Pubmed du 10/05/18

jeudi 10 mai 2018

1. Abbas H, Garberson F, Glover E, Wall DP. Machine learning approach for early detection of autism by combining questionnaire and home video screening. Journal of the American Medical Informatics Association : JAMIA. 2018.

Background : Existing screening tools for early detection of autism are expensive, cumbersome, time- intensive, and sometimes fall short in predictive value. In this work, we sought to apply Machine Learning (ML) to gold standard clinical data obtained across thousands of children at-risk for autism spectrum disorder to create a low-cost, quick, and easy to apply autism screening tool. Methods : Two algorithms are trained to identify autism, one based on short, structured parent-reported questionnaires and the other on tagging key behaviors from short, semi-structured home videos of children. A combination algorithm is then used to combine the results into a single assessment of higher accuracy. To overcome the scarcity, sparsity, and imbalance of training data, we apply novel feature selection, feature engineering, and feature encoding techniques. We allow for inconclusive determination where appropriate in order to boost screening accuracy when conclusive. The performance is then validated in a controlled clinical study. Results : A multi-center clinical study of n = 162 children is performed to ascertain the performance of these algorithms and their combination. We demonstrate a significant accuracy improvement over standard screening tools in measurements of AUC, sensitivity, and specificity. Conclusion : These findings suggest that a mobile, machine learning process is a reliable method for detection of autism outside of clinical settings. A variety of confounding factors in the clinical analysis are discussed along with the solutions engineered into the algorithms. Final results are statistically limited and will benefit from future clinical studies to extend the sample size.

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2. Bortolato M, Floris G, Shih JC. From aggression to autism : new perspectives on the behavioral sequelae of monoamine oxidase deficiency. J Neural Transm (Vienna). 2018.

The two monoamine oxidase (MAO) enzymes, A and B, catalyze the metabolism of monoamine neurotransmitters, such as serotonin, norepinephrine, and dopamine. The phenotypic outcomes of MAO congenital deficiency have been studied in humans and animal models, to explore the role of these enzymes in behavioral regulation. The clinical condition caused by MAOA deficiency, Brunner syndrome, was first described as a disorder characterized by overt antisocial and aggressive conduct. Building on this discovery, subsequent studies were focused on the characterization of the role of MAOA in the neurobiology of antisocial conduct. MAO A knockout mice were found to display high levels of intermale aggression ; however, further analyses of these mutants unveiled additional behavioral abnormalities mimicking the core symptoms of autism-spectrum disorder. These findings were strikingly confirmed in newly reported cases of Brunner syndrome. The role of MAOB in behavioral regulation remains less well-understood, even though Maob-deficient mice have been found to exhibit greater behavioral disinhibition and risk-taking responses, supporting previous clinical studies showing associations between low MAO B activity and impulsivity. Furthermore, lack of MAOB was found to exacerbate the severity of psychopathological deficits induced by concurrent MAOA deficiency. Here, we summarize how the convergence of clinical reports and behavioral phenotyping in mutant mice has helped frame a complex picture of psychopathological features in MAO-deficient individuals, which encompass a broad spectrum of neurodevelopmental problems. This emerging knowledge poses novel conceptual challenges towards the identification of the endophenotypes shared by autism-spectrum disorder, antisocial behavior and impulse-control problems, as well as their monoaminergic underpinnings.

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3. Ip JPK, Mellios N, Sur M. Rett syndrome : insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci. 2018.

Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Almost two decades of research into RTT have greatly advanced our understanding of the function and regulation of the multifunctional protein MeCP2. Here, we review recent advances in understanding how loss of MeCP2 impacts different stages of brain development, discuss recent findings demonstrating the molecular role of MeCP2 as a transcriptional repressor, assess primary and secondary effects of MeCP2 loss and examine how loss of MeCP2 can result in an imbalance of neuronal excitation and inhibition at the circuit level along with dysregulation of activity-dependent mechanisms. These factors present challenges to the search for mechanism-based therapeutics for RTT and suggest specific approaches that may be more effective than others.

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4. Jeoung B. Motor proficiency differences among students with intellectual disabilities, autism, and developmental disability. Journal of exercise rehabilitation. 2018 ; 14(2) : 275-81.

There is considerable overlap in the manifestations of intellectual disability, autism, and developmental disability. We aimed to determine whether students with such disabilities have differences in their motor proficiency. We compared the motor proficiency of 82 students (age, 11 to 20 years) with different severities of intellectual disability (borderline, 11 students ; mild, 27 students ; moderate, 19 students), developmental disability (15 students), or autism (10 students). The Bruininks-Oseretsky Test of Motor Proficiency, Second edition was used to assess motor skills. The data were analyzed using descriptive statistics, independent t-tests, and analysis of variance. Compared to students with borderline intellectual disabilities, mild intellectual disabilities, or autism, those with moderate intellectual disabilities scored significantly lower on al-most all items regarding motor skill on the Bruininks-Oseretsky Test of Motor Proficiency. The results of this study provide key information for developing exercise programs to improve the motor proficiency and quality of life of children with various developmental disorders.

