1. Akshoomoff N, Mattson SN, Grossfeld PD. {{Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q}}. {Genet Med};2014 (Jul 24)
Purpose:Jacobsen syndrome, also called the 11q terminal deletion disorder, is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11. Intellectual skills range from low average to severe/profound intellectual disability and usually correlate with deletion size. Comprehensive genotype/phenotype evaluations are limited, and little is known about specific behavioral characteristics associated with 11q terminal deletion disorder.Methods:In this prospective study, 17 patients with 11q terminal deletion disorder underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization.Results:Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. We found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. There was no correlation between deletion size and the presence of autism spectrum disorder, implicating at least one predisposing gene in the distal 8.7 Mb of 11q. The findings from three additional patients with autistic features and « atypical » distal 11q deletions led to the identification of an autism « critical region » in distal 11q containing four annotated genes including ARHGAP32 (also known as RICS), a gene encoding rho GTPase activating protein.Conclusion:Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.Genet Med advance online publication 24 July 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.86.
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2. Beebe K, Wang Y, Kulesza R. {{Distribution of fragile X mental retardation protein in the human auditory brainstem}}. {Neuroscience};2014 (Jul 25);273:79-91.
Fragile X mental retardation protein (FMRP) binds select mRNAs, functions in intracellular transport of these mRNAs and represses their translation. FMRP is highly expressed in neurons and lack of FMRP has been shown to result in dendritic dysmorphology and altered synaptic function. FMRP is known to interact with mRNAs for the Kv3.1b potassium channel which is required for neurons to fire action potentials at high rates with remarkable temporal precision. Auditory brainstem neurons are known for remarkably high spike rates and expression of Kv3.1b potassium channels. Fragile X syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X mental retardation 1 gene (Fmr1) resulting in decreased expression of FMRP and subsequent intellectual disability, seizures, attention deficit and hypersensitivity to auditory and other sensory stimuli. We therefore hypothesize that the auditory difficulties in FXS result, at least in part, from dysfunction of auditory brainstem neurons. To examine this hypothesis, we have studied normal human brainstem tissue with immunohistochemical techniques and confocal microscopy. Our results demonstrate that FMRP is widely expressed in cell bodies and dendritic arbors of neurons in the human cochlear nucleus and superior olivary complex and also that coincidence detector neurons of the medial superior olive colocalization of FMRP and Kv3.1b. We interpret these observations to suggest that the lower auditory brainstem is a potential site of dysfunction in FXS.
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3. Dimitriou D, Leonard HC, Karmiloff-Smith A, Johnson MH, Thomas MS. {{Atypical development of configural face recognition in children with autism, Down syndrome and Williams syndrome}}. {J Intellect Disabil Res};2014 (Jul 25)
BACKGROUND: Configural processing in face recognition is a sensitivity to the spacing between facial features. It has been argued both that its presence represents a high level of expertise in face recognition, and also that it is a developmentally vulnerable process. METHOD: We report a cross-syndrome investigation of the development of configural face recognition in school-aged children with autism, Down syndrome and Williams syndrome compared with a typically developing comparison group. Cross-sectional trajectory analyses were used to compare configural and featural face recognition utilising the ‘Jane faces’ task. Trajectories were constructed linking featural and configural performance either to chronological age or to different measures of mental age (receptive vocabulary, visuospatial construction), as well as the Benton face recognition task. RESULTS: An emergent inversion effect across age for detecting configural but not featural changes in faces was established as the marker of typical development. Children from clinical groups displayed atypical profiles that differed across all groups. CONCLUSION: We discuss the implications for the nature of face processing within the respective developmental disorders, and how the cross-sectional syndrome comparison informs the constraints that shape the typical development of face recognition.
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4. Gonzales HK, O’Reilly M, Lang R, Sigafoos J, Lancioni G, Kajian M, Kuhn M, Longino D, Rojeski L, Watkins L. {{Research involving anxiety in non-human primates has potential implications for the assessment and treatment of anxiety in autism spectrum disorder: A translational literature review}}. {Dev Neurorehabil};2014 (Jul 24):1-18.
Abstract Objective: The purpose of this translational review (i.e. moving from basic primate research toward possible human applications) was to summarize non-human primate literature on anxiety to inform the development of future assessments of anxiety in non-verbal individuals with autism spectrum disorder (ASD). Methods: Systematic searches of databases identified 67 studies that met inclusion criteria. Each study was analysed and summarised in terms of (a) strategies used to evoke anxiety, (b) non-verbal behavioural indicators of anxiety and (c) physiological indicators of anxiety. Results: Eighteen strategies were used to evoke anxiety, 48 non-verbal behavioural indicators and 17 physiological indicators of anxiety were measured. Conclusions: A number of the strategies used with non-human primates, if modified carefully, could be considered in the ongoing effort to study anxiety in individuals with ASD. Potential applications to the assessment of anxiety in humans with ASD are discussed.
