1. Bashir S, Al-Ayadhi L. {{Endothelial antibody levels in the sera of children with autism spectrum disorders}}. {J Chin Med Assoc};2015 (Jun 15)
BACKGROUND: The neurobiological basis of autism remains poorly understood. We hypothesized that endothelial antibodies may be associated with the pathophysiology of autism and may predict intellectual/social developmental abnormalities. METHODS: Plasma levels of antiendothelial cell antibodies (AECAs) were measured by enzyme-linked immunosorbent assay in autistic children (n = 55) and age-matched healthy controls (n = 25). RESULTS: The serum level of AECAs in children with autism {n = 55, 306.4 +/- 45.6 pg/mL [mean +/- standard error of the mean (SEM)]} was higher (two-tailed Student t test: p = 0.05) than that of healthy controls [n = 25, 209.6 +/- 24.6 pg/mL (mean +/- SEM)]. Children with severe autism exhibited significantly higher AECAs than healthy controls (diagnoses of autistic children based on the Childhood Autism Rating Scale score, >40) [n = 20, 369.6 +/- 65.6 pg/mL (mean +/- SEM)] (p = 0.03). Disease severity and the Childhood Autism Rating Scale score, which represent stereotyped patterns of behavior in children with autism, were positively correlated (r2 = 0.27, p = 0.05). CONCLUSION: Elevated AECA serum levels may be implicated in the pathogenesis of autism. However, these data should be interpreted with caution until further investigations are performed using larger sample sizes to determine whether the increase in serum AECA levels is a mere consequence of autism or it plays a pathogenic role in the disease.
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2. Chandley MJ, Crawford JD, Szebeni A, Szebeni K, Ordway GA. {{Erratum to: NTRK2 expression levels are reduced in laser captured pyramidal neurons from the anterior cingulate cortex in males with autism spectrum disorder}}. {Mol Autism};2015;6:38.
[This corrects the article DOI: 10.1186/s13229-015-0023-2.].
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3. Dominick K, Wink LK, McDougle CJ, Erickson CA. {{A Retrospective Naturalistic Study of Ziprasidone for Irritability in Youth with Autism Spectrum Disorder}}. {J Child Adolesc Psychopharmacol};2015 (Jun);25(5):397-401.
OBJECTIVE: The purpose of this study was to assess the impact of ziprasidone monoantipsychotic treatment targeting irritability in a naturalistic outpatient autism spectrum disorder (ASD) clinical setting. METHODS: We examined the use of ziprasidone, predominantly in combination with other psychotropic agents, targeting irritability in 42 youth with ASD in a large ASD-specific treatment database. Mean age at start of treatment, treatment duration, final dose, body mass index (BMI), BMI Z score, and Clinical Global Impressions-Improvement Scale (CGI-I) score at final visit were determined, and changes with treatment were analyzed using paired t tests. Cardiac corrected QT (QTc) interval data were extracted from electrocardiograms when available. RESULTS: Mean age at start of treatment was 11.8 years. And final mean dose of ziprasidone was 98.7 mg/day or 1.7 mg/kg/day. Seventeen (40%) participants were considered treatment responders based on the CGI-I. No changes in QTc (although only examined in nine participants), weight, BMI, or other vital signs were noted, with ziprasidone use. The rate of treatment response was less than what has been reported for the two atypical antipsychotics, risperidone and aripiprazole, approved by the Food and Drug Administration (FDA) for the treatment of irritability in autistic disorder. The response rate with ziprasidone may be more consistent with response rates for other atypical antipsychotics, although none of these agents has been studied in larger-scale double-blind, placebo-controlled trials. The lower rate of response to ziprasidone in this open-label trial is likely influenced by the treatment-refractory nature of the population studied. CONCLUSIONS: The weight neutrality of ziprasidone appears favorable compared with other second generation antipsychotics in this population. The response rate to ziprasidone targeting irritability may be lower than response rates associated with FDA-approved agents for this indication. Overall, ziprasidone use appeared well tolerated in youth with ASD.
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4. Estes A, Munson J, Rogers SJ, Greenson J, Winter J, Dawson G. {{Long-Term Outcomes of Early Intervention in 6-Year-Old Children With Autism Spectrum Disorder}}. {J Am Acad Child Adolesc Psychiatry};2015 (Jul);54(7):580-587.
