Pubmed du 16/05/19

jeudi 16 mai 2019

1. Living with Fragile X syndrome. Arch Dis Child. 2019.

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2. Atherton G, Cross L. Animal Faux Pas : Two Legs Good Four Legs Bad for Theory of Mind, but Not in the Broad Autism Spectrum. The Journal of genetic psychology. 2019 : 1-15.

Research shows that the general population varies with regard to both autistic traits and theory of mind (ToM) ability. Other work has shown that autistic individuals may not underperform on ToM tests when the agent of evaluation is anthropomorphic rather than typically human. Two studies examined the relation between ToM and autistic trait profiles in over 650 adults using either the standard Faux Pas Recognition Test (FPT) or an anthropomorphized version of the FPT (FPTa). Results showed that autistic trait profiles were related to faux pas detection ability in the FPT but not the FPTa. Furthermore, while those with the broad autism phenotype scored significantly worse than those who were typically developed on the FPT, scores did not significantly differ on the FPTa. These findings add to a growing body of work suggesting that ToM ability is not at a global deficit in those on the autistic spectrum, but may relate to the mindreading of specifically human agents.

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3. Caplan B, Blacher J, Eisenhower A. Responsive Parenting and Prospective Social Skills Development in Early School-Aged Children with Autism Spectrum Disorder. J Autism Dev Disord. 2019.

Children with autism spectrum disorder (ASD) vary greatly in social functioning, and in turn, long-term relational and academic outcomes. Responsive parenting which follows a child’s lead and focus of attention is predictive of language and social gains for children with or without developmental risk. The present study prospectively assessed 176 families of children with ASD (ages 4 to 7 years) to examine predictors of observed responsive parenting and associations of responsive parenting with concurrent and prospective growth in social functioning by multi-method assessment. Responsive parenting concurrently associated with child characteristics (IQ, language, sex) and child social engagement within the interaction. Structural equation models revealed that responsive parenting positively predicted prospective growth in social skills by teacher but not parent report.

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4. Cheng J, Eskenazi B, Widjaja F, Cordero JF, Hendren RL. Improving autism perinatal risk factors : A systematic review. Med Hypotheses. 2019 ; 127 : 26-33.

BACKGROUND : Current understanding of the etiology of autism is based on the interaction of multiple genes with each other and with environmental factors, leading to a neurodevelopmental process that results in the expression of autism spectrum disorder (ASD) in the child. This suggests that it might be possible to strengthen resilience to environmental stressors during the perinatal period to improve outcomes and possibly prevent the development of ASD. METHODS : We searched the MEDLINE database for multiple perinatal factors associated with the development of ASD published between January 1, 2005 and July 1, 2018. The search terms used were "autism" crossed with either "perinatal," "prenatal," "gestational," or "pregnancy," and crossed again with each perinatal risk factor highlighted in this review including topics on parental health, infections, medications, and environmental stressors. We then searched interventions that may improve neurodevelopmental outcome before and during pregnancy, including supplements, breastfeeding, and postpartum stress reduction. We identified recent or unique metanalyses and systematic reviews of the identified focus and on randomized controlled trials and summarized these using the most recent and comprehensive reviews. RESULTS : Folate, omega-3, vitamin D3, environmental toxin avoidance, correcting deficiencies, immune boosting, and prolonged breast feeding are all reported to be linked to the possible reduction of adverse pregnancy outcomes including ASD. CONCLUSIONS : Studies of individual components for improving pregnancy outcomes and several uncontrolled preconception to infancy medical practices suggest that multiple interventions might improve the outcomes of pregnancies where there is risk for developing ASD.

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5. Chirumbolo S, Bjorklund G. Use of anti-histamines and osthole in autistic children. International immunopharmacology. 2019 ; 73 : 201-2.

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6. Coll-Tane M, Krebbers A, Castells-Nobau A, Zweier C, Schenck A. Intellectual disability and autism spectrum disorders ’on the fly’ : insights from Drosophila. Disease models & mechanisms. 2019 ; 12(5).

