1. {{Research Opportunities in the Area of People With Autism Spectrum Disorder}}. {Am J Occup Ther}. 2017; 71(2): 7102400010p1-p2.
The American Occupational Therapy Association (AOTA) Evidence-Based Practice Project has developed a table summarizing the research opportunities on people with autism spectrum disorder. The table provides an overview of the state of the current available evidence on interventions within the scope of occupational therapy practice and is based on the systematic reviews from the AOTA Evidence-Based Practice Guidelines Series. Researchers, students, and clinicians can use this information in developing innovative research to answer important questions within the occupational therapy field.
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2. Cannell JJ. {{Vitamin D and autism, what’s new?}}. {Rev Endocr Metab Disord}. 2017.
An increasing amount of evidence points to the possibility that gestational and early childhood vitamin D deficiency [25(OH)D < 40 ng/ml] cause some cases of autism. Vitamin D is metabolized into a seco-steroid hormone that regulates about 3% of the 26,000 genes in the coding human genome. It is also a neurosteroid that is active in brain development, having effects on cellular proliferation, differentiation, calcium signaling, neurotrophic and neuroprotective actions; it also appears to have an effect on neurotransmission and synaptic plasticity. Children who are, or who are destined to become, autistic have lower 25(OH)D levels at 3 months of gestation, at birth and at age 8 compared to their unaffected siblings. Two open label trials found high dose vitamin D improves the core symptoms of autism in about 75% of autistic children. A few of the improvements were remarkable. The vitamin D doses used in these children were 300 IU/KG/day up to a maximum of 5000 IU/day (highest final 25(OH)D level reached was 45 ng/ml). The other study used 150,000 IU/month IM as well as 400 IU/day [highest final 25(OH)D level was 52 ng/ml]. These two open label trials were recently confirmed with a randomized controlled trial (RCT) using 300 IU/kg/day with a maximum of 5000 IU/day and resulted in effects similar to the two open label studies. In terms of prevention, a recent small study showed vitamin D supplementation during pregnancy (5000 IU/day) and during infancy and early childhood (1000 IU/day) significantly reduced the expected incidence of autism in mothers who already had one autistic child from 20% to 5%. Vitamin D is safe; for example, over the last 15 years, Poison Control reports there have been approximately 15,000 cases of vitamin D overdose. However only three of these 15,000 people developed clinical toxicity and no one died. Given those facts, practitioners might consider treating autism with 300 IU/kg/day, and seek to prevent autism by supplementing pregnant and lactating women (5000 IU/day) and infants and young children (150 IU/kg/day) checking 25(OH)D levels every 3 months. These doses will increase 25(OH)D blood levels to those recommended by the Endocrine Society. As the American Academy of Pediatrics recommends vitamin D supplementation during infancy and childhood, pediatricians and family practitioners should evaluate the current evidence on autism and vitamin D and act accordingly. Lien vers le texte intégral (Open Access ou abonnement)
3. Curie A, Lesca G, Bussy G, Manificat S, Arnaud V, Gonzalez S, Revol O, Calender A, Gerard D, des Portes V. {{Asperger syndrome and early-onset schizophrenia associated with a novel MECP2 deleterious missense variant}}. {Psychiatr Genet}. 2017.
Methyl-CpG-binding protein 2 (MECP2) deleterious variants, which are responsible for Rett syndrome in girls, are involved in a wide spectrum of developmental disabilities in males. A neuropsychiatric phenotype without intellectual disability is uncommon in patients with MECP2 deleterious variants. We report on two dizygotic twins with an MECP2-related psychiatric disorder without intellectual disability. Neuropsychological and psychiatric phenotype assessments were performed, and a genetic analysis was carried out. Both patients fulfilled the Pervasive Developmental Disorder criteria on Autism Diagnostic Observation Schedule and Asperger syndrome criteria on Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). One patient developed early-onset schizophrenia (DSM-IV criteria) with two acute psychotic episodes, the latest one following corticosteroids and sodium valproate intake, with major hyperammonemia. A novel MECP2 gene transversion c.491 G>T [p.(Ser164Ile)] was found in both twins. Pathogenicity of this variant was considered on the basis of strong clinical and molecular data. The underlying molecular basis of neuropsychiatric disorders may have important consequences on genetic counseling and therapeutic strategies.
