1. Buzhardt J, Rusinko L, Heitzman-Powell L, Trevino-Maack S, McGrath A. {{Exploratory Evaluation and Initial Adaptation of a Parent Training Program for Hispanic Families of Children with Autism}}. {Fam Process};2015 (Mar 16)
The present paper takes a translational approach in applying the themes of the current special section to prevention and intervention science in Latino families. The paper reviews the current literature on cultural processes in prevention and intervention research with Latino families. Overall, many prevention and intervention programs have either been developed specifically for Latino families or have been modified for Latino families with great attention paid to the socio-cultural needs of these families. Nevertheless, few studies have tested the role of cultural values or acculturation processes on outcomes. We make recommendations based on findings within basic science and in particular this special section on the incorporation of these values and processes into prevention and intervention science with Latino families.
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2. Chanda S, Aoto J, Lee SJ, Wernig M, Sudhof TC. {{Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking}}. {Mol Psychiatry};2015 (Mar 17)
Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Although the general synaptic role of neuroligins is undisputed, their specific functions at a synapse remain unclear, even controversial. Moreover, many neuroligin gene mutations were associated with autism, but the pathophysiological relevance of these mutations is often unknown, and their mechanisms of action uninvestigated. Here, we examine the synaptic effects of an autism-associated neuroligin-4 substitution (called R704C), which mutates a cytoplasmic arginine residue that is conserved in all neuroligins. We show that the R704C mutation, when introduced into neuroligin-3, enhances the interaction between neuroligin-3 and AMPA receptors, increases AMPA-receptor internalization and decreases postsynaptic AMPA-receptor levels. When introduced into neuroligin-4, conversely, the R704C mutation unexpectedly elevated AMPA-receptor-mediated synaptic responses. These results suggest a general functional link between neuroligins and AMPA receptors, indicate that both neuroligin-3 and -4 act at excitatory synapses but perform surprisingly distinct functions, and demonstrate that the R704C mutation significantly impairs the normal function of neuroligin-4, thereby validating its pathogenicity.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.20.
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3. Fujita-Jimbo E, Tanabe Y, Yu Z, Kojima K, Mori M, Li H, Iwamoto S, Yamagata T, Momoi MY, Momoi T. {{The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis}}. {Mol Autism};2015;6:17.
BACKGROUND: Autism spectrum disorder (ASD) has a complex genetic etiology. Some symptoms and mutated genes, including neuroligin (NLGN), neurexin (NRXN), and SH3 and multiple ankyrin repeat domains protein (SHANK), are shared by schizophrenia and ASD. Little is known about the molecular pathogenesis of ASD. One of the possible molecular pathogenesis is an imbalance of excitatory and inhibitory receptors linked with the NLGN-PSD-95-SHANK complex via postsynaptic density protein/Drosophila disc large tumor suppressor/zonula occludens-1 protein (PDZ) binding. In the present study, we focused on GPR85 as a candidate gene for ASD because the C-terminal amino acid sequence of GPR85 [Thr-Cys-Val-Ile (YCVI)] is classified as a type II PDZ-binding motif, and GPR85 is a risk factor for schizophrenia. GPR85 is an orphan receptor that regulates neural and synaptic plasticity and modulates diverse behaviors, including learning and memory. While searching for molecules that associate with GPR85, we found that GPR85 was associated with postsynaptic density protein (PSD)-95 linked with NLGN in the brain. METHODS: We examined the proteins that associate with the C-terminal sequence of GPR85 by pull-down assay and immunoblot analysis and searched for a mutation of the GPR85 gene in patients with ASD. We used immunostaining to examine the intracellular localization of mutated GPR85 and its influence on the morphology of cells and neurons. RESULTS: The C-terminal sequence of GPR85 interacted with PSD-95 at PDZ1, while NLGN interacted with PSD-95 at PDZ3. Two male patients with ASD from independent Japanese families possessed inherited missense mutations at conserved sites in GPR85: one had T1033C (M152T) and the other had G1239T (V221L). These mutations were located in a domain related to G protein interaction and signal transduction. In contrast to wild-type GPR85, mutated GPR85 was more preferentially accumulated, causing endoplasmic reticulum stress, and disturbed the dendrite formation of hippocampal neurons. CONCLUSIONS: GPR85 associated with the PSD-95 linked with NLGN, which is related to ASD. GPR85 carrying the mutations detected in ASD patients disturbed dendrite formation that could be the candidate for molecular pathogenesis of ASD through the associated NLGN-PSD-95 receptor complex.