Intellectual disability (ID) and autism spectrum disorders (ASD) are frequently co-occurring neurodevelopmental disorders and affect 2-3% of the population. Rapid advances in exome and genome sequencing have increased the number of known implicated genes by threefold, to more than a thousand. The main challenges in the field are now to understand the various pathomechanisms associated with this bewildering number of genetic disorders, to identify new genes and to establish causality of variants in still-undiagnosed cases, and to work towards causal treatment options that so far are available only for a few metabolic conditions. To meet these challenges, the research community needs highly efficient model systems. With an increasing number of relevant assays and rapidly developing novel methodologies, the fruit fly Drosophila melanogaster is ideally positioned to change gear in ID and ASD research. The aim of this Review is to summarize some of the exciting work that already has drawn attention to Drosophila as a model for these disorders. We highlight well-established ID- and ASD-relevant fly phenotypes at the (sub)cellular, brain and behavioral levels, and discuss strategies of how this extraordinarily efficient and versatile model can contribute to ’next generation’ medical genomics and to a better understanding of these disorders.

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7. DiCarlo GE, Aguilar JI, Matthies HJ, Harrison FE, Bundschuh KE, West A, Hashemi P, Herborg F, Rickhag M, Chen H, Gether U, Wallace MT, Galli A. Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. The Journal of clinical investigation. 2019 ; 130.

The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.

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8. Guo BQ, Li HB, Zhai DS, Ding SB. Association of maternal prenatal folic acid intake with subsequent risk of autism spectrum disorder in children : A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019 ; 94 : 109650.

BACKGROUND : A number of studies have explored the link of antenatal folic acid (FA) intake with autism spectrum disorder (ASD) in children, with inconsistent findings. Therefore, we conducted a systematic review and meta-analysis of relevant studies to elucidate the actual association between maternal FA intake during the prenatal period and the risk of ASD in offspring. METHODS : PubMed, EMBASE, PsycINFO, Scopus, Web of Science, and Cochrane Library were searched up to June 7, 2018, without language restriction. The random-effects model was applied to summarize results. The adjusted odds ratios (ORs) and hazard ratios (HRs) were pooled separately. RESULTS : Eight observational studies (a total of 13 reports ; 840,776 children and 7127 cases) were included. FA intake was mainly estimated from self-report of mothers or available databases. The results of overall analysis from 6 studies (9 reports) combined by OR and 2 studies (4 reports) presenting HR showed that the likelihoods of ASD in offspring whose mothers were prenatally exposed to FA did not vary significantly compared with those in offspring of mothers without such exposure (OR=0.91, 95% CI : 0.73-1.13 and HR=0.66, 95% CI : 0.38-1.17, respectively). Further analysis revealed that the primary outcome of the meta-analysis was stable regardless of the study design, and not unduly affected by any single report. Additionally, no publication bias was observed, and the findings of overall analysis were in agreement with those of subgroup analyses. CONCLUSIONS : This study does not provide support for the association between maternal FA intake during the prenatal period and the reduced risk of ASD in children. However, in view of the types and limited number of studies in the literature, more investigation is needed to confirm the findings of this meta-analysis.

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9. Hollins S, Lodge KM, Lomax P. The case for removing intellectual disability and autism from the Mental Health Act - ERRATUM. The British journal of psychiatry : the journal of mental science. 2019 : 1.

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10. Hollowood K, Melnyk S, Pavliv O, Evans T, Sides A, Schmidt RJ, Hertz-Picciotto I, Elms W, Guerrero E, Kruger U, Hahn J, James SJ. Maternal metabolic profile predicts high or low risk of an autism pregnancy outcome. Res Autism Spectr Disord. 2018 ; 56 : 72-82.

Background : Currently there is no test for pregnant mothers that can predict the probability of having a child that will be diagnosed with autism spectrum disorder (ASD). Recent estimates indicate that if a mother has previously had a child with ASD, the risk of having a second child with ASD is 18.7% (High Risk) whereas the risk of ASD in the general population is 1.7% (Low Risk). Methods : In this study, metabolites of the folate-dependent transmethylation and transsulfuration biochemical pathways of pregnant mothers were measured to determine whether or not the risk of having a child with autism could be predicted by her metabolic profile. Pregnant mothers who have had a child with autism before were separated into two groups based on the diagnosis of their child whether the child had autism (ASD) or not (TD). Then these mothers were compared to a group of control mothers who have not had a child with autism before. A total of 107 mothers were in the High Risk category and 25 mothers in the Low Risk category. The High Risk category was further separated into 29 mothers in the ASD group and 78 mothers in the TD group. Results : The metabolic results indicated that among High Risk mothers, it was not possible to predict an autism pregnancy outcome. However, the metabolic profile was able to predict with approximately 90% sensitivity and specificity whether a mother fell into the High Risk group (18.7% risk) or Low Risk group (1.7% risk). Conclusions : Based upon these measurements it is not possible to determine during a pregnancy if a child will be diagnosed with ASD by age 3. However, differences in the folate-dependent transmethylation and transsulfuration metabolites are indicative of the risk level (High Risk of 18.7% vs. Low Risk of 1.7%) of the mother for having a child with ASD.

