1. Bebbington A, Glasson E, Bourke J, de Klerk N, Leonard H. {{Hospitalisation rates for children with intellectual disability or autism born in Western Australia 1983-1999: a population-based cohort study}}. {BMJ Open};2013;3(2)
OBJECTIVES: To describe the hospitalisation patterns in children with intellectual disability (ID) and/or autism spectrum disorder (ASD) after the first year of life and compare with those unaffected. DESIGN: Prospective cohort study using data linkage between health, ID and hospitalisation population-based datasets. SETTING: Western Australia. PARTICIPANTS: 416 611 individuals born between 1983 and 1999 involving 1 027 962 hospital admission records. Five case categories were defined (mild/moderate ID, severe ID, biomedically caused ID, ASD with ID and ASD without ID) and compared with the remainder of children and young people. PRIMARY AND SECONDARY OUTCOME MEASURES: Time to event analysis was used to compare time hospitalisation and rate of hospitalisation between the different case-groups by estimating HR, accounting for birth year and preterm birth status. RESULTS: ID and/or ASD were found to be associated with an increased risk of hospitalisation compared with the remainder of the population. The increase in risk was highest in those with severe ID and no ASD (HR=10.33, 95% CI 8.66 to 12.31). For those with ID of known biomedical cause or mild ID of unknown cause, the risk of hospitalisation was lower (HR=7.36, 95% CI 6.73 to 8.07 and HR=3.08, 95% CI 2.78 to 3.40, respectively). Those with ASDs had slightly increased risk (HR=2.82, 95% CI 2.26 to 3.50 for those with ID and HR=2.09, 95% CI 1.85 to 2.36 for those without ID). CONCLUSIONS: Children with an ID or ASD experience an increased risk of hospitalisation after the first year of life which varied from 2 to 10 times that of the rest of the population. Findings can inform service planning or resource allocation for these children with special needs.
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2. Castro J, Mellios N, Sur M. {{Mechanisms and therapeutic challenges in autism spectrum disorders: insights from Rett syndrome}}. {Curr Opin Neurol};2013 (Feb 27)
PURPOSE OF REVIEW: A major challenge for understanding neurodevelopmental disorders, including autism spectrum disorders (ASDs), is to advance the findings from gene discovery to an exposition of neurobiological mechanisms that underlie these disorders and subsequently translate this knowledge into mechanism-based therapeutics. A promising way to proceed is revealed by the recent studies of rare subsets of ASDs. In this review, we summarize the latest advances in the mechanisms and emerging therapeutics for a rare single-gene ASD, Rett syndrome. RECENT FINDINGS: Rett syndrome is caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2). Although MeCP2 has diverse functions, examination of MeCP2 mutant mice suggests the hypothesis that MeCP2 deficiency leads to aberrant maturation and maintenance of synapses and circuits in multiple brain systems. Some of the deficits arise from alterations in specific intracellular pathways such as the PI3K/Akt signaling pathway. These abnormalities can be at least partially rescued in MeCP2 mutant mice by treatment with therapeutic agents. SUMMARY: Mechanism-based therapeutics are emerging for single-gene neurodevelopmental disorders such as Rett syndrome. Given the complexity of MeCP2 function, future directions include combination therapeutics that target multiple molecules and pathways. Such approaches will likely be applicable to other ASDs as well.
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3. de Boer-Schellekens L, Eussen M, Vroomen J. {{Diminished sensitivity of audiovisual temporal order in autism spectrum disorder}}. {Front Integr Neurosci};2013;7:8.
We examined sensitivity of audiovisual temporal order in adolescents with autism spectrum disorder (ASD) using an audiovisual temporal order judgment (TOJ) task. In order to assess domain-specific impairments, the stimuli varied in social complexity from simple flash/beeps to videos of a handclap or a speaking face. Compared to typically-developing controls, individuals with ASD were generally less sensitive in judgments of audiovisual temporal order (larger just noticeable differences, JNDs), but there was no specific impairment with social stimuli. This suggests that people with ASD suffer from a more general impairment in audiovisual temporal processing.