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4. Gambino G. {{The autism spectrum disorders (ASD)}}. {Ital J Pediatr};2014 (Dec);40(1):452.
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5. Ginn NC, Clionsky LN, Eyberg SM, Warner-Metzger C, Abner JP. {{Child-Directed Interaction Training for Young Children With Autism Spectrum Disorders: Parent and Child Outcomes}}. {J Clin Child Adolesc Psychol};2015 (Mar 18):1-9.
This study examined the efficacy of the Child-Directed Interaction Training (CDIT) phase of Parent-Child Interaction Therapy for children with an Autism Spectrum Disorder (ASD). Thirty mother-child dyads with children ages 3-7 years with a diagnosis of ASD participated in this randomized controlled study. Following manualized CDIT, statistically significant and meaningful improvements in child disruptive behavior and social awareness as well as maternal distress associated with child disruptive behavior occurred. Across 8 sessions, mothers learned to provide positive attention to their children’s appropriate social and play behaviors. Both child and parent changes were maintained at 6-week follow-up. A relatively brief, time-limited, and accessible intervention may be efficacious for improving child and parent behaviors in families of young children with ASD. By decreasing child disruptive behaviors, CDIT may also help to prepare children to benefit further from future interventions.
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6. Hampton J, Strand PS. {{A Review of Level 2 Parent-Report Instruments Used to Screen Children Aged 1.5-5 for Autism: A Meta-Analytic Update}}. {J Autism Dev Disord};2015 (Mar 17)
The present study utilized meta-analytic procedures to estimate the diagnostic validity of instruments used to screen young children, ages 1.5-5 years, for autism. Five scales met inclusion criteria, and data from 18 studies contributed the meta-analysis. Results revealed that 4 of 5 scales met criteria for « good » validity, including two broad band scales (instruments not restricted to screening for autism). The current results suggest that validity differences might be a function of how instruments sample across the DSM content domains. Specifically, high validity instruments included a higher proportion of items assessing social interaction skills. The availability of valid broad- and narrow-band instruments, as well as implications for constructing future screening instruments, is discussed.
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7. Hellings JA, Reed G, Cain SE, Zhou X, Barth FX, Aman MG, Palaguachi GI, Mikhnev D, Teng R, Andridge R, Logan M, Butler MG, Han JC. {{Loxapine Add-on for Adolescents and Adults with Autism Spectrum Disorders and Irritability}}. {J Child Adolesc Psychopharmacol};2015 (Mar);25(2):150-159.
OBJECTIVES: Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation. METHODS: We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores >14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped. RESULTS: Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype. CONCLUSIONS: Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study.
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8. Li Q, Loh DH, Kudo T, Truong D, Derakhshesh M, Kaswan ZM, Ghiani CA, Tsoa R, Cheng Y, Sun YE, Colwell CS. {{Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT}}. {Neurobiol Dis};2015 (Mar 14)
Disturbances in the sleep/wake cycle are prevalent in patients with Rett syndrome (RTT). We sought to determine whether the circadian system is disrupted in a RTT model, Mecp2-/y mice. We found that MeCP2 mutants showed decreased strength and precision of daily rhythms of activity coupled with extremely fragmented sleep. The central circadian clock (suprachiasmatic nucleus) exhibited significant reduction in the number of neurons expressing vasoactive intestinal peptide (VIP) as well as compromised spontaneous neural activity. The molecular clockwork was disrupted both centrally in the SCN and in peripheral organs, indicating a general disorganization of the circadian system. Disruption of the molecular clockwork was observed in fibroblasts of RTT patients. Finally, MeCP2 mutant mice were vulnerable to circadian disruption as chronic jet lag accelerated mortality. Our findings suggest that an integral role for MeCP2 in the circadian timing system provides a possible mechanistic explanation for the sleep/wake disturbances observed in RTT patients. The work raises the possibility that RTT patients may benefit from a temporally structured environment.
