1. Burket JA, Benson AD, Green TL, Rook JM, Lindsley CW, Jeffrey Conn P, Deutsch SI. {{Effects of VU0410120, a Novel GlyT1 Inhibitor, on Measures of Sociability, Cognition and Stereotypic Behaviors in a Mouse Model of Autism}}. {Prog Neuropsychopharmacol Biol Psychiatry};2015 (Mar 14)
The NMDA receptor is a highly regulated glutamate-gated cationic channel receptor that has an important role in the regulation of sociability and cognition. The genetically-inbred Balb/c mouse has altered endogenous tone of NMDA receptor-mediated neurotransmission and is a model of impaired sociability, relevant to Autism Spectrum Disorders (ASDs). Because glycine is an obligatory co-agonist that works cooperatively with glutamate to promote opening of the ion channel, one prominent strategy to promote NMDA receptor-mediated neurotransmission involves inhibition of the glycine type 1 transporter (GlyT1). The current study evaluated the dose-dependent effects of VU0410120, a selective, high-affinity competitive GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in Balb/c and Swiss Webster mice. The data show that doses of VU0410120 (i.e., 18 and 30 mg/kg) that improve measures of sociability and spatial working memory in the Balb/c mouse strain elicit intense stereotypic behaviors in the Swiss Webster comparator strain (i.e., burrowing and jumping). Furthermore, the data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation in the Balb/c strain. However, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggest that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy.
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2. Chen S, Li Z, He Y, Zhang F, Li H, Liao Y, Wei Z, Wan G, Xiang X, Hu M, Xia K, Chen X, Tang J. {{Elevated mitochondrial DNA copy number in peripheral blood cells is associated with childhood autism}}. {BMC Psychiatry};2015 (Dec);15(1):432.
BACKGROUND: Several lines of evidence indicate mitochondrial impairment in the pathophysiology of autism. As one of the most common biomarkers for mitochondrial dysfunction, mitochondrial DNA (mtDNA) copy number has also been linked to autism, but the relationship between mtDNA copy number and autism was still obscured. In this study, we performed a case-control study to investigate whether mtDNA copy number in peripheral blood cells is related to patients with autism. METHODS: Relative mtDNA copy number in peripheral blood cells was measured by using real-time polymerase chain reaction method. The participants in this study included 78 patients with childhood autism and 83 typically developing children. RESULTS: We observed children with autism had significantly elevated relative mtDNA copy number than healthy controls (Beta = -0.173, P = 0.0003). However, there were no significant correlations between mtDNA copy number and clinical features (paternal age, maternal age, age of onset, illness of duration, CARS score and ABC score) in childhood autism. CONCLUSION: We show that elevated mtDNA copy number in peripheral blood is associated with autism, indicating that there may be mitochondrial dysfunction in children with autism.
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3. Engchuan W, Dhindsa K, Lionel AC, Scherer SW, Chan JH, Merico D. {{Performance of case-control rare copy number variation annotation in classification of autism}}. {BMC Med Genomics};2015;8 Suppl 1:S7.
BACKGROUND: A substantial proportion of Autism Spectrum Disorder (ASD) risk resides in de novo germline and rare inherited genetic variation. In particular, rare copy number variation (CNV) contributes to ASD risk in up to 10% of ASD subjects. Despite the striking degree of genetic heterogeneity, case-control studies have detected specific burden of rare disruptive CNV for neuronal and neurodevelopmental pathways. Here, we used machine learning methods to classify ASD subjects and controls, based on rare CNV data and comprehensive gene annotations. We investigated performance of different methods and estimated the percentage of ASD subjects that could be reliably classified based on presumed etiologic CNV they carry. RESULTS: We analyzed 1,892 Caucasian ASD subjects and 2,342 matched controls. Rare CNVs (frequency 1% or less) were detected using Illumina 1M and 1M-Duo BeadChips. Conditional Inference Forest (CF) typically performed as well as or better than other classification methods. We found a maximum AUC (area under the ROC curve) of 0.533 when considering all ASD subjects with rare genic CNVs, corresponding to 7.9% correctly classified ASD subjects and less than 3% incorrectly classified controls; performance was significantly higher when considering only subjects harboring de novo or pathogenic CNVs. We also found rare losses to be more predictive than gains and that curated neurally-relevant annotations (brain expression, synaptic components and neurodevelopmental phenotypes) outperform Gene Ontology and pathway-based annotations. CONCLUSIONS: CF is an optimal classification approach for case-control rare CNV data and it can be used to prioritize subjects with variants potentially contributing to ASD risk not yet recognized. The neurally-relevant annotations used in this study could be successfully applied to rare CNV case-control data-sets for other neuropsychiatric disorders.