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4. Dimian AF, Botteron KN, Dager SR, Elison JT, Estes AM, Pruett JR, Jr., Schultz RT, Zwaigenbaum L, Piven J, Wolff JJ. {{Potential Risk Factors for the Development of Self-Injurious Behavior among Infants at Risk for Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2017.
Prevalence of self-injurious behavior (SIB) is as high as 50% among children with autism spectrum disorder (ASD). Identification of risk factors for the development of SIB is critical to early intervention and prevention. However, there is little empirical research utilizing a prospective design to identify early risk factors for SIB. The purpose of this study was to evaluate behavioral characteristics predicting SIB at age 2 years among 235 infants at high familial risk for ASD. Logistic regression results indicated that presence of SIB or proto-SIB and lower developmental functioning at age 12 months significantly predicted SIB at 24 months. A pattern of persistent SIB over this period was associated with a diagnosis of autism and poorer cognitive and adaptive outcomes.
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5. Finegold SM, Summanen PH, Downes J, Corbett K, Komoriya T. {{Detection of Clostridium perfringens toxin genes in the gut microbiota of autistic children}}. {Anaerobe}. 2017.
We studied stool specimens from 33 autistic children aged 2-9 years with gastrointestinal (GI) abnormalities and 13 control children without autism and without GI symptoms. We performed quantitative comparison of all Clostridium species and Clostridium perfringens strains from the fecal microbiota by conventional, selective anaerobic culture methods. We isolated C. perfringens strains and performed PCR analysis for the main C. perfringens toxin genes, alpha, beta, beta2, epsilon, iota and C. perfringens enterotoxin gene. Our results indicate that autistic subjects with gastrointestinal disease harbor statistically significantly (p = 0.031) higher counts of C. perfringens in their gut compared to control children. Autistic subjects also harbor statistically significantly (p = 0.015) higher counts of beta2-toxin gene-producing C. perfringens in their gut compared to control children, and the incidence of beta2-toxin gene-producing C. perfringens is significantly higher in autistic subjects compared to control children (p = 0.014). Alpha toxin gene was detected in all C. perfringens strains studied. C. perfringens enterotoxin gene was detected from three autistic and one control subject. Beta, epsilon, and iota toxin genes were not detected from autistic or control subjects.
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6. Govindaraj S, Shanmuganathan A, Rajan R. {{Maternal psychological stress-induced developmental disability, neonatal mortality and stillbirth in the offspring of Wistar albino rats}}. {PLoS One}. 2017; 12(2): e0171089.
BACKGROUND: Stress is an inevitable part of life, and maternal stress during the gestational period has dramatic effects in the early programming of the physiology and behavior of offspring. The developmental period is crucial for the well-being of the offspring. Prenatal stress influences the developmental outcomes of the fetus, in part because the developing brain is particularly vulnerable to stress. The etiology of birth defects of the offspring is reported to be 30-40% genetic and 7-10% multifactorial, with the remaining 50% still unknown and also there is no clear cause for neonatal mortality and still-birth. OBJECTIVE: The present study explores the association of maternal psychological stress on mother and the offspring’s incidence of birth defects, stillbirth, and neonatal mortality. STUDY DESIGN: Pregnant animals were restrained to induce psychological stress (3 times per day, 45 minutes per session). Except control group, other animals were exposed to restraint stress during the gestational period: early gestational stress (EGS, stress exposure during 1st day to 10th days of gestational period), late gestational stress (LGS, stress exposure during 11th day to till parturition), and full term gestational stress (FGS, stress exposure to the whole gestational period). The effects of maternal stress on the mother and their offspring were analyzed. RESULTS: Expectant female rats exposed to stress by physical restraint showed decreased body weight gain, food intake, and fecal pellet levels. Specifically, the offspring of female rats subjected to late gestational and full term gestational restraint stress showed more deleterious effects, such as physical impairment (LGS 24.44%, FGS 10%), neonatal mortality (EGS 2.56%, LGS 24.44%, FGS 17.5%), stillbirths (FGS 27.5%), low birth weight (EGS 5.42g, LGS 4.40g, FGS 4.12g), preterm births (EGS 539 Hrs, LGS 514 Hrs, FGS 520.6 Hrs), and delayed eyelid opening (EGS 15.16 Days, LGS 17 Days, FGS 17.67 Days). CONCLUSION: The results of this study reveal that maternal stress may be associated with the offspring’s abnormal structural phenotyping, preterm birth, stillbirth and neonatal mortality.