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11. Jung M, Tu Y, Park J, Jorgenson K, Lang C, Song W, Kong J. Surface-based shared and distinct resting functional connectivity in attention-deficit hyperactivity disorder and autism spectrum disorder. The British journal of psychiatry : the journal of mental science. 2019 ; 214(6) : 339-44.

BACKGROUND : Both attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental disorders with a high prevalence. They are often comorbid and both exhibit abnormalities in sustained attention, yet common and distinct neural patterns of ASD and ADHD remain unidentified.AimsTo investigate shared and distinct functional connectivity patterns in a relatively large sample of boys (7- to 15-year-olds) with ADHD, ASD and typical development matched by age, gender and IQ. METHOD : We applied machine learning techniques to investigate patterns of surface-based brain resting-state connectivity in 86 boys with ASD, 83 boys with ADHD and 125 boys with typical development. RESULTS : We observed increased functional connectivity within the limbic and somatomotor networks in boys with ASD compared with boys with typical development. We also observed increased functional connectivity within the limbic, visual, default mode, somatomotor, dorsal attention, frontoparietal and ventral attention networks in boys with ADHD compared with boys with ASD. In addition, using a machine learning approach, we were able to discriminate typical development from ASD, typical development from ADHD and ASD from ADHD with accuracy rates of 76.3%, 84.1%, and 79.3%, respectively. CONCLUSIONS : Our results may shed new light on the underlying mechanisms of ASD and ADHD and facilitate the development of new diagnostic methods for these disorders.Declaration of interestJ.K. holds equity in a startup company, MNT.

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12. Lahbib S, Trabelsi M, Dallali H, Sakka R, Bourourou R, Kefi R, Mrad R, Abdelhak S, Gaddour N. Novel MED12 variant in a multiplex Fragile X syndrome family : dual molecular etiology of two X-linked intellectual disabilities with autism in the same family. Molecular biology reports. 2019.

Studies of X-linked pedigrees were the first to identify genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD). However, some pedigrees present a huge clinical variability between the affected members. This intrafamilial heterogeneity may be due to cooccurrence of two disorders. In the present study, we describe a multiplex X-linked pedigree in which three siblings have ID, ASD and dysmorphic features but with variable severity. Through Fragile X syndrome test, we identified the full FMR1 mutation in only two males. Whole exome sequencing allowed us to identify a novel hemizygous variant (p.Gln2080_Gln2083del) in MED12 gene in two males. So, the first patient has FXS, the second has both FMR1 and MED12 mutations while the third has only the MED12 variant. MED12 mutations are implicated in several forms of X-linked ID. Family segregation and genotype-phenotype-correlation were in favor of a cooccurrence of two forms of X-linked ID. Our work provides further evidence of the involvement of MED12 in XLID. Moreover, through these results, it is noteworthy to raise awareness that intrafamilial heterogeneity in FXS multiplex families could result from the cooccurrence of multiple clinical entities involving at least two separate genetic loci. This should be taken into consideration for genetic testing and counselling in patients/families with atypical disease symptoms.

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13. Owada K, Okada T, Munesue T, Kuroda M, Fujioka T, Uno Y, Matsumoto K, Kuwabara H, Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y, Arioka Y, Kojima M, Yuhi T, Yassin W, Kushima I, Benner S, Ogawa N, Kawano N, Eriguchi Y, Uemura Y, Yamamoto M, Kano Y, Kasai K, Higashida H, Ozaki N, Kosaka H, Yamasue H. Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism. Brain. 2019.