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9. Lisiecka DM, Holt R, Tait R, Ford M, Lai MC, Chura LR, Baron-Cohen S, Spencer MD, Suckling J. {{Developmental white matter microstructure in autism phenotype and corresponding endophenotype during adolescence}}. {Transl Psychiatry};2015;5:e529.
During adolescence, white matter microstructure undergoes an important stage of development. It is hypothesized that the alterations of brain connectivity that have a key role in autism spectrum conditions (ASCs) may interact with the development of white matter microstructure. This interaction may be present beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to 20 times more likely to develop certain forms of ASC. We use diffusion tensor imaging to examine how white matter microstructure measurements correlate with age in typically developing individuals, and how this correlation differs in n=43 adolescents with ASC and their n=38 siblings. Correlations observed in n=40 typically developing individuals match developmental changes noted in previous longitudinal studies. In comparison, individuals with ASC display weaker negative correlation between age and mean diffusivity in a broad area centred in the right superior longitudinal fasciculus. These differences may be caused either by increased heterogeneity in ASC or by temporal alterations in the group’s developmental pattern. Siblings of individuals with ASC also show diminished negative correlation between age and one component of mean diffusivity-second diffusion eigenvalue-in the right superior longitudinal fasciculus. As the observed differences match for location and correlation directionality in our comparison of typically developing individuals to those with ASC and their siblings, we propose that these alterations constitute a part of the endophenotype of autism.
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10. Oza VS, Marco E, Frieden IJ. {{Improving the Dermatologic Care of Individuals with Autism: A Review of Relevant Issues and a Perspective}}. {Pediatr Dermatol};2015 (Mar 17)
Autism spectrum disorder (ASD) is a neurodevelopmental condition that effects verbal and nonverbal communication and social cognition and often presents with altered sensory processing, stereotyped behavior, and restricted interests. The prevalence of this diagnosis has increased markedly over the past two decades. Dermatologists undoubtedly will be evaluating and managing more patients with this diagnosis, but there has been little written regarding the dermatologic care of patients with ASD. Difficulties with communication and sensory processing create significant challenges in clinical evaluation and management. Individuals with ASD are also at higher risk for certain dermatologic conditions. This review is intended to build an awareness of the complexity of caring for individuals with ASD and discuss strategies that can help improve the dermatologic care of these patients.
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11. Quinlan CA, McVeigh KH, Driver CR, Govind P, Karpati A. {{Parental Age and Autism Spectrum Disorders Among New York City Children 0-36 Months of Age}}. {Matern Child Health J};2015 (Mar 17)
We examined trends in autism spectrum disorders (ASD) and the association of ASD with parental age among young New York City (NYC) children. Children born in NYC to resident mothers from 1994-2001 were identified through vital statistics records (N = 927,003). Records were linked to data from NYC Early Intervention (EI) Program through 2004. The independent parental age-specific odds of having an ASD before 36 months of age were estimated using multiple logistic regression controlling for risk factors. The increase in ASD attributable to changes in parental age at birth was examined. Births to mothers and fathers 35 years or older increased 14.9 and 11.5 %, respectively, between 1994 and 2001. ASD prevalence in EI increased significantly from 1 in 3,300 children born in 1994 to 1 in 233 children born in 2001. Children born to mothers ages 25-29, 30-34 and 35 or older had significantly greater odds of being diagnosed with ASD than children of mothers younger than 25 years (OR 1.5, 1.6, and 1.9, respectively). Children born to fathers ages 35 or older (OR 1.4) had greater odds of ASD than children of fathers younger than 25. The change in parental age accounted for only 2.7 % of the increase in ASD prevalence. Older paternal age and maternal age were independently associated with increased risk of ASD. However, while parental age at birth increased between the 1994 and 2001 birth cohorts in NYC, it did not explain the increase in number of ASD cases.