OBJECTIVE: We prospectively examined evidence for the sustained effects of early intervention based on a follow-up study of 39 children with ASD who began participation in a randomized clinical trial testing the effectiveness of the Early Start Denver Model (ESDM) at age 18 to 30 months. The intervention, conducted at a high level of intensity in-home for 2 years, showed evidence of efficacy immediately posttreatment. METHOD: This group of children was assessed at age 6 years, 2 years after the intervention ended, across multiple domains of functioning by clinicians naive to previous intervention group status. RESULTS: The ESDM group, on average, maintained gains made in early intervention during the 2-year follow-up period in overall intellectual ability, adaptive behavior, symptom severity, and challenging behavior. No group differences in core autism symptoms were found immediately posttreatment; however, 2 years later, the ESDM group demonstrated improved core autism symptoms and adaptive behavior as compared with the community-intervention-as-usual (COM) group. The 2 groups were not significantly different in terms of intellectual functioning at age 6 years. Both groups received equivalent intervention hours during the original study, but the ESDM group received fewer hours during the follow-up period. CONCLUSION: These results provide evidence that gains from early intensive intervention are maintained 2 years later. Notably, core autism symptoms improved in the ESDM group over the follow-up period relative to the COM group. This improvement occurred at the same time that the ESDM group received significantly fewer services. This is the first study to examine the role of early ESDM behavioral intervention initiated at less than 30 months of age in altering the longer-term developmental course of autism.
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5. Favre MR, La Mendola D, Meystre J, Christodoulou D, Cochrane MJ, Markram H, Markram K. {{Predictable enriched environment prevents development of hyper-emotionality in the VPA rat model of autism}}. {Front Neurosci};2015;9:127.
Understanding the effects of environmental stimulation in autism can improve therapeutic interventions against debilitating sensory overload, social withdrawal, fear and anxiety. Here, we evaluate the role of environmental predictability on behavior and protein expression, and inter-individual differences, in the valproic acid (VPA) model of autism. Male rats embryonically exposed (E11.5) either to VPA, a known autism risk factor in humans, or to saline, were housed from weaning into adulthood in a standard laboratory environment, an unpredictably enriched environment, or a predictably enriched environment. Animals were tested for sociability, nociception, stereotypy, fear conditioning and anxiety, and for tissue content of glutamate signaling proteins in the primary somatosensory cortex, hippocampus and amygdala, and of corticosterone in plasma, amygdala and hippocampus. Standard group analyses on separate measures were complemented with a composite emotionality score, using Cronbach’s Alpha analysis, and with multivariate profiling of individual animals, using Hierarchical Cluster Analysis. We found that predictable environmental enrichment prevented the development of hyper-emotionality in the VPA-exposed group, while unpredictable enrichment did not. Individual variation in the severity of the autistic-like symptoms (fear, anxiety, social withdrawal and sensory abnormalities) correlated with neurochemical profiles, and predicted their responsiveness to predictability in the environment. In controls, the association between socio-affective behaviors, neurochemical profiles and environmental predictability was negligible. This study suggests that rearing in a predictable environment prevents the development of hyper-emotional features in animals exposed to an autism risk factor, and demonstrates that unpredictable environments can lead to negative outcomes, even in the presence of environmental enrichment.
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6. Gabriels RL, Pan Z, Dechant B, Agnew JA, Brim N, Mesibov G. {{Randomized Controlled Trial of Therapeutic Horseback Riding in Children and Adolescents With Autism Spectrum Disorder}}. {J Am Acad Child Adolesc Psychiatry};2015 (Jul);54(7):541-549.
OBJECTIVE: This study expands previous equine-assisted intervention research by evaluating the effectiveness of therapeutic horseback riding (THR) on self-regulation, socialization, communication, adaptive, and motor behaviors in children with autism spectrum disorder (ASD). METHOD: Participants with ASD (aged 6-16 years; N = 127) were stratified by nonverbal IQ standard scores (</=85 or >85) and randomized to 1 of 2 groups for 10 weeks: THR intervention or a barn activity (BA) control group without horses that used similar methods. The fidelity of the THR intervention was monitored. Participants were evaluated within 1 month pre- and postintervention by raters blinded to intervention conditions and unblinded caregiver questionnaires. During the intervention, caregivers rated participants’ behaviors weekly. RESULTS: Intent-to-treat analysis conducted on the 116 participants who completed a baseline assessment (THR n = 58; BA control n = 58) revealed significant improvements in the THR group compared to the control on measures of irritability (primary outcome) (p = .02; effect size [ES] = 0.50) and hyperactivity (p = .01; ES = 0.53), beginning by week 5 of the intervention. Significant improvements in the THR group were also observed on a measure of social cognition (p = .05; ES = 0.41) and social communication (p = .003; ES = 0.63), along with the total number of words (p = .01; ES = 0.54) and new words (p = .01; ES = 0.54) spoken during a standardized language sample. Sensitivity analyses adjusting for age, IQ, and per protocol analyses produced consistent results. CONCLUSION: This is the first large-scale, randomized, controlled trial demonstrating efficacy of THR for the ASD population, and findings are consistent with previous equine-assisted intervention studies. CLINICAL TRIAL REGISTRATION INFORMATION: Trial of Therapeutic Horseback Riding in Children and Adolescents With Autism Spectrum Disorder; http://clinicaltrials.gov; NCT02301195.