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder’s core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule : the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, -0.57 ; 95% CI, -1.27 to 0.13 ; P = 0.023) and confirmatory trials (-0.41 ; -0.62 to -0.20 ; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen’s d = -0.78 ; 95% CI, -1.21 to -0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen’s d = -0.46 ; 95% CI, -0.90 to -0.01) and 6 weeks (P = 0.10, Cohen’s d = -0.35 ; 95% CI, -0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen’s d = -1.24 ; 95% CI, -1.71 to -0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals’ facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

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14. Peverill S, Smith IM, Duku E, Szatmari P, Mirenda P, Vaillancourt T, Volden J, Zwaigenbaum L, Bennett T, Elsabbagh M, Georgiades S, Ungar WJ. Developmental Trajectories of Feeding Problems in Children with Autism Spectrum Disorder. Journal of pediatric psychology. 2019.

OBJECTIVE : Although feeding problems are a common concern in children with autism spectrum disorder (ASD), few longitudinal studies have examined their persistence over time. The purpose of this study was to examine the developmental progression of feeding problems across four time points in preschoolers with ASD. METHODS : Group-based trajectory analyses revealed four distinct trajectories of feeding problems in our sample (N = 396). RESULTS : The majority of children showed levels of feeding problems that were low from the outset and stable (Group 1 ; 26.3%) or moderate and declining over time (Group 2 ; 38.9%). A third group (26.5%) showed high levels of feeding problems as preschoolers that declined to the average range by school age. Few participants (8.3%) showed evidence of severe chronic feeding problems. Feeding problems were more highly correlated with general behavior problems than with autism symptom severity. CONCLUSIONS : Overall, our findings demonstrated that in our sample of children with ASD, most feeding problems remitted over time, but a small subgroup showed chronic feeding problems into school age. It is important to consider and assess feeding problems in ASD against the backdrop of typical development, as many children with ASD may show improvement with age.

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15. Pomper R, Ellis Weismer S, Saffran J, Edwards J. Specificity of Phonological Representations for Children with Autism Spectrum Disorder. J Autism Dev Disord. 2019.

This study investigated whether children with autism spectrum disorder (ASD) are sensitive to mispronunciations of familiar words and compared their sensitivity to children with typical-development. Sixty-four toddlers with ASD and 31 younger, typical controls participated in a looking-while-listening task that measured their accuracy in fixating the correct object when it was labelled with a correct pronunciation versus mispronunciation. A cognitive style that prioritizes processing local, rather than global features, as claimed by the weak central coherence theory, predicts that children with ASD should be more sensitive to mispronunciations than typical controls. The results, however, reveal no differences in the effect of mispronunciations on lexical processing between groups, even when matched for receptive language or non-verbal cognitive skills.

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16. Ruble L, McGrew JH, Wong V, Adams M, Yu Y. A Preliminary Study of Parent Activation, Parent-Teacher Alliance, Transition Planning Quality, and IEP and Postsecondary Goal Attainment of Students with ASD. J Autism Dev Disord. 2019.

The school, student and family factors underlying poor postsecondary outcomes of students with autism spectrum disorder (ASD) are not well understood. The potential impact of school [e.g., transition planning quality (TPQ)], family (e.g., parent activation), and student factors (e.g., adaptive functioning) and their interaction (e.g., parent-teacher alliance) on student outcomes were examined. Student IQ and adaptive behavior, TPQ, and alliance correlated with IEP progress, with postsecondary goal attainment generally and with student participation in training/education, specifically. However, only parent activation and student externalizing behavior correlated with employment. Families and students, rather than school personnel, were the primary persons in charge and in control of the implementation of postsecondary plans and required help across multiple coaching sessions to implement plans fully.

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17. Saad K, Abdel-Rahman A, Elserogy Y, Al-Atram A, El-Houfey A, Othman H, Bjorklund G, Jia F, Urbina M, Abo-Elela M, Ahmad F, Abd El-Baseer A, Ahmed A, Abdel-Salam A. Retraction : Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry. 2019 ; 60(6) : 711.