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12. Reaven J, Washington L, Moody EJ, Stern JA, Hepburn SL, Blakeley-Smith A. {{Examining the Relationship Between Parental Anxiety and Treatment Response in Children and Adolescents with Autism Spectrum Disorder and Anxiety}}. {J Autism Dev Disord};2015 (Mar 17)
In response to the high co-occurrence of anxiety symptoms in youth with autism spectrum disorder (ASD), several interventions have been developed for this population. In spite of promising findings, some youth with ASD respond only minimally to such interventions. To understand potential factors that may impact treatment response, the current study explores the role of parental anxiety in youth treatment outcome. Thirty-one youth with ASD, ages 7-18, and their parents participated in the study. Parents completed the State/Trait Anxiety Inventory pre- and post-treatment. Contrary to previous research, there was no correlation between parental anxiety and youth anxiety at baseline or post-treatment. However, parental trait anxiety significantly decreased from pre- to post-treatment for parents of treatment responders. The findings are consistent with previous research and suggest a youth-to-parent influence.
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13. Saiano M, Pellegrino L, Casadio M, Summa S, Garbarino E, Rossi V, Dall’Agata D, Sanguineti V. {{Natural interfaces and virtual environments for the acquisition of street crossing and path following skills in adults with Autism Spectrum Disorders: a feasibility study}}. {J Neuroeng Rehabil};2015 (Dec);12(1):10.
BACKGROUND: Lack of social skills and/or a reduced ability to determine when to use them are common symptoms of Autism Spectrum Disorder (ASD). Here we examine whether an integrated approach based on virtual environments and natural interfaces is effective in teaching safety skills in adults with ASD. We specifically focus on pedestrian skills, namely street crossing with or without traffic lights, and following road signs. METHODS: Seven adults with ASD explored a virtual environment (VE) representing a city (buildings, sidewalks, streets, squares), which was continuously displayed on a wide screen. A markerless motion capture device recorded the subjects’ movements, which were translated into control commands for the VE according to a predefined vocabulary of gestures. The treatment protocol consisted of ten 45-minutes sessions (1 session/week). During a familiarization phase, the participants practiced the vocabulary of gestures. In a subsequent training phase, participants had to follow road signs (to either a police station or a pharmacy) and to cross streets with and without traffic lights. We assessed the performance in both street crossing (number and type of errors) and navigation (walking speed, path length and ability to turn without stopping). To assess their understanding of the practiced skill, before and after treatment subjects had to answer a test questionnaire. To assess transfer of the learned skill to real-life situations, another specific questionnaire was separately administered to both parents/legal guardians and the subjects’ personal caregivers. RESULTS: One subject did not complete the familiarization phase because of problems with depth perception. The six subjects who completed the protocol easily learned the simple body gestures required to interact with the VE. Over sessions they significantly improved their navigation performance, but did not significantly reduce the errors made in street crossing. In the test questionnaire they exhibited no significant reduction in the number of errors. However, both parents and caregivers reported a significant improvement in the subjects’ street crossing performance. Their answers were also highly consistent, thus pointing at a significant transfer to real-life behaviors. CONCLUSIONS: Rehabilitation of adults with ASD mainly focuses on educational interventions that have an impact in their quality of life, which includes safety skills. Our results confirm that interaction with VEs may be effective in facilitating the acquisition of these skills.