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7. Krajnc N. {{Management of epilepsy in patients with Rett syndrome: perspectives and considerations}}. {Ther Clin Risk Manag};2015;11:925-932.
Rett syndrome (RTT) is a common neurodevelopmental disorder that appears in infancy with regression of acquired motor skills, loss of purposeful activity, hand stereotypies, loss of acquired spoken language, and seizures. Epilepsy affects the majority of patients in a specific clinical stage of the disease and is drug resistant in approximately one-third of cases. The association of epilepsy and even drug-resistant epilepsy has been reported in certain genotypes of the methyl-CpG-binding protein 2 mutation, which is present in a majority of patients with classical RTT. The evolution of electroencephalographic abnormalities accompanying the clinical development of the syndrome is well described, but much less is known about the seizure semiology and the effectiveness of specific antiepileptic drugs. The aim of this review is to present the clinical and electrophysiological aspects of epilepsy in RTT and the current treatment approach.
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8. Kreslins A, Robertson AE, Melville C. {{The effectiveness of psychosocial interventions for anxiety in children and adolescents with autism spectrum disorder: a systematic review and meta-analysis}}. {Child Adolesc Psychiatry Ment Health};2015;9:22.
Anxiety is a common problem in children and adolescents with autism spectrum disorder (ASD). This meta-analysis aimed to systematically evaluate the evidence for the use of psychosocial interventions to manage anxiety in this population. Cognitive behavioural therapy (CBT) was the primary intervention modality studied. A comprehensive systematic search and study selection process was conducted. Separate statistical analyses were carried out for clinician-, parent-, and self-reported outcome measures. Sensitivity analyses were conducted by removing any outlying studies and any studies that did not use a CBT intervention. A subgroup analysis was performed to compare individual and group delivery of treatment. Ten randomised control trials involving a total of 470 participants were included. The overall SMD was d = 1.05 (95 % CI 0.45, 1.65; z = 3.45, p = 0.0006) for clinician- reported outcome measures; d = 1.00 (95%CI 0.21, 1.80; z = 2.47, p = 0.01) for parent-reported outcome measures; and d = 0.65 (95%CI -0.10, 1.07; z = 1.63, p = 0.10) for self-reported outcome measures. Clinician- and parent-reported outcome measures showed that psychosocial interventions were superior to waitlist and treatment-as-usual control conditions at post-treatment. However, the results of self-reported outcome measures failed to reach significance. The sensitivity analyses did not significantly change these results and the subgroup analysis indicated that individual treatment was more effective than group treatment. The main limitations of this review were the small number of included studies as well as the clinical and methodological variability between studies.
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9. Matsuda S, Minagawa Y, Yamamoto J. {{Gaze Behavior of Children with ASD toward Pictures of Facial Expressions}}. {Autism Res Treat};2015;2015:617190.
Atypical gaze behavior in response to a face has been well documented in individuals with autism spectrum disorders (ASDs). Children with ASD appear to differ from typically developing (TD) children in gaze behavior for spoken and dynamic face stimuli but not for nonspeaking, static face stimuli. Furthermore, children with ASD and TD children show a difference in their gaze behavior for certain expressions. However, few studies have examined the relationship between autism severity and gaze behavior toward certain facial expressions. The present study replicated and extended previous studies by examining gaze behavior towards pictures of facial expressions. We presented ASD and TD children with pictures of surprised, happy, neutral, angry, and sad facial expressions. Autism severity was assessed using the Childhood Autism Rating Scale (CARS). The results showed that there was no group difference in gaze behavior when looking at pictures of facial expressions. Conversely, the children with ASD who had more severe autistic symptomatology had a tendency to gaze at angry facial expressions for a shorter duration in comparison to other facial expressions. These findings suggest that autism severity should be considered when examining atypical responses to certain facial expressions.