The above article, published in print in the Jan 2018 issue of the Journal of Child Psychology & Psychiatry and online in Wiley Online Library (, has been retracted by the JCPP Editor-in-Chief, Edmund Sonuga-Barke, and John Wiley & Sons. Following a series of communications from readers highlighting concerns about the paper (now published on the journal website), the journal editors requested that the authors send them the raw data from the trial. In response the authors informed the editors that ; (i) the electronic data base had been lost following a computer outage and (ii) that they could send only 95 out of 120 hard-copy participant data sheets as one site had closed and was no longer contactable. The substantial data loss in and of itself posed a serious difficulty in verifying the correctness of the data presented in the paper. The JCPP then analysed the data from the 95 cases itself. A number of significant discrepancies emerged between the re-analysis and the findings reported in the paper both in terms of means and standard deviations of key outcome variables across the trial. These involved very substantial differences that we judged to be extremely unlikely to have arisen due to variations in composition of the original and re-analysed samples. We also discovered previously unidentified/reported problems with missing data and recording irregularities regarding changes in treatment regimen and subject identifiers. As a result of these issues the Editors no longer have confidence in the findings reported in the original paper. Based on all these matters combined and following published guidance from the Committee on Publishing Ethics (COPE) and Wiley’s Best Practice Guidelines on Publishing Ethics, we have decided that the only course of action available to us is to retract the paper.

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18. Schmidt RJ, Niu Q, Eyles DW, Hansen RL, Iosif AM. Neonatal vitamin D status in relation to autism spectrum disorder and developmental delay in the CHARGE case-control study. Autism Res. 2019.

Vitamin D appears essential for normal neurodevelopment and cognitive and behavioral function. We examined neonatal vitamin D in relation to the child’s later diagnosis of autism spectrum disorder (ASD) or developmental delay (DD). Children aged 24-60 months enrolled in the population-based CHARGE case-control study were evaluated clinically for ASD (n = 357), DD (n = 134), or typical development (TD, n = 234) at the MIND Institute (Sacramento, CA) using standardized assessments. Total 25-hydroxyvitamin D (25[OH]D) was measured using sensitive isotope dilution liquid chromatography-tandem mass spectrometry in archived dried blood spots collected for the California Department of Public Health’s Newborn Screening Program. Multinomial logistic regression was used to calculate ORs as measures of the associations between 25 nmol/L change in 25(OH)D and ASD and DD. Associations between 25(OH)D and scores on Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales were assessed using robust linear regression. Effect modification was examined using stratified models and interaction product terms. Unadjusted mean (SD) 25(OH)D was lower for DD (73.2 [37.6]) than for TD (82.7 [39.3]) and ASD (80.1 [37.4]). After adjustment for maternal prepregnancy body mass index and education, a 25 nmol/L increase in total 25(OH)D was not associated with ASD (OR = 0.97 ; CI : 0.87-1.08) or DD (OR = 0.91 ; 95% CI : 0.78-1.06). Neonatal 25(OH)D was associated with significantly reduced ASD only in females (adjusted OR = 0.74 ; 95% CI : 0.55-0.99, Pinteraction = 0.03), and significantly reduced DD only in non-Hispanic white children (adjusted OR = 0.79 ; 95% CI : 0.63-0.98, Pinteraction = 0.11 for Hispanic, Pinteraction = 0.31 for other), driven by DD children with trisomy 21. This study provides evidence that neonatal vitamin D could be associated with ASD in females and with DD in non-Hispanic white children. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Vitamin D appears essential for brain development and function. We examined neonatal total 25-hydroxyvitamin D (25[OH]D) measured in dried blood spots in relation to later diagnoses of autism spectrum disorder (ASD) or developmental delay (DD) and related assessment scores. Higher neonatal 25(OH)D was associated with a 26% reduction in the odds for ASD only in females. After taking into account factors that could contribute to vitamin D status, a significant association with 21% reduced odds for DD was found only in non-Hispanic white children. Though results were nonsignificant overall, certain subgroups might benefit from higher neonatal vitamin D.

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19. Serra D, Almeida LM, Dinis TCP. Polyphenols as food bioactive compounds in the context of Autism Spectrum Disorders : A critical mini-review. Neurosci Biobehav Rev. 2019 ; 102 : 290-8.