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5. Jonsson U, Olsson NC, Coco C, Gorling A, Flygare O, Rade A, Chen Q, Berggren S, Tammimies K, Bolte S. Long-term social skills group training for children and adolescents with autism spectrum disorder : a randomized controlled trial. Eur Child Adolesc Psychiatry. 2018.

Social skills group training (SSGT) is widely used for intellectually able children and adolescents with autism spectrum disorder (ASD). Previous studies indicate small to moderate effects on social communication capacities. The duration of most available programs is relatively short, and extended training might lead to further improvement. This randomized controlled trial compared an extended 24-week version of the SSGT program KONTAKT with standard care. The weekly sessions gradually shifted in content from acquisition of new skills to real-world application of the acquired skills. A total of 50 participants with ASD (15 females ; 35 males) aged 8-17 years were included. The study was conducted at two child and adolescent psychiatry outpatient units in Sweden. The primary outcome was the Social Responsiveness Scale-Second Edition (SRS-2) rated by parents and blinded teachers. Secondary outcomes included parent- and teacher-rated adaptive behaviors, trainer-rated global functioning and clinical severity, and self-reported child and caregiver stress. Assessments were made at baseline, posttreatment, and at 3-months follow-up. Parent-rated SRS-2 scores indicated large effects posttreatment [- 19.2 ; 95% CI - 29.9 to - 8.5 ; p < .001, effect size (ES) = 0.76], which were maintained at follow-up (- 20.7 ; 95% CI - 31.7 to - 9.7 ; p < .0001, ES = 0.82). These estimates indicate substantially larger improvement than previously reported for shorter SSGT. However, the effects on teacher-rated SRS-2 and most secondary outcomes did not reach statistical significance. Our results suggest added benefits of extended SSGT training, implying that service providers might reach better results by optimizing the delivery of SSGT.

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6. Jorge P, Garcia E, Goncalves A, Marques I, Maia N, Rodrigues B, Santos H, Fonseca J, Soares G, Correia C, Reis-Lima M, Cirigliano V, Santos R. Classical fragile-X phenotype in a female infant disclosed by comprehensive genomic studies. BMC Med Genet. 2018 ; 19(1) : 74.

BACKGROUND : We describe a female infant with Fragile-X syndrome, with a fully expanded FMR1 allele and preferential inactivation of the homologous X-chromosome carrying a de novo deletion. This unusual and rare case demonstrates the importance of a detailed genomic approach, the absence of which could be misguiding, and calls for reflection on the current clinical and diagnostic workup for developmental disabilities. CASE PRESENTATION : We present a female infant, referred for genetic testing due to psychomotor developmental delay without specific dysmorphic features or relevant family history. FMR1 mutation screening revealed a methylated full mutation and a normal but inactive FMR1 allele, which led to further investigation. Complete skewing of X-chromosome inactivation towards the paternally-inherited normal-sized FMR1 allele was found. No pathogenic variants were identified in the XIST promoter. Microarray analysis revealed a 439 kb deletion at Xq28, in a region known to be associated with extreme skewing of X-chromosome inactivation. CONCLUSIONS : Overall results enable us to conclude that the developmental delay is the cumulative result of a methylated FMR1 full mutation on the active X-chromosome and the inactivation of the other homologue carrying the de novo 439 kb deletion. Our findings should be taken into consideration in future guidelines for the diagnostic workup on the diagnosis of intellectual disabilities, particularly in female infant cases.

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7. Jorge-Torres OC, Szczesna K, Roa L, Casal C, Gonzalez-Somermeyer L, Soler M, Velasco CD, Martinez-San Segundo P, Petazzi P, Saez MA, Delgado-Morales R, Fourcade S, Pujol A, Huertas D, Llobet A, Guil S, Esteller M. Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice. Cell reports. 2018 ; 23(6) : 1665-77.

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT : the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.

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8. Lytle S, Hunt A, Moratschek S, Hall-Mennes M, Sajatovic M. Youth With Autism Spectrum Disorder in the Emergency Department. J Clin Psychiatry. 2018 ; 79(3).

