1. Alter MD, Kharkar R, Ramsey KE, Craig DW, Melmed RD, Grebe TA, Bay RC, Ober-Reynolds S, Kirwan J, Jones JJ, Turner JB, Hen R, Stephan DA. {{Autism and increased paternal age related changes in global levels of gene expression regulation}}. {PLoS One};2011;6(2):e16715.

A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

2. Ganz JB, Earles-Vollrath TL, Heath AK, Parker RI, Rispoli MJ, Duran JB. {{A Meta-Analysis of Single Case Research Studies on Aided Augmentative and Alternative Communication Systems with Individuals with Autism Spectrum Disorders}}. {J Autism Dev Disord};2011 (Mar 5)

Many individuals with autism cannot speak or cannot speak intelligibly. A variety of aided augmentative and alternative communication (AAC) approaches have been investigated. Most of the research on these approaches has been single-case research, with small numbers of participants. The purpose of this investigation was to meta-analyze the single case research on the use of aided AAC with individuals with autism spectrum disorders (ASD). Twenty-four single-case studies were analyzed via an effect size measure, the Improvement Rate Difference (IRD). Three research questions were investigated concerning the overall impact of AAC interventions on targeted behavioral outcomes, effects of AAC interventions on individual targeted behavioral outcomes, and effects of three types of AAC interventions. Results indicated that, overall, aided AAC interventions had large effects on targeted behavioral outcomes in individuals with ASD. AAC interventions had positive effects on all of the targeted behavioral outcome; however, effects were greater for communication skills than other categories of skills. Effects of the Picture Exchange Communication System and speech-generating devices were larger than those for other picture-based systems, though picture-based systems did have small effects.

3. Kalkbrenner AE, Daniels JL, Emch M, Morrissey J, Poole C, Chen JC. {{Geographic access to health services and diagnosis with an autism spectrum disorder}}. {Ann Epidemiol};2011 (Apr);21(4):304-310.

PURPOSE: To assess the impact of geographic health services factors on the timely diagnosis of autism. METHODS: Children residing in central North Carolina were identified by records-based surveillance as meeting a standardized case definition for autism. Individual-level geographic access to health services was measured by the density of providers likely to diagnose autism, distance to early intervention service agencies and medical schools, and residence within a Health Professional Shortage Area. We compared the presence of an autism diagnosis by age 8 and timing of first diagnosis across level of accessibility, using Poisson regression and Cox proportional hazards regression and adjusting for family and neighborhood characteristics. RESULTS: Of 206 identified cases, 23% had no previous documented diagnosis of autism. Most adjusted estimates had confidence limits including the null. Point estimates across analyses suggested that younger age at diagnosis was found for areas with many neurologists and psychiatrists and proximal to a medical school but not areas with many primary care physicians or proximal to early intervention services agencies. CONCLUSIONS: Further study of the distribution of medical specialists diagnosing autism may suggest interventions to promote the early diagnosis, and initiation of targeted services, for children with autism spectrum disorders.

4. Lo YC, Soong WT, Gau SS, Wu YY, Lai MC, Yeh FC, Chiang WY, Kuo LW, Jaw FS, Tseng WY. {{The loss of asymmetry and reduced interhemispheric connectivity in adolescents with autism: A study using diffusion spectrum imaging tractography}}. {Psychiatry Res};2011 (Mar 4)

Evidence from neuroimaging and neurobiological studies suggests that abnormalities in cortical-cortical connectivity involving both local and long-distance scales may be related to autism. The present study analyzed the microstructural integrity of the long-range connectivity related to social cognition and language processing with diffusion tractography among adolescents with autism compared with neurotypical adolescents. Tract-specific analyses were used to study the long-range connectivity responsible for integrating social cognition and language processing. Specifically, three pairs of association fibers and three portions of callosal fiber tracts were analyzed. Generalized fractional anisotropy (GFA) values were measured along individual targeted fiber tracts to investigate alterations in microstructure integrity. The asymmetry patterns were also assessed in three pairs of association fibers. In neurotypical participants, we found a consistent leftward asymmetry in three pairs of association fibers. However, adolescents with autism did not demonstrate such asymmetry. Moreover, adolescents with autism had significantly lower mean GFA in three callosal fiber tracts than neurotypical participants. The loss of leftward asymmetry and reduction of interhemispheric connection in adolescents with autism suggest alterations of the long-range connectivity involved in social cognition and language processing. Our results warrant further investigation by combining developmental and neurocognitive data.