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14. Shi L, Zhou Y, Ou J, Gong J, Wang S, Cui X, Lyu H, Zhao J, Luo X. {{Different visual preference patterns in response to simple and complex dynamic social stimuli in preschool-aged children with autism spectrum disorders}}. {PLoS One};2015;10(3):e0122280.
Eye-tracking studies in young children with autism spectrum disorder (ASD) have shown a visual attention preference for geometric patterns when viewing paired dynamic social images (DSIs) and dynamic geometric images (DGIs). In the present study, eye-tracking of two different paired presentations of DSIs and DGIs was monitored in a group of 13 children aged 4 to 6 years with ASD and 20 chronologically age-matched typically developing children (TDC). The results indicated that compared with the control group, children with ASD attended significantly less to DSIs showing two or more children playing than to similar DSIs showing a single child. Visual attention preference in 4- to 6-year-old children with ASDs, therefore, appears to be modulated by the type of visual stimuli.
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15. Smith T, Klorman R, Mruzek DW. {{Predicting Outcome of Community-Based Early Intensive Behavioral Intervention for Children with Autism}}. {J Abnorm Child Psychol};2015 (Mar 17)
We examined predictors of outcome (IQ, adaptive behavior, and ASD severity) after 12 and 24 months of early intensive behavioral intervention (EIBI) in 71, 20-59 months old children with autism spectrum disorder (ASD) who were enrolled in publicly-funded, community-based agencies. Predictors included social engagement (combining variables loading onto a single factor: social approach, joint attention, and imitation) and sensorimotor rituals. Younger age and higher IQ at intake predicted favorable outcomes at both 12 and 24 months. Adjusting for age, IQ, baseline predictor scores, EIBI hours, treatment site, and sensorimotor rituals, social engagement predicted superior later IQ and adaptive behavior. In contrast, sensorimotor rituals did not predict outcome. Although limited by the absence of a control group, the study indicates social engagement predicts some EIBI outcomes.
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16. Torrico B, Fernandez-Castillo N, Hervas A, Mila M, Salgado M, Rueda I, Buitelaar JK, Rommelse N, Oerlemans AM, Bralten J, Freitag CM, Reif A, Battaglia A, Mazzone L, Maestrini E, Cormand B, Toma C. {{Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability}}. {Eur J Hum Genet};2015 (Mar 18)
Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P=6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P=0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P=7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P=0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P=0.003, permP=0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder.European Journal of Human Genetics advance online publication, 18 March 2015; doi:10.1038/ejhg.2015.37.
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17. Wolf-Fordham S, Curtin C, Maslin M, Bandini L, Hamad CD. {{Emergency preparedness of families of children with developmental disabilities: What public health and safety emergency planners need to know}}. {J Emerg Manag};2015 (Jan-Feb);13(1):7-18.
OBJECTIVE: To assess the emergency preparedness knowledge, behaviors, and training needs of families of children with developmental disabilities (DD). DESIGN: An online survey. PARTICIPANTS: A sample of 314 self-selecting US parents/guardians of children with DD, aged birth-21 years. MAIN OUTCOME MEASURES: 1) Preparedness self-assessment; 2) self-report regarding the extent to which families followed 11 specific preparedness action steps derived from publicly available preparedness guides; and 3) parent training and support needs. RESULTS: Although most participants assessed themselves to be somewhat to moderately well prepared, even those who reported being « very well prepared » had taken fewer than half of 11 recommended action steps. Most participants expressed a need for preparedness support; virtually all the respondents felt that training was either important or very important. CONCLUSIONS: Children with disabilities are known to be particularly vulnerable to negative disaster impacts. Overall, parents in this study appeared under-prepared to meet family disaster needs, although they recognized its importance. The results suggest opportunities and methods for public health and safety planning, education and outreach to parents of children with DD who would benefit from targeted training such as information and skill building to develop effective family preparedness plans and connections to local emergency management and responders.
