Hum Mutat ;2019 (Jun 10)

The X-linked NLGN3 gene, encoding a postsynaptic cell adhesion molecule, was involved in a non-syndromic monogenic form of Autism Spectrum Disorder (ASD) by the description of one unique missense variant, p.Arg451Cys (Jamain et al. 2003). We investigated here the pathogenicity of additional missense variants identified in two multiplex families with intellectual disability (ID) and ASD : c.1789C>T, p.Arg597Trp, previously reported by our group (Redin et al. 2014) and present in three affected cousins and c.1540C>T, p.Pro514Ser, identified in two affected brothers. Overexpression experiments in HEK293 and HeLa cell lines revealed that both variants affect the level of the mature NLGN3 protein, its localization at the plasma membrane and its presence as a cleaved form in the extracellular environment, even more drastically than what was reported for the initial p.Arg451Cys mutation. The variants also induced an Unfolded Protein Response (UPR), probably due to the retention of immature NLGN3 proteins in the endoplasmic reticulum. In comparison, the c.1894A>G, p.Ala632Thr and c.1022T>C, p.Val341Ala variants, present in males from the general population, have no effect. Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected individuals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD. This article is protected by copyright. All rights reserved.

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11. Smile S. A 4-year-old boy with food selectivity and autism-spectrum disorder. Cmaj ;2019 (Jun 10) ;191(23):E636-e637.

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12. Solberg BS, Zayats T, Posserud MB, Halmoy A, Engeland A, Haavik J, Klungsoyr K. Patterns of Psychiatric Comorbidity and Genetic Correlations Provide New Insights Into Differences Between Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder. Biol Psychiatry ;2019 (Apr 28)

BACKGROUND : Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share common genetic factors but seem to have specific patterns of psychiatric comorbidities. There are few systematic studies on adults ; therefore, we compared psychiatric comorbidities in adults with these two neurodevelopmental disorders using population-based data and analyzed their genetic correlations to evaluate underlying factors. METHODS : Using data from Norwegian registries, we assessed patterns of psychiatric disorders in adults with ADHD (n = 38,636 ; 2.3%), ASD (n = 7528 ; 0.4%), and both diagnoses (n = 1467 ; 0.1%) compared with the remaining adult population (n = 1,653,575). We calculated their prevalence ratios (PRs) and differences using Poisson regression, also examining sex-specific relations. Genetic correlations (rg) among ADHD, ASD, and the examined psychiatric disorders were calculated by linkage disequilibrium score regression, exploiting summary statistics from relevant genome-wide association studies. RESULTS : For all psychiatric comorbidities, PRs differed between ADHD and ASD. Associations were strongest in individuals with ADHD and ADHD+ASD for most comorbidities, in both men and women. The relative prevalence increase of substance use disorder was three times larger in ADHD than in ASD (PRADHD, 6.2 ; 95% confidence interval [CI], 6.1-6.4 ; PRASD, 1.9 ; 95% CI, 1.7-2.2 ; p < .001) ; however, the opposite was true for schizophrenia (PRASD, 13.9 ; 95% CI, 12.7-15.2 ; PRADHD, 4.4 ; 95% CI, 4.1-4.7 ; p < .001). Genetic correlations supported these patterns but were significantly different between ADHD and ASD only for the substance use disorder proxies and personality traits (p < .006 for all). CONCLUSIONS : Adults with ADHD, ASD, or both ADHD and ASD have specific patterns of psychiatric comorbidities. This may partly be explained by differences in underlying genetic factors.

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13. Verma V, Paul A, Amrapali Vishwanath A, Vaidya B, Clement JP. Understanding intellectual disability and autism spectrum disorders from common mouse models : synapses to behaviour. Open Biol ;2019 (Jun 28) ;9(6):180265.

Normal brain development is highly dependent on the timely coordinated actions of genetic and environmental processes, and an aberration can lead to neurodevelopmental disorders (NDDs). Intellectual disability (ID) and autism spectrum disorders (ASDs) are a group of co-occurring NDDs that affect between 3% and 5% of the world population, thus presenting a great challenge to society. This problem calls for the need to understand the pathobiology of these disorders and to design new therapeutic strategies. One approach towards this has been the development of multiple analogous mouse models. This review discusses studies conducted in the mouse models of five major monogenic causes of ID and ASDs : Fmr1, Syngap1, Mecp2, Shank2/3 and Neuroligins/Neurnexins. These studies reveal that, despite having a diverse molecular origin, the effects of these mutations converge onto similar or related aetiological pathways, consequently giving rise to the typical phenotype of cognitive, social and emotional deficits that are characteristic of ID and ASDs. This convergence, therefore, highlights common pathological nodes that can be targeted for therapy. Other than conventional therapeutic strategies such as non-pharmacological corrective methods and symptomatic alleviation, multiple studies in mouse models have successfully proved the possibility of pharmacological and genetic therapy enabling functional recovery.

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