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4. 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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5. Guglielmi L, Servettini I, Caramia M, Catacuzzeno L, Franciolini F, D’Adamo MC, Pessia M. {{Update on the implication of potassium channels in autism: K(+) channelautism spectrum disorder}}. {Front Cell Neurosci};2015;9:34.
Autism spectrum disorders (ASDs) are characterized by impaired ability to properly implement environmental stimuli that are essential to achieve a state of social and cultural exchange. Indeed, the main features of ASD are impairments of interpersonal relationships, verbal and non-verbal communication and restricted and repetitive behaviors. These aspects are often accompanied by several comorbidities such as motor delay, praxis impairment, gait abnormalities, insomnia, and above all epilepsy. Genetic analyses of autistic individuals uncovered deleterious mutations in several K(+) channel types strengthening the notion that their intrinsic dysfunction may play a central etiologic role in ASD. However, indirect implication of K(+) channels in ASD has been also reported. For instance, loss of fragile X mental retardation protein (FMRP) results in K(+) channels deregulation, network dysfunction and ASD-like cognitive and behavioral symptoms. This review provides an update on direct and indirect implications of K(+) channels in ASDs. Owing to a mounting body of evidence associating a channelopathy pathogenesis to autism and showing that nearly 500 ion channel proteins are encoded by the human genome, we propose to classify ASDs – whose susceptibility is significantly enhanced by ion channels defects, either in a monogenic or multigenic condition – in a new category named » c hannel A utism S pectrum D isorder » (channelASD; cASD) and introduce a new taxonomy (e.g., Kv x.y-channelASD and likewise Nav x.y-channelASD, Cav x.y-channelASD; etc.). This review also highlights some degree of clinical and genetic overlap between K(+) channelASDs and K(+) channelepsies, whereby such correlation suggests that a subcategory characterized by a channelASD-channelepsy phenotype may be distinguished. Ultimately, this overview aims to further understand the different clinical subgroups and help parse out the distinct biological basis of autism that are essential to establish patient-tailored treatments.
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6. Isomura T, Ogawa S, Shibasaki M, Masataka N. {{Delayed disengagement of attention from snakes in children with autism}}. {Front Psychol};2015;6:241.
In the visual search task, it is well known that detection of a tilted straight line as the target among vertical lines that act as distractors is easier than vice versa, and that detection of a snake image as the target among flower images is easier than vice versa. In this study, the degree of such search asymmetry was compared between 18 children with autism and 14 typically developing (TD) children. The results revealed that compared to TD children, children with autism were disproportionally slow when asked to detect the flower among the snake images, suggesting the possibility that they experienced difficulty of disengaging their attention from the snake images. This delayed disengagement would serve itself as an enhanced attentional bias toward snakes in children with autism that is similar to characteristics of visual search performance in anxiety patients.
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7. So WC, Lui M, Wong TK, Sit LT. {{The Use of Hand Gestures to Communicate About Nonpresent Objects in Mind Among Children With Autism Spectrum Disorder}}. {J Speech Lang Hear Res};2015 (Mar 17):1-10.
Purpose: The current study examined whether children with autism spectrum disorder (ASD), in comparison with typically developing children, perceive and produce gestures to identify nonpresent objects (i.e., referent-identifying gestures), which is crucial for communicating ideas in a discourse. Method: An experimenter described the uses of daily-life objects to 6- to 12-year-old children both orally and with gestures. The children were then asked to describe how they performed daily activities using those objects. Results: All children gestured. A gesture identified a nonpresent referent if it was produced in the same location that had previously been established by the experimenter. Children with ASD gestured at the specific locations less often than typically developing children. Verbal and spatial memory were positively correlated with the ability to produce referent-identifying gestures for all children. However, the positive correlation between Raven’s Children Progressive Matrices score and the production of referent-identifying gestures was found only in children with ASD. Conclusions: Children with ASD might be less able to perceive and produce referent-identifying gestures and may rely more heavily on visual-spatial skills in producing referent-identifying gestures. The results have clinical implications for designing an intervention program to enhance the ability of children with ASD to communicate about nonpresent objects with gestures.
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8. 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.