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4. Grant R, Nozyce M. {{Proposed Changes to the American Psychiatric Association Diagnostic Criteria for Autism Spectrum Disorder: Implications for Young Children and Their Families}}. {Matern Child Health J};2013 (Mar 2)
The American Psychiatric Association has revised the diagnostic criteria for their DSM-5 manual. Important changes have been made to the diagnosis of the current (DSM-IV) category of Pervasive Developmental Disorders. This category includes Autistic Disorder (autism), Asperger’s Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). The DSM-5 deletes Asperger’s Disorder and PDD-NOS as diagnostic entities. This change may have unintended consequences, including the possibility that the new diagnostic framework will adversely affect access to developmental interventions under Individuals with Disabilities Education Act (IDEA) programs, Early Intervention (for birth to 2 years olds) and preschool special education (for 3 and 4 years olds). Changing the current diagnosis of PDD-NOS to a « Social Communication Disorder » focused on language pragmatics in the DSM-5 may restrict eligibility for IDEA programs and limit the scope of services for affected children. Young children who meet current criteria for PDD-NOS require more intensive and multi-disciplinary services than would be available with a communication domain diagnosis and possible service authorization limited to speech-language therapy. Intensive behavioral interventions, inclusive group setting placements, and family support services are typically more available for children with an autism spectrum disorder than with diagnoses reflecting speech-language delay. The diagnostic distinction reflective of the higher language and social functioning between Asperger’s Disorder and autism is also undermined by eliminating the former as a categorical diagnosis and subsuming it under autism. This change may adversely affect treatment planning and misinform parents about prognosis for children who meet current criteria for Asperger’s Disorder.
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5. Peterson K, Barbel P. {{On alert for Autism spectrum disorders}}. {Nursing};2013 (Feb 27)
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6. Stavropoulos KK, Carver LJ. {{Research Review: Social motivation and oxytocin in autism – implications for joint attention development and intervention}}. {J Child Psychol Psychiatry};2013 (Mar 2)
BACKGROUND AND SCOPE: The social motivation hypothesis (SMH) suggests that individuals with autism spectrum disorders (ASD) are less intrinsically rewarded by social stimuli than their neurotypical peers. This difference in social motivation has been posited as a factor contributing to social deficits in ASD. Social motivation is thought to involve the neuropeptide oxytocin. Here, we review the evidence for oxytocin effects in ASD, and discuss its potential role in one important social cognitive behavior. METHODS: Systematic searches were conducted using the PsychINFO and MEDLINE databases and the search terms ‘oxytocin’ and ‘autism’; the same databases were used for separate searches for ‘joint attention’, ‘intervention’, and ‘autism’, using the same inclusion criteria as an earlier 2011 review but updating it for the period 2010 to October 2012. FINDINGS: Several studies suggest that giving oxytocin to both individuals with ASD and neurotypical individuals can enhance performance on social cognitive tasks. Studies that have attempted to intervene in joint attention in ASD suggest that social motivation may be a particular obstacle to lasting effects. CONCLUSIONS: The review of the evidence for the SMH suggests a potential role for oxytocin in social motivation deficits in ASD. Because of its importance for later communicative and social development, the focus here is on implications of oxytocin and social motivation in the development of and interventions in joint attention. Joint attention is a central impairment in ASD, and as a result is the focus of several behavioral interventions. In describing this previous research on joint attention interventions in ASD, we pay particular attention to problems encountered in such studies, and propose ways that oxytocin may facilitate behavioral intervention in this area. For future research, integrating behavioral and pharmacological interventions (oxytocin administration) would be a worthwhile experimental direction to improve understanding of the role of oxytocin in ASD and help optimize outcomes for children with ASD.
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7. Vaishnavi V, Manikandan M, Tiwary BK, Munirajan AK. {{Insights on the Functional Impact of MicroRNAs Present in Autism-Associated Copy Number Variants}}. {PLoS One};2013;8(2):e56781.