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7. Hutchins TL, Deraway C, Prelock P, O’Neill A. {{Mothers’ and Children’s Story-Telling: A Study of Dyads with Typically Developing Children and Children with ASD}}. {J Autism Dev Disord}. 2017.
The production of specific mental state terms types and functions by caregivers and their TD children and caregivers and their children with ASD were assessed in two contexts: a parent’s story-telling task and a child’s story-telling task. Caregivers of children with ASD produced less causal talk and proportionally less desire and cognitive talk than did caregivers of TD children. When focusing only on variation in our ASD sample, caregivers’ and children’s production of different mental state references varied with context and were predicted by different child characteristics (i.e., theory of mind, autism severity, language level). We conclude that caregivers are likely adjusting different aspects of mental state input depending on different aspects of child development although these adjustments may not always be optimal.
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8. Ioannou C, Zein ME, Wyart V, Scheid I, Amsellem F, Delorme R, Chevallier C, Grezes J. {{Shared mechanism for emotion processing in adolescents with and without autism}}. {Sci Rep}. 2017; 7: 42696.
Although, the quest to understand emotional processing in individuals with Autism Spectrum Disorders (ASD) has led to an impressive number of studies, the picture that emerges from this research remains inconsistent. Some studies find that Typically Developing (TD) individuals outperform those with ASD in emotion recognition tasks, others find no such difference. In this paper, we move beyond focusing on potential group differences in behaviour to answer what we believe is a more pressing question: do individuals with ASD use the same mechanisms to process emotional cues? To this end, we rely on model-based analyses of participants’ accuracy during an emotion categorisation task in which displays of anger and fear are paired with direct vs. averted gaze. Behavioural data of 20 ASD and 20 TD adolescents revealed that the ASD group displayed lower overall performance. Yet, gaze direction had a similar impact on emotion categorisation in both groups, i.e. improved accuracy for salient combinations (anger-direct, fear-averted). Critically, computational modelling of participants’ behaviour reveals that the same mechanism, i.e. increased perceptual sensitivity, underlies the contextual impact of gaze in both groups. We discuss the specific experimental conditions that may favour emotion processing and the automatic integration of contextual information in ASD.
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9. Johnston KH, Iarocci G. {{Are Generalized Anxiety and Depression Symptoms Associated with Social Competence in Children with and without Autism Spectrum Disorder?}}. {J Autism Dev Disord}. 2017.
Generalized anxiety and depression symptoms may be associated with poorer social outcomes among children with Autism Spectrum Disorder (ASD) without intellectual disability. The goal of this study was to examine whether generalized anxiety and depression symptoms were associated with social competence after accounting for IQ, age, and gender in typically developing children and in children with ASD. Results indicated that for the TD group, generalized anxiety and depression accounted for 38% of the variance in social competence and for children with ASD, they accounted for 29% of the variance in social competence. However, only depression accounted for a significant amount of the variance. The findings underscore the importance of assessing the social impact of internalizing symptoms in children with ASD.