OBJECTIVE : This comprehensive literature review summarizes reports on emergency department (ED) use by youth with autism spectrum disorder (ASD). DATA SOURCES : We conducted a systematic search of the PubMed, PsycINFO, CINAHL, and EMBASE databases (1985-2016), limited to studies published in English. The following search terms were used : autism, autistic, Asperger, emergency department/room/physician/doctor/treatment/medicine, childhood developmental disorders (pervasive), and emergencies. STUDY SELECTION : Our search found 332 articles, of which 12 specifically addressed ED services in ASD youth. DATA EXTRACTION : Abstracts or full text articles were reviewed for relevance. Case reports, review articles, and studies that reported on adults only or that included youth and adults but did not stratify results by age were excluded. RESULTS : Youth (aged 0-17 years) with ASD were up to 30 times more likely to present to the ED than youth without ASD. Individuals with ASD who visited the ED were older, more likely to have public insurance, and more likely to have nonurgent ED visits. For youth with ASD, up to 13% of visits were for behavioral or psychiatric problems, whereas for youth without ASD less than 2% were for psychiatric problems. ASD youth were more likely to present for externalizing problems or psychotic symptoms. Youth with ASD were also likely to have repeat visits to the ED and more likely to be admitted to a psychiatric unit or medical floor than youth without ASD. CONCLUSIONS : This review found significant gaps in the literature related to ED service use by youth with ASD. More research is needed to avoid unnecessary ED utilization and hospitalization, reduce medical costs, and improve outcome for youth with ASD.

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9. Palser ER, Fotopoulou A, Pellicano E, Kilner JM. The link between interoceptive processing and anxiety in children diagnosed with autism spectrum disorder : extending adult findings into a developmental sample. Biological psychology. 2018.

Anxiety is a major associated feature of autism spectrum disorders. The incidence of anxiety symptoms in this population has been associated with altered interoceptive processing. Here, we investigated whether recent findings of impaired interoceptive accuracy (quantified using heartbeat detection tasks) and exaggerated interoceptive sensibility (subjective sensitivity to internal sensations on self-report questionnaires) in autistic adults, can be extended into a school-age sample of children and adolescents (n=75). Half the sample had a verified diagnosis of an Autism Spectrum Disorder (ASD) and half were IQ- and age-matched children and adolescents without ASD. The discrepancy between an individual’s score on these two facets of interoception (interoceptive accuracy and interoceptive sensibility), conceptualized as an interoceptive trait prediction error, was previously found to predict anxiety symptoms in autistic adults. We replicated the finding of reduced interoceptive accuracy in autistic participants, but did not find exaggerated interoceptive sensibility relative to non-autistic participants. Nonetheless, the positive association between anxiety and interoceptive trait prediction error was replicated. However, in this sample, the best predictor of anxiety symptoms was interoceptive sensibility. Finally, we observed lower metacognitive accuracy for interoception in autistic children and adolescents, relative to their non-autistic counterparts. Despite their reduced interoceptive accuracy on the heartbeat tracking task and comparable accuracy on the heartbeat discrimination task, the autistic group reported higher confidence than the typical group in the discrimination task. Findings are consistent with theories of ASD as a disorder of interoceptive processing, but highlight the importance of validating cognitive models of developmental conditions within developmental populations.

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10. Reichow B, Hume K, Barton EE, Boyd BA. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2018 ; 5 : Cd009260.

