1. Amaral DG. {{The promise and the pitfalls of autism research: an introductory note for new autism researchers}}. {Brain Res};2010 (Nov 30)
2. Betancur C. {{Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting}}. {Brain Res};2010 (Nov 30)
There is increasing evidence that autism spectrum disorders (ASDs) can arise from rare highly penetrant mutations and genomic imbalances. The rare nature of these variants, and the often differing orbits of clinical and research geneticists, can make it difficult to fully appreciate the extent to which we have made progress in understanding the genetic etiology of autism. In fact, there is a persistent view in the autism research community that there are only a modest number of autism loci known. We carried out an exhaustive review of the clinical genetics and research genetics literature in an attempt to collate all genes and recurrent genomic imbalances that have been implicated in the etiology of ASD. We provide data on 103 disease genes and 44 genomic loci reported in subjects with ASD or autistic behavior. These genes and loci have all been causally implicated in intellectual disability, indicating that these two neurodevelopmental disorders share common genetic bases. A genetic overlap between ASD and epilepsy is also apparent in many cases. Taken together, these findings clearly show that autism is not a single clinical entity but a behavioral manifestation of tens or perhaps hundreds of genetic and genomic disorders. Increased recognition of the etiological heterogeneity of ASD will greatly expand the number of target genes for neurobiological investigations and thereby provide additional avenues for the development of pathway-based pharmacotherapy. Finally, the data provide strong support for high-resolution DNA microarrays as well as whole-exome and whole-genome sequencing as critical approaches for identifying the genetic causes of ASDs.
3. Cochrane LE, Tansey KE, Gill M, Gallagher L, Anney RJ. {{Lack of association between markers in the ITGA3, ITGAV, ITGA6 and ITGB3 and autism in an Irish sample}}. {Autism Res};2010 (Dec 3)
Autism is a neurodevelopmental disorder characterized by impairments in three core areas-language, social interaction and restricted/repetitive behaviours. It is generally accepted that genetics plays a large role in the aetiology of autism, but the exact mechanism is still unknown. We recently published evidence of an association between autism and the ITGA4 gene [Conroy et al., 2008]. Two genomic regions have shown evidence of linkage to autism in multiple studies- 2q31-q33 and 17q21-q22. Both of these regions harbour multiple integrin subunit genes. We tested markers in ITGA3, ITGA6, ITGAV and ITGB3 for association with autism in the Irish autism sample. No markers in ITGA3, ITGA6, ITGAV and ITGB3 were found to be associated with autism. Three 3-marker haplotypes in ITGAV, ITGA3 and ITGA6 were found to be nominally associated (0.01<P<0.05) and to have unremarkable findings. Our data indicates that in the Irish autism sample the integrin genes tested here do not play an important role in the aetiology of autism.
4. Eagleson KL, Campbell DB, Thompson BL, Bergman MY, Levitt P. {{The autism risk genes MET and PLAUR differentially impact cortical development}}. {Autism Res};2010 (Dec 3)
Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Met(fx/fx)/ Dlx5/6(cre) mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Met(fx/fx)/ Dlx5/6(cre) mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements.
5. Gandal MJ, Edgar JC, Ehrlichman RS, Mehta M, Roberts TP, Siegel SJ. {{Validating gamma Oscillations and Delayed Auditory Responses as Translational Biomarkers of Autism}}. {Biol Psychiatry};2010 (Dec 15);68(12):1100-1106.
BACKGROUND: Difficulty modeling complex behavioral phenotypes in rodents (e.g., language) has hindered pathophysiological investigation and treatment development for autism spectrum disorders. Recent human neuroimaging studies, however, have identified functional biomarkers that can be more directly related to the abnormal neural dynamics of autism spectrum disorders. This study assessed the translational potential of auditory evoked-response endophenotypes of autism in parallel mouse and human studies of autism. METHODS: Whole-cortex magnetoencephalography was recorded in 17 typically developing and 25 autistic children during auditory pure-tone presentation. Superior temporal gyrus activity was analyzed in time and frequency domains. Auditory evoked potentials were recorded in mice prenatally exposed to valproic acid (VPA) and analyzed with analogous methods. RESULTS: The VPA-exposed mice demonstrated selective behavioral alterations related to autism, including reduced social interactions and ultrasonic vocalizations, increased repetitive self-grooming, and prepulse inhibition deficits. Autistic subjects and VPA-exposed mice showed a similar 10% latency delay in the N1/M100 evoked response and a reduction in gamma frequency (30-50 Hz) phase-locking factor. Electrophysiological measures were associated with mouse behavioral deficits. In mice, gamma phase-locking factor was correlated with expression of the autism risk gene neuroligin-3 and neural deficits were modulated by the mGluR5-receptor antagonist MPEP. CONCLUSIONS: Results demonstrate a novel preclinical approach toward mechanistic understanding and treatment development for autism.