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10. Komesidou R, Brady NC, Fleming K, Esplund A, Warren SF. {{Growth of Expressive Syntax in Children With Fragile X Syndrome}}. {J Speech Lang Hear Res}. 2017; 60(2): 422-34.
Purpose: This research explored syntactic growth in children with fragile X syndrome (FXS) over a 5-year period, and variability in growth in relation to autism symptoms, nonverbal cognition, maternal responsivity, and gender. Method: Language samples at 4 time points from 39 children with FXS, 31 boys and 8 girls, were analyzed using the Index of Productive Syntax (Scarborough, 1990) and mean length of utterance (Brown, 1973). The degree of autism symptoms was evaluated using the Childhood Autism Rating Scale (Schopler, Reichler, & Renner, 1988) at the first time point. Maternal responsivity estimates were averaged across time points. Results: Children with FXS showed significant syntactic growth over time and a significant plateau (quadratic trend) in the later observations. Children who exhibited more autism symptoms at Time 1 had significantly lower syntactic abilities over time than children who exhibited fewer autism symptoms. Nonverbal cognition significantly predicted mean length of utterance scores but not Index of Productive Syntax scores. Maternal responsivity was not a significant predictor of syntactic outcomes. Girls with FXS generally demonstrated better expressive syntax than boys with FXS with notable individual differences. Conclusion: Despite significant growth over time, expressive syntax is a vulnerable domain for children with FXS, especially for those with severe autism symptoms. Clinical implications arising from the current findings are discussed.
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11. Long JJ, Butchart M, Brown M, Bain J, McMillan A, Karatzias T. {{Improving vision awareness in autism services: Evaluation of a dedicated education programme for support practitioners}}. {J Appl Res Intellect Disabil}. 2017.
BACKGROUND: The research reported here sought to evaluate whether a dedicated education programme in vision awareness improved the knowledge and skills of autism support practitioners in identifying visual impairment in autistic people with intellectual disabilities and providing better support to those individuals identified as visually impaired. METHODS: Researchers undertook a mixed methods evaluation. A survey questionnaire was devised and administered before and after training and focus groups were undertaken in order to gain qualitative data relating how practitioners implemented their learning in practice. RESULTS: Knowledge confidence and practice confidence scores of participants were significantly improved by the programme, which maintained its impact one year on. Practitioners reported increased access to optometry, changes to support practice and improvements to service environments as a result of the training. CONCLUSION: Autism support practitioners’ skills in identifying and supporting people with visual impairments were demonstrably enhanced through dedicated vision training.
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12. MacDonald M, Hatfield B, Twardzik E. {{Child Behaviors of Young Children With Autism Spectrum Disorder Across Play Settings}}. {Adapt Phys Activ Q}. 2017; 34(1): 19-32.
The hallmark characteristics of a diagnosis of autism spectrum disorder (ASD) are deficits in social communicative skills and the use of repetitive and/or stereotyped behaviors. In addition, children with ASD experience known motor-skill delays. The purpose of this study was to examine salient child behaviors of young children with and without ASD in 2 distinctly different play settings: a traditional social-play-based setting and a motor-behavior-based play setting. Child behavior (engagement toward parent, negativity, and attention) and dyad characteristics (connectedness) were examined in 2 distinctly different play settings. Results indicated that children with ASD performed more like their peers without ASD in a social-play-based setting and less like their peers in a motor-behavior-based play setting. Aspects of our results shed light on the critical need to develop creative methods of early intervention that combine efforts in all aspects of child development, including motor-skill development.
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13. Mazahery H, Stonehouse W, Delshad M, Kruger MC, Conlon CA, Beck KL, von Hurst PR. {{Relationship between Long Chain n-3 Polyunsaturated Fatty Acids and Autism Spectrum Disorder: Systematic Review and Meta-Analysis of Case-Control and Randomised Controlled Trials}}. {Nutrients}. 2017; 9(2).