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5. Key AP, Ibanez LV, Henderson HA, Warren Z, Messinger DS, Stone WL. {{Positive Affect Processing and Joint Attention in Infants at High Risk for Autism: An Exploratory Study}}. {J Autism Dev Disord};2014 (Jul 24)
Few behavioral indices of risk for autism spectrum disorders (ASD) are present before 12 months, and potential biomarkers remain largely unexamined. This prospective study of infant siblings of children with ASD (n = 16) and low-risk comparison infants (n = 15) examined group differences in event-related potentials (ERPs) indexing processing of facial positive affect (N290/P400, Nc) at 9 months and their relation to joint attention at 15 months. Group differences were most pronounced for subtle facial expressions, in that the low-risk group exhibited relatively longer processing (P400 latency) and greater attention resource allocation (Nc amplitude). Exploratory analyses found associations between ERP responses and later joint attention, suggesting that attention to positive affect cues may support the development of other social competencies.
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6. Kumari D, Usdin K. {{Polycomb Group Complexes are recruited to reactivated FMR1 alleles in Fragile X syndrome in response to FMR1 transcription}}. {Hum Mol Genet};2014 (Jul 23)
The FMR1 gene is subject to repeat mediated-gene silencing when the CGG-repeat tract in the 5′ UTR exceeds 200 repeat units. This results in Fragile X syndrome, the most common heritable cause of intellectual disability and a major cause of autism-spectrum disorders. The mechanism of gene silencing is not fully understood and efforts to reverse this gene silencing have had limited success. Here we show that the level of trimethylation of histone H3 on lysine 27, a hallmark of the activity of EZH2, a component of repressive Polycomb Group (PcG) complexes like PRC2, is increased on reactivation of the silenced allele by either the DNA demethylating agent 5-azadeoxycytidine or the SIRT1 inhibitor splitomicin. The level of H3K27me3 increases and decreases in parallel with the FMR1 mRNA level. Furthermore, reducing the levels of the FMR1 mRNA reduces the accumulation of H3K27me3. This suggests a model for FMR1 gene silencing in which the FMR1 mRNA generated from the reactivated allele acts in cis to repress its own transcription via the recruitment of PcG Complexes to the FMR1 locus.
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7. Luckhardt C, Jarczok TA, Bender S. {{Elucidating the neurophysiological underpinnings of autism spectrum disorder: new developments}}. {J Neural Transm};2014 (Jul 25)
The study of neurophysiological approaches together with rare and common risk factors for Autism Spectrum Disorder (ASD) allows elucidating the specific underlying neurobiology of ASD. Whereas most neurophysiologically based research in ASD to date has focussed on case-control differences based on the DSM- or ICD-based categorical ASD diagnosis, more recent studies have aimed at studying genetically and/or neurophysiologically defined homogeneous ASD subgroups for specific neuronal biomarkers. This review addresses the neurophysiological investigation of ASD by evoked and event-related potentials, by EEG/MEG connectivity measures such as coherence, and transcranial magnetic stimulation. As an example of classical neurophysiological studies in ASD, we report event-related potential studies which have illustrated which brain areas and processing stages are affected in the visual perception of socially relevant stimuli. However, a paradigm shift has taken place in recent years focussing on how these findings can be tracked down to basic neuronal functions such as deficits in cortico-cortical connectivity and the interaction between brain areas. Disconnectivity, for example, can again be related to genetically induced shifts in the excitation/inhibition balance. Genetic causes of ASD may be grouped by their effects on the brain’s system level to identify ASD subgroups which respond differentially to therapeutic interventions.
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8. Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM. {{Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile x syndrome in a mouse model}}. {J Neurosci};2014 (Jul 23);34(30):9867-9879.
Fmr1 knock-out (ko) mice display key features of fragile X syndrome (FXS), including delayed dendritic spine maturation and FXS-associated behaviors, such as poor socialization, obsessive-compulsive behavior, and hyperactivity. Here we provide conclusive evidence that matrix metalloproteinase-9 (MMP-9) is necessary to the development of FXS-associated defects in Fmr1 ko mice. Genetic disruption of Mmp-9 rescued key aspects of Fmr1 deficiency, including dendritic spine abnormalities, abnormal mGluR5-dependent LTD, as well as aberrant behaviors in open field and social novelty tests. Remarkably, MMP-9 deficiency also corrected non-neural features of Fmr1 deficiency-specifically macroorchidism-indicating that MMP-9 dysregulation contributes to FXS-associated abnormalities outside the CNS. Further, MMP-9 deficiency suppressed elevations of Akt, mammalian target of rapamycin, and eukaryotic translation initiation factor 4E phosphorylation seen in Fmr1 ko mice, which are also associated with other autistic spectrum disorders. These findings establish that MMP-9 is critical to the mechanisms responsible for neural and non-neural aspects of the FXS phenotype.