BACKGROUND : The rising prevalence of autism spectrum disorders (ASD) increases the need for evidence-based behavioral treatments to lessen the impact of symptoms on children’s functioning. At present, there are no curative or psychopharmacological therapies to effectively treat all symptoms of the disorders. Early intensive behavioral intervention (EIBI) is a treatment based on the principles of applied behavior analysis. Delivered for multiple years at an intensity of 20 to 40 hours per week, it is one of the more well-established treatments for ASD. This is an update of a Cochrane review last published in 2012. OBJECTIVES : To systematically review the evidence for the effectiveness of EIBI in increasing functional behaviors and skills, decreasing autism severity, and improving intelligence and communication skills for young children with ASD. SEARCH METHODS : We searched CENTRAL, MEDLINE, Embase, 12 additional electronic databases and two trials registers in August 2017. We also checked references and contacted study authors to identify additional studies. SELECTION CRITERIA : Randomized control trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs) in which EIBI was compared to a no-treatment or treatment-as-usual control condition. Participants must have been less than six years of age at treatment onset and assigned to their study condition prior to commencing treatment. DATA COLLECTION AND ANALYSIS : We used standard methodological procedures expected by Cochrane.We synthesized the results of the five studies using a random-effects model of meta-analysis, with a mean difference (MD) effect size for outcomes assessed on identical scales, and a standardized mean difference (SMD) effect size (Hedges’ g) with small sample correction for outcomes measured on different scales. We rated the quality of the evidence using the GRADE approach. MAIN RESULTS : We included five studies (one RCT and four CCTs) with a total of 219 children : 116 children in the EIBI groups and 103 children in the generic, special education services groups. The age of the children ranged between 30.2 months and 42.5 months. Three of the five studies were conducted in the USA and two in the UK, with a treatment duration of 24 months to 36 months. All studies used a treatment-as-usual comparison group.Primary outcomesThere is low quality-evidence at post-treatment that EIBI improves adaptive behaviour (MD 9.58 (assessed using Vineland Adaptive Behavior Scale (VABS) Composite ; normative mean = 100, normative SD = 15), 95% confidence interval (CI) 5.57 to 13.60, P < 0.0001 ; 5 studies, 202 participants), and reduces autism symptom severity (SMD -0.34, 95% CI -0.79 to 0.11, P = 0.14 ; 2 studies, 81 participants ; lower values indicate positive effects) compared to treatment as usual.No adverse effects were reported across studies.Secondary outcomesThere is low-quality evidence at post-treatment that EIBI improves IQ (MD 15.44 (assessed using standardized IQ tests ; scale 0 to 100, normative SD = 15), 95% CI 9.29 to 21.59, P < 0.001 ; 5 studies, 202 participants) ; expressive (SMD 0.51, 95% CI 0.12 to 0.90, P = 0.01 ; 4 studies, 165 participants) and receptive (SMD 0.55, 95% CI 0.23 to 0.87, P = 0.001 ; 4 studies, 164 participants) language skills ; and problem behaviour (SMD -0.58, 95% CI -1.24 to 0.07, P = 0.08 ; 2 studies, 67 participants) compared to treatment as usual. AUTHORS’ CONCLUSIONS : There is weak evidence that EIBI may be an effective behavioral treatment for some children with ASD ; the strength of the evidence in this review is limited because it mostly comes from small studies that are not of the optimum design. Due to the inclusion of non-randomized studies, there is a high risk of bias and we rated the overall quality of evidence as ’low’ or ’very low’ using the GRADE system, meaning further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.It is important that providers of EIBI are aware of the current evidence and use clinical decision-making guidelines, such as seeking the family’s input and drawing upon prior clinical experience, when making recommendations to clients on the use EIBI. Additional studies using rigorous research designs are needed to make stronger conclusions about the effects of EIBI for children with ASD.

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11. Sapey-Triomphe LA, Sonie S, Henaff MA, Mattout J, Schmitz C. Correction to : Adults with Autism Tend to Underestimate the Hidden Environmental Structure : Evidence from a Visual Associative Learning Task. J Autism Dev Disord. 2018.

The original version of this article unfortunately contained a mistake in the article title.

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12. The L. Progress in the USA for autistic spectrum disorder. Lancet (London, England). 2018 ; 391(10132) : 1750.

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13. Vermaat LEW, van der Miesen AIR, de Vries ALC, Steensma TD, Popma A, Cohen-Kettenis PT, Kreukels BPC. Self-Reported Autism Spectrum Disorder Symptoms Among Adults Referred to a Gender Identity Clinic. LGBT health. 2018.

PURPOSE : The purpose of this study was to (1) investigate autism spectrum disorder (ASD) symptoms in a sample of adults referred for gender dysphoria (GD) compared to typically developing (TD) populations, (2) see whether males assigned at birth with GD (MaBGDs) and females assigned at birth with GD (FaBGDs) differ in ASD symptom levels, (3) study the role of sexual orientation, and (4) investigate ASD symptoms’ correlation with GD symptoms. METHODS : The Autism-Spectrum Quotient (AQ) was used to measure ASD symptoms, and the Utrecht Gender Dysphoria Scale (UGDS) was used to measure the intensity of GD. Mean AQ scores of adults referred for GD (n = 326 ; 191 MaBGD and 135 FaBGD) were compared to three TD populations taken from the literature (n = 1316 ; 667 male and 644 female, 5 birth-assigned sex unknown). RESULTS : The mean AQ score in individuals referred for GD was similar to the TD samples. FaBGDs showed higher mean AQ scores than MaBGDs, and they had mean scores similar to TD individuals of the same experienced gender (TD males). After selecting individuals with an UGDS score indicative of GD, a positive association between ASD and GD symptoms was found. CONCLUSION : The co-occurrence of GD and ASD in adults may not be as prevalent as previously suggested. Attenuation of sex differences in ASD might explain FaBGDs’ and MaBGDs’ ASD symptoms’ similarity to those of TD individuals of the same experienced gender. Intensity of ASD symptoms might be correlated with intensity of GD symptoms, warranting further studies to elaborate on their potential co-occurrence.

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