Omega-3 long chain polyunsaturated fatty acid supplementation (n-3 LCPUFA) for treatment of Autism Spectrum Disorder (ASD) is popular. The results of previous systematic reviews and meta-analyses of n-3 LCPUFA supplementation on ASD outcomes were inconclusive. Two meta-analyses were conducted; meta-analysis 1 compared blood levels of LCPUFA and their ratios arachidonic acid (ARA) to docosahexaenoic acid (DHA), ARA to eicosapentaenoic acid (EPA), or total n-6 to total n-3 LCPUFA in ASD to those of typically developing individuals (with no neurodevelopmental disorders), and meta-analysis 2 compared the effects of n-3 LCPUFA supplementation to placebo on symptoms of ASD. Case-control studies and randomised controlled trials (RCTs) were identified searching electronic databases up to May, 2016. Mean differences were pooled and analysed using inverse variance models. Heterogeneity was assessed using I(2) statistic. Fifteen case-control studies (n = 1193) were reviewed. Compared with typically developed, ASD populations had lower DHA (-2.14 [95% CI -3.22 to -1.07]; p < 0.0001; I(2) = 97%), EPA (-0.72 [95% CI -1.25 to -0.18]; p = 0.008; I(2) = 88%), and ARA (-0.83 [95% CI, -1.48 to -0.17]; p = 0.01; I(2) = 96%) and higher total n-6 LCPUFA to n-3 LCPUFA ratio (0.42 [95% CI 0.06 to 0.78]; p = 0.02; I(2) = 74%). Four RCTs were included in meta-analysis 2 (n = 107). Compared with placebo, n-3 LCPUFA improved social interaction (-1.96 [95% CI -3.5 to -0.34]; p = 0.02; I(2) = 0) and repetitive and restricted interests and behaviours (-1.08 [95% CI -2.17 to -0.01]; p = 0.05; I(2) = 0). Populations with ASD have lower n-3 LCPUFA status and n-3 LCPUFA supplementation can potentially improve some ASD symptoms. Further research with large sample size and adequate study duration is warranted to confirm the efficacy of n-3 LCPUFA. Lien vers le texte intégral (Open Access ou abonnement)
14. Mundy P, Novotny S, Swain-Lerro L, McIntyre N, Zajic M, Oswald T. {{Joint-Attention and the Social Phenotype of School-Aged Children with ASD}}. {J Autism Dev Disord}. 2017.
The validity of joint attention assessment in school-aged children with ASD is unclear (Lord, Jones, Journal of Child Psychology and Psychiatry 53(5):490-509, 2012). This study examined the feasibility and validity of a parent-report measure of joint attention related behaviors in verbal children and adolescents with ASD. Fifty-two children with ASD and 34 controls were assessed with the Childhood Joint Attention Rating Scale (C-JARS). The C-JARS exhibited internally consistency, alpha = 0.88, and one factor explained 49% of the scale variance. Factor scores correctly identified between 88 and 94% of the children with ASD and 62-82% of controls. These scores were correlated with the ADOS-2, but not other parent-report symptom measures. The C-JARS appears to assess a unique dimension of the social-phenotype of children with ASD.
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15. Ptomey LT, Gibson CA, Lee J, Sullivan DK, Washburn RA, Gorczyca AM, Donnelly JE. {{Caregivers’ effect on weight management in adults with intellectual and developmental disabilities}}. {Disabil Health J}. 2017.
