1. {{Selecting Children for an Autism Spectrum Disorder Study: Justice and Geography}}. {Am J Bioeth};2016 (Apr);16(4):69-70.
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2. Casanova EL, Sharp JL, Chakraborty H, Sumi NS, Casanova MF. {{Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression}}. {Mol Autism};2016;7:18.
BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions.
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3. Estabillo JA, Matson JL, Jiang X. {{The association between familial ASD diagnosis, autism symptomatology and developmental functioning in young children}}. {Eur Child Adolesc Psychiatry};2016 (Mar 16)
Few studies have directly compared individuals with and without a relative diagnosed with ASD on various domains. The present study aimed to examine the relationship between familial ASD diagnosis and the exhibition of ASD symptoms in young children with and without ASD diagnoses. Participants included 8353 children aged 17-37 months old and their families. They were divided into four groups based on individual and family diagnosis, then compared on autism symptomatology and developmental domains. No differences were found between ASD groups on overall scores and each of the factor domains, indicating no association between family ASD diagnosis and ASD symptomatology or developmental functioning. Disparate results were found for atypically developing groups with and without relatives diagnosed with ASD. Implications of these results are discussed.
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4. Grainger C, Williams DM, Lind SE. {{Metacognitive monitoring and control processes in children with autism spectrum disorder: Diminished judgement of confidence accuracy}}. {Conscious Cogn};2016 (Mar 14);42:65-74.
Metacognition consists of monitoring processes (the ability to accurately represent one’s own mental states) and control processes (the ability to control one’s cognitive processes effectively). Both processes play vital roles in self-regulated learning. However, currently it is unclear whether these processes are impaired in individuals with autism spectrum disorders (ASDs). This study aimed to assess metacognition in thirty-two children with ASD, and 30 IQ-/age-matched neurotypical children, using a judgment of confidence task. It was found that children with ASD showed diminished accuracy in their judgments of confidence, indicating metacognitive monitoring impairments in ASD. Children with ASD also used monitoring to influence control processes significantly less than neurotypical children, despite little evidence of impairments in overall control ability.
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5. Hage A, Banaschewski T, Buitelaar JK, Dijkhuizen RM, Franke B, Lythgoe DJ, Mechler K, Williams SC, Dittmann RW. {{Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) – study protocol for a randomised controlled trial}}. {Trials};2016;17(1):141.
BACKGROUND: Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer’s dementia in a number of countries. METHODS/DESIGN: This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children’s Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits. DISCUSSION: This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders. TRIAL REGISTRATION: EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014.
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6. Kargas N, Lopez B, Morris P, Reddy V. {{Relations Among Detection of Syllable Stress, Speech Abnormalities, and Communicative Ability in Adults With Autism Spectrum Disorders}}. {J Speech Lang Hear Res};2016 (Mar 17):1-10.
Purpose: To date, the literature on perception of affective, pragmatic, and grammatical prosody abilities in autism spectrum disorders (ASD) has been sparse and contradictory. It is interesting to note that the primary perception of syllable stress within the word structure, which is crucial for all prosody functions, remains relatively unexplored in ASD. Thus, in the current study, we explored syllable stress perception sensitivity and its relationship to speech production abnormalities and communicative ability in adults with ASD. Method: A same-different syllable stress perception task using pairs of identical 4-syllable words was delivered to 42 adults with/without high-functioning ASD, matched for age, to investigate primary speech perception ability in ASD. Speech production and communicative ability in ASD was measured using the Autism Diagnostic Observation Schedule (Lord et al., 2000). Results: As predicted, the results showed that adults with ASD were less sensitive in making judgments about syllable stress relative to controls. Also, partial correlations revealed a key association of speech production abnormalities with stress perception sensitivity, rather than communicative ability. Conclusions: Our findings provide empirical evidence for deficits on primary syllable stress perception in ASD and its role on sociocommunicative difficulties. This information could facilitate the development of effective interventions for speech and language therapy and social communication.
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7. Mullins C, Fishell G, Tsien RW. {{Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops}}. {Neuron};2016 (Mar 16);89(6):1131-1156.
Understanding the mechanisms underlying autism spectrum disorders (ASDs) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry, and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops and provide detailed commentary for exemplar genes within each module.
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8. Raghavan DV, Doshi VV, Nambi S. {{Joubert syndrome with autism in two siblings: A rare presentation}}. {Indian J Psychiatry};2016 (Jan-Mar);58(1):90-92.
Joubert syndrome is a rare autosomal recessive disorder with partial or complete agenesis of cerebellar vermis. This syndrome is identified mainly by the presence of molar tooth sign in magnetic resonance imaging of the brain since it has a varied phenotypic presentation. Of the 200 cases reported so far in the literature, only three reports show the presence of autistic symptoms in siblings suggesting a link between the cerebellar vermis and autistic spectrum disorders. In this case report of two siblings, the female child satisfied the criterion for autistic spectrum disorder in accordance with Diagnostic and Statistical Manual of Mental Disorders Fifth Editon. The boy showed developmental delay with autistic features (not amounting to diagnostic threshold). This report is important in that it adds evidence to the literature that abnormalities of cerebellum are involved in the cognitive development and autistic symptoms.
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9. Stein MA, King BH. {{Unequal Individual Risk and Potential Benefit Balanced by Benefits to the Population at Large in Autism Clinical Trials?}}. {Am J Bioeth};2016 (Apr);16(4):72-74.