Dietary polyphenols are bioactive compounds with potential in preventing and treating several chronic disorders, mainly due to their ability to modulate key pro-inflammatory and pro-oxidant signalling pathways. Although some studies have expressed concern about their efficacy in vivo, accumulating evidence has suggested that these compounds may achieve large concentrations in the gastrointestinal tract, which may be important in the context of intestinal and of neurological disorders, via modulation of the "gut-brain axis". Autism Spectrum disorders (ASD) are a group of lifelong neurodevelopmental disorders in which many patients suffer from gastrointestinal impairments. Thus, in the scope of these disorders, a growing number of studies have been focused on the microbiota-gut-brain axis. In this mini-review, we present gathered data on gut-to-brain communication in the scope of ASD and we address the advantages of polyphenols in the treatment of these disorders, presenting the more recent preclinical and clinical data on this issue. According to most studies, dietary polyphenols can be a promising strategy for the alleviation of ASD symptoms.

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20. Talebizadeh Z, Shah A, DiTacchio L. The potential role of a retrotransposed gene and a long noncoding RNA in regulating an X-linked chromatin gene (KDM5C) : Novel epigenetic mechanism in autism. Autism Res. 2019.

A growing body of evidence supports the potential role of the circadian system and chromatin remodeling genes in autism. Considering the heterogeneity and gender discrepancy in autism, and the complex nature of the epigenetic landscape, identification of biologically relevant epigenetic factors requires reducing heterogeneity using proper subtyping. For this study, we used X chromosome inactivation (XCI) status in females with autism as an epigenetic marker for subtyping and examined the expression level of members of KDM5, a chromatin remodeling gene family. KDM5 are histone demethylases involved in the circadian molecular machinery. We used human blood samples to characterize alternatively spliced KDM5 isoforms and noticed that KDM5C undergoes a complex splicing process. We also identified a KDM5C isoform (KDM5C-3’UTR-lncRNA) containing a novel 3’UTR originated from a retrotransposed gene (retro-SUV39H2) of an autosomal methyltransferase (SUV39H2). This 3’UTR shows 84% sequence homology with long ncRNAs (lncRNAs) and is located 32 kb downstream of KDM5C. The KDM5C-3’UTR-lncRNA isoform was differentially expressed in autistic females with XCI skewness compared with controls. KDM5C plays a crucial role in balancing histone H3K4 methylation states. The identified retro-SUV39H2 originated lncRNA also shows H3K4 marks. By assessing the expression level of alternatively spliced Kdm5 isoforms at different circadian time-points, we showed that some isoforms follow a circadian oscillation pattern in wild type mouse brain.This study provides the first evidence and a suggestive model for the potential role of retrotransposed elements in autism through linking methylases and demethylases, two functionally complementary components of chromatin remodeling, which may collectively contribute to disease etiology through lncRNAs. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Genes do not function in isolated conditions and their proper expression level also depends on a mechanism called gene regulation. An example of gene regulation is when changes outside DNA sequences influence the function of autism susceptibility genes. Alternative splicing is one type of gene regulation, which produces several versions of a gene (called variants) that may slightly differ from each other and be expressed at different levels in response to environmental changes. The circadian clock is an essential timing mechanism that enables organisms to maintain internal processes in sync with the dynamic environment brought about by the day-night cycle. The goal of this study was to assess if a subset of females with autism with certain genetic marker had a unique pattern of alternative splicing of three circadian genes. We identified a novel variant that is differentially expressed in this subset. Our study provides a novel subject stratification strategy, and a suggestive model of how biologically relevant components of a gene regulatory process may be linked and, possibly, collectively contribute to the etiology of autism.

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21. Tekola B, Girma F, Kinfe M, Abdurahman R, Tesfaye M, Yenus Z, Salomone E, Pacione L, Fekadu A, Servili C, Hanlon C, Hoekstra RA. Adapting and pre-testing the World Health Organization’s Caregiver Skills Training programme for autism and other developmental disorders in a very low-resource setting : Findings from Ethiopia. Autism. 2019 : 1362361319848532.