INTRODUCTION: Caregivers of adults with IDD often play a large role in the ability of adults with IDD to lose weight. OBJECTIVE: The purpose of this study was to determine to examine the effects of the caregivers’ perceived burdens and self-efficacy and their relationship to an individual (family member or paid staff) on weight changes across a weight management intervention for adults with IDD. METHODS: Overweight/obese adults with mild to moderate IDD, along with assigned caregivers who served as their study partner, were randomized to an 18-month weight management intervention. The living environment and caregiver relationship were assessed at baseline. Caregivers completed questionnaires regarding perceived hassles, uplifts, and self-efficacy in helping the participant follow a weight management intervention. RESULTS: 147 adults with IDD ( approximately 57% women and approximately 16% minorities) were included in data analysis. After 18 months, there were no differences in weight loss between participants who had a family member as their study partner and those who had a paid assistant as their study partner (-5.5 +/- 5.2% vs. -5.6+/- 5.3% p = 0.16). However, paid assistants reported more hassles with following the diet intervention at 6 months (p < 0.05). Participants who had a paid assistant as their study partner were more likely to have multiple study partners during the study, which was correlated with smaller weight loss. CONCLUSION: While caregivers are important for weight management of adults with IDD, the caregiver's relationship to the participant does not affect weight change in an intervention. Lien vers le texte intégral (Open Access ou abonnement)
16. Reiff M, Bugos E, Giarelli E, Bernhardt BA, Spinner NB, Sankar PL, Mulchandani S. {{« Set in Stone » or « Ray of Hope »: Parents’ Beliefs About Cause and Prognosis After Genomic Testing of Children Diagnosed with ASD}}. {J Autism Dev Disord}. 2017.
Despite increasing utilization of chromosomal microarray analysis (CMA) for autism spectrum disorders (ASD), limited information exists about how results influence parents’ beliefs about etiology and prognosis. We conducted in-depth interviews and surveys with 57 parents of children with ASD who received CMA results categorized as pathogenic, negative or variant of uncertain significance. Parents tended to incorporate their child’s CMA results within their existing beliefs about the etiology of ASD, regardless of CMA result. However, parents’ expectations for the future tended to differ depending on results; those who received genetic confirmation for their children’s ASD expressed a sense of concreteness, acceptance and permanence of the condition. Some parents expressed hope for future biomedical treatments as a result of genetic research.
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17. Ripamonti L. {{Disability, Diversity, and Autism: Philosophical Perspectives on Health}}. {New Bioeth}. 2016; 22(1): 56-70.
This paper aims to explore the connection between health and developmental disorders, particularly in regard to the notion of ‘neurodiversity’, which considers high-functioning autism not as a lifelong disability but a neurological form within a diversity of human minds. In recent years, autistic activist movements have called for a more positive, humanizing, identity-first language when describing this condition, rejecting negative language such as ‘disorder’, ‘deficit’, and ‘impairment’, and instead describing autism as a way of being, part of one’s personal identity, which does not always need to be cured. Is a different form of neurodevelopment necessarily a degenerate one? Is well-being mostly affected by disability itself or by its being classified as abnormality? Drawing on philosophical insights, as well as autism research papers and popular science, I explore advantages and disadvantages of these classifications and the connections between health, autism, personhood, and disability.
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18. Sethna F, Feng W, Ding Q, Robison AJ, Feng Y, Wang H. {{Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model}}. {Nat Commun}. 2017; 8: 14359.
Fragile X syndrome (FXS), caused by the loss of functional FMRP, is a leading cause of autism. Neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, we identify that, in Fmr1 knockout neurons, type 1 adenylyl cyclase (Adcy1) mRNA translation is enhanced, leading to excessive production of ADCY1 protein and insensitivity to neuronal stimulation. Genetic reduction of Adcy1 normalizes the aberrant ERK1/2- and PI3K-mediated signalling, attenuates excessive protein synthesis and corrects dendritic spine abnormality in Fmr1 knockout mice. Genetic reduction of Adcy1 also ameliorates autism-related symptoms including repetitive behaviour, defective social interaction and audiogenic seizures. Moreover, peripheral administration of NB001, an experimental compound that preferentially suppresses ADCY1 activity over other ADCY subtypes, attenuates the behavioural abnormalities in Fmr1 knockout mice. These results demonstrate a connection between the elevated Adcy1 translation and abnormal ERK1/2 signalling and behavioural symptoms in FXS.