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10. Valarmathi P, Kumar G, Robin S, Manonmani S, Dasgupta I, Rabindran R. {{Evaluation of virus resistance and agronomic performance of rice cultivar ASD 16 after transfer of transgene against Rice tungro bacilliform virus by backcross breeding}}. {Virus Genes};2016 (Mar 16)
Severe losses of rice yield in south and southeast Asia are caused by Rice tungro disease (RTD) induced by mixed infection of Rice tungro bacilliform virus (RTBV) and Rice tungro spherical virus (RTSV). In order to develop transgene-based resistance against RTBV, one of its genes, ORF IV, was used to generate transgenic resistance based on RNA-interference in the easily transformed rice variety Pusa Basmati-1, and the transgene was subsequently introgressed to rice variety ASD 16, a variety popular in southern India, using transgene marker-assisted selection. Here, we report the evaluation of BC3F4 and BC3F5 generation rice plants for resistance to RTBV as well as for agronomic traits under glasshouse conditions. The BC3F4 and BC3F5 generation rice plants tested showed variable levels of resistance, which was manifested by an average of twofold amelioration in height reduction, 1.5-fold decrease in the reduction in chlorophyll content, and 100- to 10,000-fold reduction in the titers of RTBV, but no reduction of RTSV titers, in three backcrossed lines when compared with the ASD 16 parent. Agronomic traits of some of the backcrossed lines recorded substantial improvements when compared with the ASD 16 parental line after inoculation by RTBV and RTSV. This work represents an important step in transferring RTD resistance to a susceptible popular rice variety, hence enhancing its yield in areas threatened by the disease.
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11. Wink LK, Badran I, Pedapati EV, Sorensen R, Benton SC, Johnson MC, Wissel G, Erickson CA. {{Clozapine for Drug-Refractory Irritability in Individuals with Developmental Disability}}. {J Child Adolesc Psychopharmacol};2016 (Mar 17)
OBJECTIVES: In this case series, we describe the acute clinical impact and tolerability of rapid titration of clozapine for treatment of refractory irritability in five hospitalized youth with developmental disability. We offer this descriptive report in an effort to expand the evidence base guiding treatment of refractory aggression in this population. METHODS: Five youth with developmental disability and severe irritability were admitted to a 10-bed psychiatric crisis stabilization unit where they received thorough psychiatric and medical evaluation. Informed consent was obtained in each case, and each patient underwent rapid titration onto clozapine. Clozapine monitoring guidelines were followed for all patients throughout treatment, and clinical severity at baseline and improvement with treatment was measured by use of the Clinical Global Impressions-Severity scale (CGI-S) and the Clinical Global Impressions-Improvement scale (CGI-I). RESULTS: One female and four males diagnosed with developmental disability and at least one other psychiatric diagnosis, mean age of 13.1 +/- 2.1 years, and mean CGI-S at baseline of 5.8, each received clozapine treatment by rapid titration. The mean therapeutic total daily dose of clozapine was 380 +/- 200 mg. All patients demonstrated acute clinical improvement with the mean final CGI-I of 2.0, or « much improved. » CONCLUSION: These initial results support the potential utility of clozapine rapid titration for treatment of severe refractory irritability in youth with developmental disability. These patients tolerated clozapine treatment in the short term. Future studies are needed to thoroughly evaluate the long-term safety of clozapine treatment in this population.
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12. Yakubova G, Hughes EM, Shinaberry M. {{Learning with Technology: Video Modeling with Concrete-Representational-Abstract Sequencing for Students with Autism Spectrum Disorder}}. {J Autism Dev Disord};2016 (Mar 17)
The purpose of this study was to determine the effectiveness of a video modeling intervention with concrete-representational-abstract instructional sequence in teaching mathematics concepts to students with autism spectrum disorder (ASD). A multiple baseline across skills design of single-case experimental methodology was used to determine the effectiveness of the intervention on the acquisition and maintenance of addition, subtraction, and number comparison skills for four elementary school students with ASD. Findings supported the effectiveness of the intervention in improving skill acquisition and maintenance at a 3-week follow-up. Implications for practice and future research are discussed.
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13. Zahorakova D, Lelkova P, Gregor V, Magner M, Zeman J, Martasek P. {{MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning}}. {J Hum Genet};2016 (Mar 17)
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT.Journal of Human Genetics advance online publication, 17 March 2016; doi:10.1038/jhg.2016.19.
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14. Zhou Y, Shi L, Cui X, Wang S, Luo X. {{Functional Connectivity of the Caudal Anterior Cingulate Cortex Is Decreased in Autism}}. {PLoS One};2016;11(3):e0151879.
The anterior cingulate cortex (ACC) is frequently reported to have functionally distinct sub-regions that play key roles in different intrinsic networks. However, the contribution of the ACC, which is connected to several cortical areas and the limbic system, to autism is not clearly understood, although it may be involved in dysfunctions across several distinct but related functional domains. By comparing resting-state fMRI data from persons with autism and healthy controls, we sought to identify the abnormalities in the functional connectivity (FC) of ACC sub-regions in autism. The analyses found autism-related reductions in FC between the left caudal ACC and the right rolandic operculum, insula, postcentral gyrus, superior temporal gyrus, and the middle temporal gyrus. The FC (z-scores) between the left caudal ACC and the right insula was negatively correlated with the Stereotyped Behaviors and Restricted Interests scores of the autism group. These findings suggest that the caudal ACC is recruited selectively in the pathomechanism of autism.