The World Health Organization’s Caregiver Skills Training programme for children with developmental disorders or delays teaches caregivers strategies to help them support their child’s development. Ethiopia has a severe lack of services for children with developmental disorders or delays. This study explored the perspectives of Ethiopian caregivers, professionals and other stakeholders to inform adaptation and implementation of the World Health Organization’s Caregiver Skills Training in Ethiopia. Data collection included (1) a consultation and review, comprising stakeholder meetings, review of draft Caregiver Skills Training materials and feedback from Ethiopian Master Trainees and (2) a pre-pilot including quantitative feasibility and acceptability measures and qualitative interviews with caregivers (n = 9) and programme facilitators/observers (n = 5). The consultation participants indicated that the Caregiver Skills Training addresses an urgent need and is relevant to the Ethiopian context. Several adaptations were proposed, including more emphasis on psycho-education, stigma, parental feelings of guilt and expectations of a cure. The adapted Caregiver Skills Training was pre-piloted with excellent participation (100%) and retention (90%) rates. Four themes were developed from the qualitative data : (1) Programme acceptability and relevance, (2) Perceived programme benefits, (3) Challenges and barriers and (4) Suggestions for improvement. The World Health Organization’s Caregiver Skills Training addresses a local need and, with careful adaptations, is feasible and acceptable to be implemented in Ethiopia. These findings may have relevance to low-resource settings worldwide.

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22. Torrico B, Shaw AD, Mosca R, Vivo-Luque N, Hervas A, Fernandez-Castillo N, Aloy P, Bayes M, Fullerton JM, Cormand B, Toma C. Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes. Journal of psychiatry & neuroscience : JPN. 2019 ; 44(4) : 1-10.

Background : Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism. Methods : We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100). Results : We observed no difference in the number of transmitted versus nontransmitted truncating alleles for high-functioning autism (117 v. 130, p = 0.78). Transmitted truncating and de novo variants in high-functioning autism were not enriched in gene ontology (GO) or Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, or in autism-related gene sets. However, in a patient with high-functioning autism we identified a de novo variant in a canonical splice site of LRP1, a postsynaptic density gene that is a target for fragile X mental retardation protein (FRMP). This de novo variant leads to in-frame skipping of exon 29, removing 2 of 6 blades of the beta-propeller domain 4 of LRP1, with putative functional consequences. Large data sets implicate LRP1 across a number of psychiatric disorders : de novo variants are associated with autism-spectrum disorder (p = 0.039) and schizophrenia (p = 0.008) from combined sequencing projects ; common variants using genome-wide association study data sets from the Psychiatric Genomics Consortium show gene-based association in schizophrenia (p = 6.6 x E-07) and in a meta-analysis across 7 psychiatric disorders (p = 2.3 x E-03) ; and the burden of ultra-rare pathogenic variants has been shown to be higher in autism-spectrum disorder (p = 1.2 x E-05), using whole-exome sequencing from 6135 patients with schizophrenia, 1778 patients with autism-spectrum disorder and 7875 controls. Limitations : We had a limited sample of patients with high-functioning autism, related to difficulty in recruiting probands with high cognitive performance and no family history of psychiatric disorders. Conclusion : Previous studies and ours suggest an effect of truncating mutations restricted to severe autism-spectrum disorder phenotypes that are associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

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23. Wester Oxelgren U, Aberg M, Myrelid A, Anneren G, Westerlund J, Gustafsson J, Fernell E. Autism needs to be considered in children with Down syndrome. Acta paediatrica (Oslo, Norway : 1992). 2019.

AIM : To analyse levels and profiles of autism symptoms in children with Down syndrome (DS) with and without diagnosed autism spectrum disorder (ASD) and to specifically study the groups with severe Intellectual disability (ID). METHODS : From a population-based cohort of 60 children with DS (age 5-17 years) with 41 participating children, scores obtained from the Autism Diagnostic Observation Schedule (ADOS) Module-1 algorithm were compared between those with and without diagnosed ASD. Children with DS and ASD were also compared to a cohort of children with idiopathic ASD, presented in the ADOS manual. RESULTS : Children with DS and ASD had significantly higher ADOS scores in all domains compared to those without ASD. When the groups with DS, with and without ASD, were restricted to those with severe ID, the difference remained. When the children with DS and ASD and the idiopathic autism group were compared, the ADOS profiles were similar. CONCLUSION : A considerable proportion of children with DS has ASD but there is also a group of children with DS and severe ID without autism. There is a need to increase awareness of the high prevalence of autism in children with DS to ensure that appropriate measures and care are provided. This article is protected by copyright. All rights reserved.

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24. Wilson KP, Steinbrenner JR, Kalandadze T, Handler L. Interventions Targeting Expressive Communication in Adults With Autism Spectrum Disorders : A Systematic Review. Journal of speech, language, and hearing research : JSLHR. 2019 : 1-20.