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19. Shpyleva S, Melnyk S, Pavliv O, Pogribny I, Jill James S. {{Overexpression of LINE-1 Retrotransposons in Autism Brain}}. {Mol Neurobiol}. 2017.
Long interspersed nuclear elements-1 (LINE-1 or L1) are mobile DNA sequences that are capable of duplication and insertion (retrotransposition) within the genome. Recently, retrotransposition of L1 was shown to occur within human brain leading to somatic mosaicism in hippocampus and cerebellum. Because unregulated L1 activity can promote genomic instability and mutagenesis, multiple mechanisms including epigenetic chromatin condensation have evolved to effectively repress L1 expression. Nonetheless, L1 expression has been shown to be increased in patients with Rett syndrome and schizophrenia. Based on this evidence and our reports of oxidative stress and epigenetic dysregulation in autism cerebellum, we sought to determine whether L1 expression was increased in autism brain. The results indicated that L1 expression was significantly elevated in the autism cerebellum but not in BA9, BA22, or BA24. The binding of repressive MeCP2 and histone H3K9me3 to L1 sequences was significantly lower in autism cerebellum suggesting that relaxation of epigenetic repression may have contributed to increased expression. Further, the increase in L1 expression was inversely correlated with glutathione redox status consistent with reports indicating that L1 expression is increased under pro-oxidant conditions. Finally, the expression of transcription factor FOXO3, sensor of oxidative stress, was significantly increased and positively associated with L1 expression and negatively associated with glutathione redox status. While these novel results are an important first step, future understanding of the contribution of elevated L1 expression to neuronal CNVs and genomic instability in autism will depend on emerging cell-specific genomic technologies, a challenge that warrants future investigation.
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20. Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ. {{A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors}}. {J Neurosci}. 2017; 37(8): 2216-33.
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIalpha catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIalpha substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIalpha-WT autophosphorylation. The E183V mutation also reduces CaMKIIalpha binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels and NMDA receptors, and increases CaMKIIalpha turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIalpha targeting to dendritic spines. Moreover, neuronal expression of CaMKIIalpha-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIalpha-E183V mutation have lower total forebrain CaMKIIalpha levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIalpha-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIalpha plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes.SIGNIFICANCE STATEMENT Many autism spectrum disorder (ASD)-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIalpha linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.
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21. Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, Jousson O, Leoncini S, Renzi D, Calabro A, De Filippo C. {{New evidences on the altered gut microbiota in autism spectrum disorders}}. {Microbiome}. 2017; 5(1): 24.
BACKGROUND: Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by social and behavioural impairments. In addition to neurological symptoms, ASD subjects frequently suffer from gastrointestinal abnormalities, thus implying a role of the gut microbiota in ASD gastrointestinal pathophysiology. RESULTS: Here, we characterized the bacterial and fungal gut microbiota in a cohort of autistic individuals demonstrating the presence of an altered microbial community structure. A fraction of 90% of the autistic subjects were classified as severe ASDs. We found a significant increase in the Firmicutes/Bacteroidetes ratio in autistic subjects due to a reduction of the Bacteroidetes relative abundance. At the genus level, we observed a decrease in the relative abundance of Alistipes, Bilophila, Dialister, Parabacteroides, and Veillonella in the ASD cohort, while Collinsella, Corynebacterium, Dorea, and Lactobacillus were significantly increased. Constipation has been then associated with different bacterial patterns in autistic and neurotypical subjects, with constipated autistic individuals characterized by high levels of bacterial taxa belonging to Escherichia/Shigella and Clostridium cluster XVIII. We also observed that the relative abundance of the fungal genus Candida was more than double in the autistic than neurotypical subjects, yet due to a larger dispersion of values, this difference was only partially significant. CONCLUSIONS: The finding that, besides the bacterial gut microbiota, also the gut mycobiota contributes to the alteration of the intestinal microbial community structure in ASDs opens the possibility for new potential intervention strategies aimed at the relief of gastrointestinal symptoms in ASDs.