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10. Nelson CA, Varcin KJ, Coman NK, DeVivo I, Tager-Flusberg H. {{Shortened Telomeres in Families With a Propensity to Autism}}. {J Am Acad Child Adolesc Psychiatry};2015 (Jul);54(7):588-594.
OBJECTIVE: Shortened telomeres have been linked to poorer health outcomes. Exposure to psychological stress is associated with accelerated telomere shortening, and a well-established body of evidence indicates that families with a child with autism spectrum disorder (ASD) experience heightened levels of psychological stress. Also, alterations in a number of biological processes implicated in telomere length dynamics (i.e., oxidative stress, DNA methylation) have been linked to ASD susceptibility. We examined whether families of children with ASD who have an infant show shortened telomeres. METHOD: Saliva samples were collected from infants, their older sibling (proband), and parents in families with or without a child with ASD. Infants and their families were designated as high-risk for ASD (HRA; n = 86) or low-risk for ASD (LRA; n = 118) according to the older siblings’ diagnostic status. We used the real-time polymerase chain reaction (PCR) telomere assay to determine relative average telomere length for each participant. RESULTS: HRA families demonstrated significantly shorter telomere length relative to LRA families. This effect was observed at the individual family member level, with infants, probands, and mothers in HRA families showing reduced relative telomere length compared to individuals in LRA families; although not significant, fathers of high-risk infants showed a similar pattern of decreased telomere length. CONCLUSION: Families of children with ASD who have an infant show shortened telomeres relative to families with no history of ASD. These results suggest that such « high-risk » families should be monitored for the physical and mental health consequences that are often associated with accelerated telomere shortening.
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11. Ning Z, McLellan AS, Ball M, Wynne F, O’Neill C, Mills W, Quinn JP, Kleinjan DA, Anney RJ, Carmody RJ, O’Keeffe G, Moore T. {{Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region}}. {Hum Mol Genet};2015 (Jun 18)
Sprouty proteins are regulators of cell growth and branching morphogenesis. Unlike mouse Spry3, which is X-linked, human SPRY3 maps to pseudoautosomal region 2; however, the Y-linked allele is not expressed due to epigenetic silencing by an unknown mechanism. SPRY3 maps adjacent to X-linked TMLHE, recently identified as an autism susceptibility gene. We report that Spry3 is highly expressed in central and peripheral nervous system ganglion cells in mouse and human, including cerebellar Purkinje and retinal ganglion cells. Transient over-expression or knockdown of Spry3 in cultured mouse superior cervical ganglion cells inhibits and promotes, respectively, neurite growth and branching. A 0.7 kb gene fragment spanning the human SPRY3 transcriptional start site recapitulates the endogenous Spry3 expression pattern in LacZ reporter mice. In human and mouse the SPRY3 promoter contains an AG-rich repeat and we found co-expression, promoter binding, and/or regulation of SPRY3 expression by transcription factors MAZ, EGR1, ZNF263 and PAX6. We identified eight alleles of the human SPRY3 promoter repeat in Caucasians, and similar allele frequencies in autism families. We characterised multiple SPRY3 transcripts originating at two CpG islands in the F8A3 – TMLHE region, suggesting X chromosome regulation of SPRY3. These findings may explain differential regulation of X and Y-linked SPRY3 alleles. In addition, the presence of a SPRY3 transcript exon in a previously described X chromosome deletion associated with autism, and the cerebellar interlobular variation in Spry3 expression coincident with the reported pattern of Purkinje cell loss in autism, suggest SPRY3 as a candidate susceptibility locus for autism.
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12. Nordahl CW, Iosif AM, Young GS, Perry LM, Dougherty R, Lee A, Li D, Buonocore MH, Simon T, Rogers S, Wandell B, Amaral DG. {{Erratum: Sex differences in the corpus callosum in preschool-aged children with autism spectrum disorder}}. {Mol Autism};2015;6:39.
[This corrects the article DOI: 10.1186/s13229-015-0005-4.].
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13. Pedersen LH. {{Prenatal Antidepressant Exposure and Childhood Autism Spectrum Disorders: Cause for Concern?}}. {Paediatr Drugs};2015 (Jun 20)
There is empirical evidence for a role for serotonin in autism . In experimental animals, early life exposure to serotonergic antidepressants or maternal stress affects brain development, with subsequent changes in serotonin tone in adult animals. Recently, antidepressant exposure during pregnancy has been associated with autism in epidemiological studies. At least part of the association is potentially explained by maternal depression or factors associated with depression. Importantly, even if there is no causal relation between prenatal antidepressant exposure and autism, use of antidepressants during pregnancy is a marker of potential problems later in life across five independent study populations, and exposed children may need special attention regardless of the underlying mechanism. Future studies need to disentangle the effects of maternal depression and antidepressant use during pregnancy while adjusting for the postnatal environment. One promising strategy is to use results from basic science to guide the inclusion of potential biological intermediates in advanced epidemiological studies.