Purpose The aims of this systematic review are to (a) synthesize the literature on interventions targeting expressive communication in adults with autism spectrum disorder and (b) evaluate the effectiveness of the interventions. Method The literature search resulted in 7,196 articles. The research team used 2 reviewers and consensus for title/abstract review, full-text review, and quality review. To be included, studies had to (a) include at least 1 adult (18 years of age and above) with an autism spectrum disorder ; (b) examine an intervention, treatment, or model of care ; (c) provide outcome data related to expressive communication modalities/domains ; (d) be experimental or quasi-experimental ; and (e) be published in English. Twenty-two studies (14 single-case design and 8 group design), with a total of 256 participants and varied interventions and outcome variables, met criteria for inclusion. Effect sizes are presented for group design studies, and visual analysis results are outlined for single-case design studies. Results Examination of treatment effects in the included studies showed positive effects, overall ; however, there was great variability between studies. Single-case design studies showed evidence of functional relations in all but 1 study, with most showing medium to large effects, as well as maintenance and generalization of gains. Group design studies showed a wide range of effects from near-zero to large effects. Differences in intervention strategies and durations, as well as in participant characteristics and outcome measures, presented barriers to aggregation. Conclusions This review highlights the need for increased high-quality research examining interventions targeting expressive communication in adults with autism spectrum disorder and also pinpoints interventions with potential for future study and use in this population.

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25. Wright BM, Benigno JP. Autism Spectrum Disorder and Sibling Relationships : Exploring Implications for Intervention Using a Family Systems Framework. American journal of speech-language pathology. 2019 : 1-9.

Purpose There is currently a very limited scope of research in the field of speech-language pathology on sibling involvement in the treatment of children with autism spectrum disorder (ASD). Principles of family systems theory (FST) recognize the interrelatedness and dynamic nature of the family unit, making it a relevant and useful guiding framework for future research and practice on sibling involvement in intervention. Method In this article, core principles of FST are reviewed, followed by the state of research related to sibling relationships in ASD, and roles of typically developing siblings and siblings with ASD in intervention programs. Implications for adopting an FST framework as well as considerations and future directions in this area of research and clinical practice are discussed. Results According to the principles of FST on the inclusion of siblings in treatment, there are several considerations to be made at the level of the child with ASD, the sibling(s), and the family unit. Factors such as developmental level, communication status, and areas of strength, challenge, and interest are key features of the children and family that will need to be addressed in order to promote positive sibling involvement and family functioning. Conclusions The development of family-centered sibling intervention programs for individuals with ASD is an area of research that warrants further exploration. With the guidance of the FST framework, researchers and clinicians can work to develop innovative interventions that consider the unique characteristics of each family to optimize outcomes at the levels of each individual, the sibling relationship, and the family as a unit.

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26. Zahedi Abghari F, Moradi Y, Akouchekian M. PTEN gene mutations in patients with macrocephaly and classic autism : A systematic review. Medical journal of the Islamic Republic of Iran. 2019 ; 33 : 10.

Background : Autism Spectrum Disorder (ASD) is a neurological disorder characterized by massive damage in various fields of development. Impaired social interaction and communication skills, unusual behavior or interests, and repetitive activities are considerably disabling in these patients. There are several challenges in diagnosis of ASD patients such as co-existing epilepsy, difference in clinician attitudes and possibly multifactorial etiology of autistic behavior among children and adults. Research in recent years has emphasized a possible connection between mutations in PTEN and macrocephaly (head circumference > 97th centile). Methods : Articles in English Language were searched from international databases including Medline (PubMed), Google Scholar, Scopus, and CINHAL from January 1998 to January 2016. Results : The results showed that among 2940 patients with behavioral disorders, 2755 individuals had ASD, and 35 cases with macrocephaly had mutations in PTEN. About 77% of the articles (7/9) analyzed mutations in PTEN in patients with head circumference more than 2SD away from the mean, but did not check mutations in this gene in other ASD patients without macrocephaly. To the best of our knowledge, this study is the first systematic review on human PTEN mutations and classical autistic behavior. Conclusion : We conclude that the presence of macrocephaly may not be sufficient to examine the PTEN mutation in this group ; however, surveying this gene in all cases of macrocephaly seems to be necessary.

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