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9. Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea SH, Malow BA. {{Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay}}. {J Autism Dev Disord};2014 (Jul 25)
Sleep disruption is common in individuals with autism spectrum disorder (ASD). Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in ASD. Genetic factors likely contribute to comorbid expression of sleep disorders in ASD. We studied a clinically unique ASD subgroup, consisting solely of children with comorbid expression of sleep onset delay. We evaluated variation in two melatonin pathway genes, acetylserotonin O-methyltransferase (ASMT) and cytochrome P450 1A2 (CYP1A2). We observed higher frequencies than currently reported (p < 0.04) for variants evidenced to decrease ASMT expression and related to decreased CYP1A2 enzyme activity (p </= 0.0007). We detected a relationship between genotypes in ASMT and CYP1A2 (r2 = 0.63). Our results indicate that expression of sleep onset delay relates to melatonin pathway genes.
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10. Vogan VM, Morgan BR, Lee W, Powell TL, Smith ML, Taylor MJ. {{The neural correlates of visuo-spatial working memory in children with autism spectrum disorder: effects of cognitive load}}. {J Neurodev Disord};2014;6(1):19.
BACKGROUND: Research on the neural bases of cognitive deficits in autism spectrum disorder (ASD) has shown that working memory (WM) difficulties are associated with abnormalities in the prefrontal cortex. However, cognitive load impacts these findings, and no studies have examined the relation between WM load and neural underpinnings in children with ASD. Thus, the current study determined the effects of cognitive load on WM, using a visuo-spatial WM capacity task in children with and without ASD with functional magnetic resonance imaging (fMRI). METHODS: We used fMRI and a 1-back colour matching task (CMT) task with four levels of difficulty to compare the cortical activation patterns associated with WM in children (7-13 years old) with high functioning autism (N = 19) and matched controls (N = 17) across cognitive load. RESULTS: Performance on CMT was comparable between groups, with the exception of one difficulty level. Using linear trend analyses, the control group showed increasing activation as a function of difficulty level in frontal and parietal lobes, particularly between the highest difficulty levels, and decreasing activation as a function of difficulty level in the posterior cingulate and medial frontal gyri. In contrast, children with ASD showed increasing activation only in posterior brain regions and decreasing activation in the posterior cingulate and medial frontal gyri, as a function of difficulty level. Significant differences were found in the precuneus, dorsolateral prefrontal cortex and medial premotor cortex, where control children showed greater positive linear relations between cortical activity and task difficulty level, particularly at the highest difficulty levels, but children with ASD did not show these trends. CONCLUSIONS: Children with ASD showed differences in activation in the frontal and parietal lobes-both critical substrates for visuo-spatial WM. Our data suggest that children with ASD rely mainly on posterior brain regions associated with visual and lower level processing, whereas controls showed activity in frontal lobes related to the classic WM network. Findings will help guide future work by localizing areas of vulnerability to developmental disturbances.
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11. Yucel GH, Belger A, Bizzell J, Parlier M, Adolphs R, Piven J. {{Abnormal Neural Activation to Faces in the Parents of Children with Autism}}. {Cereb Cortex};2014 (Jul 23)
Parents of children with an autism spectrum disorder (ASD) show subtle deficits in aspects of social behavior and face processing, which resemble those seen in ASD, referred to as the « Broad Autism Phenotype » (BAP). While abnormal activation in ASD has been reported in several brain structures linked to social cognition, little is known regarding patterns in the BAP. We compared autism parents with control parents with no family history of ASD using 2 well-validated face-processing tasks. Results indicated increased activation in the autism parents to faces in the amygdala (AMY) and the fusiform gyrus (FG), 2 core face-processing regions. Exploratory analyses revealed hyper-activation of lateral occipital cortex (LOC) bilaterally and right FG in autism parents with aloof personality (« BAP+ ») and autism parents without the aloof personality (« BAP-« ). Findings suggest that abnormalities of the AMY and FG are related to underlying genetic liability for ASD, whereas abnormalities in the LOC and right FG are more specific to behavioral features of the BAP. Results extend our knowledge of neural circuitry underlying abnormal face processing beyond those previously reported in ASD to individuals with shared genetic liability for autism and a subset of genetically related individuals with the BAP.