6. Gor RA, Fuhrer J, Schober JM. {{A retrospective observational study of enuresis, daytime voiding symptoms, and response to medical therapy in children with attention deficit hyperactivity disorder and autism spectrum disorder}}. {J Pediatr Urol};2010 (Dec 3)
INTRODUCTION: Children with attention deficit hyperactivity disorder (ADHD) show an increased prevalence of enuresis and other daytime voiding symptoms (DVS). There is also some evidence toward an increased prevalence of enuresis among children with autism spectrum disorder (ASD), but with no data available with respect to DVS or response to medical treatment. The aim of this study was to assess enuresis and DVS, along with treatment outcomes, in children with ASD, to aid urological management. METHODS: A retrospective observational study on the incidence of enuresis and other DVS in 671 children with/without ADHD/ASD was performed. Symptomatic improvement >/=50% was required to be considered positive. Complete resolution of symptoms for 3 months after cessation of treatment was considered cure. RESULTS: Symptomatic improvement with desmopressin or anticholinergic treatment was seen in 76% of patients without ADHD/ASD, 85% of patients with ADHD, and 100% of patients with ASD. Cure was seen in 61% of patients without ADHD/ASD, 48% of patients with ADHD, and 50% patients with ASD. Mean time to cure was 9 months in those without ADHD/ASD (N = 319), 10 months in those with ADHD (N = 62), and 8 months in those with ASD (N = 10) (P = 0.69). CONCLUSION: Despite the small sample size of patients with ASD, our data show a favorable trend toward efficacy of desmopressin and anticholinergic therapy in these children with enuresis and DVS.
7. Jou RJ, Jackowski AP, Papademetris X, Rajeevan N, Staib LH, Volkmar FR. {{Diffusion tensor imaging in autism spectrum disorders: preliminary evidence of abnormal neural connectivity}}. {Aust N Z J Psychiatry};2010 (Dec 6)
Objective: This study indirectly tested the hypothesis that individuals with autism spectrum disorders (ASDs) have impaired neural connections between the amygdala, fusiform face area, and superior temporal sulcus, key processing nodes of the ‘social brain’. This would be evidenced by abnormalities in the major fibre tracts known to connect these structures, including the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus. Method: Magnetic resonance diffusion tensor imaging was performed on 20 right-handed males (ASD = 10, controls = 10) with a mean age 13.5 +/- 4.0 years. Subjects were group-matched according to age, full-scale IQ, handedness, and ethnicity. Fractional anisotropy was used to assess structural integrity of major fibre tracts. Voxel-wise comparison of white matter fractional anisotropy was conducted between groups using ANCOVA adjusting for age, full-scale IQ, and brain volume. Volumes of interest were identified using predetermined probability and cluster thresholds. Follow-up tractography was performed to confirm the anatomic location of all volumes of interest which were observed primarily in peri-callosal regions and the temporal lobes. Results: The regions of lower fractional anisotropy, as confirmed by tractography, involved the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and corpus callosum/cingulum. Notably, some volumes of interest were adjacent to the fusiform face area, bilaterally, corresponding to involvement of the inferior longitudinal fasciculus. The largest effect sizes were noted for volumes of interest in the right anterior radiation of the corpus callosum/cingulum and right fusiform face area (inferior longitudinal fasciculus). Conclusions: This study provides preliminary evidence of impaired neural connectivity in the corpus callosum/cingulum and temporal lobes involving the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus and superior longitudinal fasciculus in ASDs. These findings provide preliminary support for aberrant neural connectivity between the amygdala, fusiform face area, and superior temporal sulcus-temporal lobe structures critical for normal social perception and cognition.
8. Lintas C, Sacco R, Persico AM. {{Genome-wide expression studies in Autism spectrum disorder, Rett syndrome, and down syndrome}}. {Neurobiol Dis};2010 (Dec 2)
Though different in their aetiology, Autism Spectrum Disorder (ASD), Rett Syndrome (RTT) and Down Syndrome (DS) are three neurodevelopmental disorders sharing significant clinical and neuropathological overlaps. Genome-wide expression studies are reviewed and available datasets from post-mortem brains reanalyzed, to identify genes and gene pathways dysregulated in all three disorders. Our results surprisingly converge upon immune, and not neurodevelopmental genes, as the most consistently shared abnormality in genome-wide expression patterns. A dysregulated immune response, accompanied by enhanced oxidative stress and abnormal mitochondrial metabolism seemingly represents the common molecular underpinning of these neurodevelopmental disorders. This conclusion may be important for the definition of pharmacological therapies able to ameliorate clinical symptoms across these disorders.