5. Muller RA, Shih P, Keehn B, Deyoe JR, Leyden KM, Shukla DK. {{Underconnected, but How? A Survey of Functional Connectivity MRI Studies in Autism Spectrum Disorders}}. {Cereb Cortex};2011 (Mar 4)

Growing consensus suggests that autism spectrum disorders (ASD) are associated with atypical brain networks, thus shifting the focus to the study of connectivity. Many functional connectivity studies have reported underconnectivity in ASD, but results in others have been divergent. We conducted a survey of 32 functional connectivity magnetic resonance imaging studies of ASD for numerous methodological variables to distinguish studies supporting general underconnectivity (GU) from those not consistent with this hypothesis (NGU). Distinguishing patterns were apparent for several data analysis choices. The study types differed significantly with respect to low-pass filtering, task regression, and whole-brain field of view. GU studies were more likely to examine task-driven time series in regions of interest, without the use of low-pass filtering. Conversely, NGU studies mostly applied task regression (for removal of activation effects) and low-pass filtering, testing for correlations across the whole brain. Results thus suggest that underconnectivity findings may be contingent on specific methodological choices. Whereas underconnectivity reflects reduced efficiency of within-network communication in ASD, diffusely increased functional connectivity can be attributed to impaired experience-driven mechanisms (e.g., synaptic pruning). Both GU and NGU findings reflect important aspects of network dysfunction associated with sociocommunicative, cognitive, and sensorimotor impairments in ASD.

6. Poon KK. {{The activities and participation of adolescents with autism spectrum disorders in Singapore: findings from an ICF-based instrument}}. {J Intellect Disabil Res};2011 (Mar 6)

Background This study sought to describe the activities and participation of adolescents with autism spectrum disorders (ASD) in Singapore and to examine the suitability of the Activity and Participation component of the International Classification of Functioning, Disability and Health for achieving this purpose. This information may guide the development of intervention programmes for adolescents and adults as well as the provision of a means to document meaningful outcomes. Methods Parents of 20 adolescents with ASD attending special schools in Singapore were interviewed using the Vineland Adaptive Behavioural Scales – Second Edition and the Activities and Participation Rating Scale (APRS), which was developed for this study. Results The adolescents with ASD were rated to have more difficulties with participation than with the engagement of activities. Individual domain analyses indicate no difficulties with mobility and mild difficulties with self-care. The performance of general tasks and demands were rated as less problematic than domestic, major life areas, communication and interpersonal interactions. The adolescents with ASD were rated to have more difficulties in communication and community environments than in at home. In addition, analysis of associations between the APRS and Vineland Adaptive Behavioural Scales – Second Edition reveal a pattern of strong relationships between sub-tests. Conclusion This study highlights the imperative for researchers and practitioners alike to develop a focus on strengths, generalisation and the quality of life of adolescents with ASD. The APRS also shows promise in helping document outcomes for adolescents with ASD in Asia and further development of this instrument is needed.

7. Volders K, Nuytens K, Creemers JW. {{The Autism Candidate Gene Neurobeachin Encodes a Scaffolding Protein Implicated in Membrane Trafficking and Signaling}}. {Curr Mol Med};2011 (Mar 4)

Autism is a developmental disorder of the central nervous system characterized by impairments in social interaction, communication and restricted repetitive and stereotyped behavior. It is generally assumed that in most cases autism has a polygenic cause, but the pathogenesis is still unknown. Neurobeachin (NBEA) has recently been identified as a candidate gene for autism in a patient with a de novo chromosomal translocation and three patients with a monoallelic deletion. This multidomain scaffolding protein has been suggested to be involved in neuronal post-Golgi membrane traffic. Knockout of Nbea in two independent mouse models has demonstrated a role in neurotransmitter release and synaptic functioning. Knockdown in a cell line has shown a role as negative regulator of secretion of large dense-core vesicles (LDCVs) and haploinsufficiency in blood platelets results in dense granules with an aberrant morphology. A potential role in vesicle transport is further supported by a study of SEL-2, the C.elegans homologue of NBEA. This protein was identified as a negative regulator of LIN-12/Notch activity, probably due to defects in endosomal trafficking. Members of the Notch pathway have also been shown to be modifiers of the NBEA homologue in Drosophila, rugose. These new insights in the function of NBEA may help identifying novel pathways affected in autistic patients. In particular, it suggests that impaired functionality of LDCVs, which contain neurotrophins, neuropeptides and monoamines, might contribute to the pathogenesis of autism in at least a subgroup of patients.

8. Waga C, Okamoto N, Ondo Y, Fukumura-Kato R, Goto YI, Kohsaka S, Uchino S. {{Novel variants of the SHANK3 gene in Japanese autistic patients with severe delayed speech development}}. {Psychiatr Genet};2011 (Mar 3)

The 22q13.3 deletion syndrome is characterized by a significant delay in language development, mental retardation, hypotonia, and autistic features. Cumulative evidence has shown that haploinsufficiency of the SHANK3 gene is a major cause of the neurological symptoms of the 22q13.3 deletion syndrome. Shank3, a multidomain protein containing the SH3 and PDZ domains, is thought to play an important role in the formation and function of synapses in the developing brain. In this study, we analyzed the SHANK3 gene in 128 autistic patients with manifestations similar to those seen in the 22q13.3 deletion syndrome. The results showed a 6-amino acid deletion upstream of the SH3 domain, a missense variant (arginine to histidine at amino acid position 656) in the PDZ domain, and the insertion or deletion of a repeated 10-bp GC sequence located 9-bp downstream from the 3′ end of exon 11. None of these variants was found in 228 controls.