Autism spectrum disorder is a complex neurodevelopmental disorder that appears during the first three years of infancy and lasts throughout a person’s life. Recently a large category of genomic structural variants, denoted as copy number variants (CNVs), were established to be a major contributor of the pathophysiology of autism. To date almost all studies have focussed only on the genes present in the CNV loci, but the impact of non-coding regulatory microRNAs (miRNAs) present in these regions remain largely unexplored. Hence we attempted to elucidate the biological and functional significance of miRNAs present in autism-associated CNV loci and their target genes by using a series of computational tools. We demonstrate that nearly 11% of the CNV loci harbor miRNAs and a few of these miRNAs were previously reported to be associated with autism. A systematic analysis of the CNV-miRNAs based on their interactions with the target genes enabled the identification of top 10 miRNAs namely hsa-miR-590-3p, hsa-miR-944, hsa-miR-570, hsa-miR-34a, hsa-miR-124, hsa-miR-548f, hsa-miR-429, hsa-miR-200b, hsa-miR-195 and hsa-miR-497 as hub molecules. Further, the CNV-miRNAs formed a regulatory loop with transcription factors and their downstream target genes, and annotation of these target genes indicated their functional involvement in neurodevelopment and synapse. Moreover, miRNAs present in deleted and duplicated CNV loci may explain the difference in dosage of the crucial genes controlled by them. These CNV-miRNAs can also impair the global processing and biogenesis of all miRNAs by targeting key molecules in the miRNA pathway. To our knowledge, this is the first report to highlight the significance of CNV-microRNAs and their target genes to contribute towards the genetic heterogeneity and phenotypic variability of autism.
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8. Wu D, Zhu Z, Zhao Z, Qu Y, Yang J. {{[Methylation analysis of CpG island DNA of FMR1 gene in the fragile X syndrome]}}. {Zhonghua Yi Xue Yi Chuan Xue Za Zhi};2013 (Feb);30(1):60-63.
OBJECTIVE: To establish a method of methylation-sensitive restriction enzymes based quantitative PCR (MSRE-qPCR) for analysis of CpG island DNA of FMR1 gene, and to assess its value for molecular diagnosis of fragile X syndrome. METHODS: Thirty boys with mental retardation and abnormal repeats of 5′(CGG)n in the FMR1 gene and 20 mothers were analyzed by conventional PCR screening. Eag I was used to digest genomic DNA, and qPCR was performed to amplify CpG island in the FMR1 gene using both undigested and digested templates. Raw Ct values were obtained through quantitative PCR amplification. The degree of CpG island methylation was calculated by 2 . The result of MSRE-qPCR was verified by Southern blotting. 30 healthy females and 30 healthy males were used as controls to optimize the established MSRE-qPCR method. RESULTS: The ranges of 2 value for normal methylation, partial methylation and full methylation were determined. Among the 30 patients, 3 were found to have partial methylation of CpG island of the FMR1 gene, and 27 were found to have full methylation (3/30 results were verified by Southern blotting). Only 7 mothers were found abnormal methylation of CpG island of FMR1 gene, whilst the remaining 13 mothers were normal. CONCLUSION: MSRE-qPCR is a quick and reliable method for quantitative analysis of CpG island methylation status in FMR1 gene, which may provide a new strategy for the diagnosis of fragile X syndrome.
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9. Zeidan-Chulia F, Rybarczyk-Filho JL, Salmina AB, de Oliveira BH, Noda M, Moreira JC. {{Exploring the Multifactorial Nature of Autism Through Computational Systems Biology: Calcium and the Rho GTPase RAC1 Under the Spotlight}}. {Neuromolecular Med};2013 (Mar 2)
Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication accompanied with repetitive behavioral patterns and unusual stereotyped interests. Autism is considered a highly heterogeneous disorder with diverse putative causes and associated factors giving rise to variable ranges of symptomatology. Incidence seems to be increasing with time, while the underlying pathophysiological mechanisms remain virtually uncharacterized (or unknown). By systematic review of the literature and a systems biology approach, our aims were to examine the multifactorial nature of autism with its broad range of severity, to ascertain the predominant biological processes, cellular components, and molecular functions integral to the disorder, and finally, to elucidate the most central contributions (genetic and/or environmental) in silico. With this goal, we developed an integrative network model for gene-environment interactions (GENVI model) where calcium (Ca2+) was shown to be its most relevant node. Moreover, considering the present data from our systems biology approach together with the results from the differential gene expression analysis of cerebellar samples from autistic patients, we believe that RAC1, in particular, and the RHO family of GTPases, in general, could play a critical role in the neuropathological events associated with autism.