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14. Sizoo BB, Horwitz EH, Teunisse JP, Kan CC, Vissers C, Forceville E, Van Voorst A, Geurts HM. {{Predictive validity of self-report questionnaires in the assessment of autism spectrum disorders in adults}}. {Autism};2015 (Jun 18)
While various screening instruments for autism spectrum disorders are widely used in diagnostic assessments, their psychometric properties have not been simultaneously evaluated in the outpatient setting where these instruments are used most. In this study, we tested the Ritvo Autism Asperger Diagnostic Scale-Revised and two short versions of the Autism-Spectrum Quotient, the AQ-28 and AQ-10, in 210 patients referred for autism spectrum disorder assessment and in 63 controls. Of the 210 patients, 139 received an autism spectrum disorder diagnosis and 71 received another psychiatric diagnosis. The positive predictive values indicate that these tests correctly identified autism spectrum disorder patients in almost 80% of the referred cases. However, the negative predictive values suggest that only half of the referred patients without autism spectrum disorder were correctly identified. The sensitivity and specificity of each of these instruments were much lower than the values reported in the literature. In this study, the sensitivity of the Ritvo Autism Asperger Diagnostic Scale-Revised was the highest (73%), and the Autism-Spectrum Quotient short forms had the highest specificity (70% and 72%). Based on the similar area under the curve values, there is no clear preference for any of the three instruments. None of these instruments have sufficient validity to reliably predict a diagnosis of autism spectrum disorder in outpatient settings.
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15. Usdin K, Kumari D. {{Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders}}. {Front Genet};2015;6:192.
The fragile X-related disorders are members of the Repeat Expansion Diseases, a group of genetic conditions resulting from an expansion in the size of a tandem repeat tract at a specific genetic locus. The repeat responsible for disease pathology in the fragile X-related disorders is CGG/CCG and the repeat tract is located in the 5′ UTR of the FMR1 gene, whose protein product FMRP, is important for the proper translation of dendritic mRNAs in response to synaptic activation. There are two different pathological FMR1 allele classes that are distinguished only by the number of repeats. Premutation alleles have 55-200 repeats and confer risk of fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Full mutation alleles on the other hand have >200 repeats and result in fragile X syndrome, a disorder that affects learning and behavior. Different symptoms are seen in carriers of premutation and full mutation alleles because the repeat number has paradoxical effects on gene expression: Epigenetic changes increase transcription from premutation alleles and decrease transcription from full mutation alleles. This review will cover what is currently known about the mechanisms responsible for these changes in FMR1 expression and how they may relate to other Repeat Expansion Diseases that also show repeat-mediated changes in gene expression.
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16. Velott DL, Agbese E, Mandell D, Stein BD, Dick AW, Yu H, Leslie DL. {{Medicaid 1915(c) Home- and Community-Based Services waivers for children with autism spectrum disorder}}. {Autism};2015 (Jun 18)
This research aims to describe the characteristics of 1915(c) Home- and Community-Based Services waivers for children with autism spectrum disorder across states and over time. While increasingly popular, little is known about these Medicaid waivers. Understanding the characteristics of these programs is important to clinicians and policymakers in designing programs to meet the needs of this vulnerable population and to set the stage for evaluating changes that occur with the implementation of health-care reform. Home- and Community-Based Services waiver applications that included children with autism spectrum disorder as a target population were collected from the Centers for Medicare and Medicaid Services website, state websites, and state administrators. A data extraction tool was used to document waiver inclusions and restrictions, estimated service provision and institutional costs, and the inclusion of four core autism spectrum disorder services: respite, caregiver support and training, personal care, and evidence-based treatments. Investigators identified 50 current or former waivers across 29 states that explicitly included children with autism spectrum disorder in their target populations. Waivers differed substantially across states in the type and breadth of autism spectrum disorder coverage provided. Specifically, waivers varied in the populations they targeted, estimated cost of services, cost control methods employed, and services offered to children with autism spectrum disorder. Home- and Community-Based Services waivers for children with autism spectrum disorder are very complex and are not consistent across states or over time. Further efforts are needed to examine the characteristics of programs that are associated with improved access to care and clinical outcomes to maximize the benefits to individuals with autism spectrum disorder and their families.