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22. Sznajer Y. {{Neurobehavioural vulnerability and autistic traits in RASopathies}}. {Dev Med Child Neurol}. 2017.
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23. Wang X, Wang S, Fan Y, Huang D, Zhang Y. {{Speech-specific categorical perception deficit in autism: An Event-Related Potential study of lexical tone processing in Mandarin-speaking children}}. {Sci Rep}. 2017; 7: 43254.
Recent studies reveal that tonal language speakers with autism have enhanced neural sensitivity to pitch changes in nonspeech stimuli but not to lexical tone contrasts in their native language. The present ERP study investigated whether the distinct pitch processing pattern for speech and nonspeech stimuli in autism was due to a speech-specific deficit in categorical perception of lexical tones. A passive oddball paradigm was adopted to examine two groups (16 in the autism group and 15 in the control group) of Chinese children’s Mismatch Responses (MMRs) to equivalent pitch deviations representing within-category and between-category differences in speech and nonspeech contexts. To further examine group-level differences in the MMRs to categorical perception of speech/nonspeech stimuli or lack thereof, neural oscillatory activities at the single trial level were further calculated with the inter-trial phase coherence (ITPC) measure for the theta and beta frequency bands. The MMR and ITPC data from the children with autism showed evidence for lack of categorical perception in the lexical tone condition. In view of the important role of lexical tones in acquiring a tonal language, the results point to the necessity of early intervention for the individuals with autism who show such a speech-specific categorical perception deficit.
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24. Xin JF, Sheppard ME, Brown M. {{Brief Report: Using iPads for Self-Monitoring of Students with Autism}}. {J Autism Dev Disord}. 2017.
This study examined the effect of using an iPad for students with autism spectrum disorder (ASD) on self-monitoring their behaviors in class. Four students with ASD were taught on-task behaviors by watching self-modeled video saved in the application « Choiceworks » on their iPads, and collected data on their own behaviors. A single subject research design with ABAB phases was used. Student behaviors were observed using interval recording and behavioral occurrences were compared across phases. Results showed that the participating students’ on-task behaviors (e.g., facing forward, looking at teacher, i.e. eye contact, and working on the assignment) were increased when an iPad was used for their self-monitoring.
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25. Ziegler A, Rudolph-Rothfeld W, Vonthein R. {{Genetic Testing for Autism Spectrum Disorder is Lacking Evidence of Cost-Effectiveness. A Systematic Review}}. {Methods Inf Med}. 2017.
BACKGROUND: Autism Spectrum Disorder (ASD) is a highly heritable neural development disorder characterized by social impairment. The earlier the diagnosis is made, the higher are the chances of obtaining relief of symptoms. A very early diagnosis uses molecular genetic tests, which are also offered commercially. OBJECTIVE: Systematic review of the economic impact of genetic tests in ASD. METHODS: We performed a systematic search of databases Pubmed, Medline, Cochrane, Econlit and the NHS Center for Reviews and Dissemination for articles in English and German from January 1, 2000 to December 31, 2015. Original articles published in peer-reviewed journals were screened in a two-step process. First, we focused our search on economic evaluations of genetic tests for ASD. Second, we searched for any economic evaluation (EE) of genetic tests. RESULTS: We identified 185 EE of genetic tests for various diseases. However, not a single EE of genetic tests has been found for ASD. The outcomes used in the EE of the genetic tests were heterogeneous, and results were generally not comparable. CONCLUSION: There is no evidence for cost-effectiveness of any genetic diagnostic test for ASD, although such genetic tests are available commercially. Cost-effectiveness analyses for genetic diagnostic tests for ASD are urgently required. There is a clear lack in research for EE of genetic tests.