9. Shic F, Bradshaw J, Klin A, Scassellati B, Chawarska K. {{Limited Activity Monitoring in Toddlers with Autism Spectrum Disorder}}. {Brain Res};2010 (Nov 30)
This study used eye-tracking to examine how 20-month old toddlers with autism spectrum disorder (ASD) (N=28), typical development (TD) (N=34), and non-autistic developmental delays (DD) (N=16) monitored the activities occurring in a context of an adult-child play interaction. Toddlers with ASD, in comparison to control groups, showed less attention to the activities of others and focused more on background objects (e.g. toys). In addition, while all groups spent the same time overall looking at people, toddlers with ASD looked less at people’s heads and more at their bodies. In ASD, these patterns were associated with cognitive deficits and greater autism severity. These results suggest that the monitoring of the social activities of others is disrupted early in the developmental progression of autism, limiting future avenues for observational learning.
10. Spengler S, Bird G, Brass M. {{Hyperimitation of actions is related to reduced understanding of others’ minds in autism spectrum conditions}}. {Biol Psychiatry};2010 (Dec 15);68(12):1148-1155.
BACKGROUND: Anecdotal evidence has noted that individuals with autism spectrum conditions (ASC) frequently exhibit heightened spontaneous imitative behavior, with symptoms of echolalia and echopraxia. This is contrasted by empiric reports that ASC results in decreased imitation and an underlying deficit in the mirror system, leading to impaired social understanding. Thus, it remains unclear whether automatic imitation is enhanced in ASC and how this is related to poorer social abilities. METHODS: This study investigated spontaneous imitation in 18 high-functioning adults with ASC and 18 age- and IQ-matched control participants during a simple imitation inhibition task. Mentalizing was experimentally assessed in the same participants using both behavioral and functional magnetic resonance imaging measures, as was social interaction using an observational measure. RESULTS: Individuals with ASC showed increased imitation of hand actions compared with control participants and this was associated with reduced mentalizing and poorer reciprocal social interaction abilities. In the functional magnetic resonance imaging mentalizing paradigm, ASC participants with increased imitation scores showed less brain activation in areas often found to be active in mental state attribution, namely the medial prefrontal cortex and temporoparietal junction. CONCLUSIONS: The results confirm the presence of hyperimitation in ASC, which is accompanied by reduced social cognition, suggesting that a general imitation impairment and a global mirror system deficit are absent. These findings offer an explanation for echopractic features based on theories of atypical functioning of top-down modulation processes in autism.
11. Stigler KA, McDonald BC, Anand A, Saykin AJ, McDougle CJ. {{Structural and Functional Magnetic Resonance Imaging of Autism Spectrum Disorders}}. {Brain Res};2010 (Dec 2)
PURPOSE: The neurobiology of autism spectrum disorders (ASDs) has become increasingly understood since the advent of magnetic resonance imaging (MRI). This review summarizes relevant structural and functional MRI studies in ASDs to date. RESULTS: Initial observations of an above-average head circumference were supported by structural MRI studies that found evidence of increased total brain volume and early rapid brain overgrowth in affected individuals. Subsequent research revealed consistent abnormalities in cortical gray and white matter volume in ASDs. The structural integrity and orientation of white matter has been further elucidated via diffusion tensor imaging methods. The emergence of functional MRI techniques led to an enhanced understanding of the neural circuitry of ASDs, demonstrating areas of dysfunctional cortical activation and atypical cortical specialization. These studies have provided evidence of underconnectivity in distributed cortical networks integral to the core impairments associated with ASDs. Abnormalities in the default mode network during the resting state have also been identified. CONCLUSIONS: Structural and functional MRI research has generated important insights into the neurobiology of ASDs. Additional research is needed to further delineate the underlying brain basis of this constellation of disorders.
12. Sumiyoshi C, Kawakubo Y, Suga M, Sumiyoshi T, Kasai K. {{Impaired ability to organize information in individuals with autism spectrum disorders and their siblings}}. {Neurosci Res};2010 (Nov 30)
Despite rigorous research on disturbances of executive function and social cognition in autism spectrum disorders (ASD), little information has been available concerning higher cognitive functions, such as the ability to focus and associate relevant features to form categories, or ‘organizing of information’, in individuals with ASD and their siblings. The purpose of this study was to investigate this issue by using the Wisconsin Card Sorting Test (WCST) and the Verbal Learning Task (VLT). Cognitive assessments were conducted in 22 individuals with ASD, 14 non-affected siblings, and 15 age-matched control subjects. Overall, individuals with ASD performed significantly worse on the WCST and VLT compared to their siblings and normal control subjects. Although siblings performed generally well on both tasks, they exhibited similar degree of perseverative responses in the WCST compared to the probands. A linear increase of the memory organization score in the VLT was not also observed in siblings as well as the ASD group. These results suggest an impaired ability to organize information is one of the cognitive endophenotypes for ASD.
