1. Beversdorf DQ, Nordgren RE, Bonab AA, Fischman AJ, Weise SB, Dougherty DD, Felopulos GJ, Zhou FC, Bauman ML. {{5-HT2 Receptor Distribution Shown by [18F] Setoperone PET in High-Functioning Autistic Adults}}. {J Neuropsychiatry Clin Neurosci};2012 (Mar 1);24(2):191-197.
The serotonergic system is implicated in disordered emotional behavior. Autism is characterized by impaired processing of emotional information. The serotonergic (5-HT) system is also critically involved in brain development, and abnormal brain synthesis of serotonin is observed in autism. Furthermore, whole blood and platelet serotonin have been reported to be elevated in autism. The authors examined the CNS serotonin system in autism in vivo. 5-HT2 receptors were visualized by PET imaging of [18F]setoperone-binding in this pilot study of 6 high-functioning autistic adults and 10 matched-control participants. Autism subjects had less thalamic [18F]setoperone binding than controls, when covaried for age, but no difference reached significance in other areas. A negative relationship between thalamic binding and history of language impairment was also observed. Further studies will be needed to gain a clearer picture of the role of the 5-HT system in autism.
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2. Fendri-Kriaa N, Rouissi A, Ghorbel R, Mkaouar-Rebai E, Belguith N, Gouider-Khouja N, Fakhfakh F. {{Novel double deletions in the MECP2 gene in Tunisian Rett patient}}. {Gene};2012 (Jul 10);502(2):163-167.
Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively girls. Rett patients present an apparently normal psychomotor development during the first 6-18months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. RTT is currently considered as monogenic X-linked dominant disorder due to mutations in the MECP2 gene, encoding the methyl-CpG binding protein 2. The aim of this study was to perform a mutational analysis of the MECP2 gene in a classical Rett patient.The results showed the presence of a novel point mutation c.C1142T (p.P381L) and two deletions at the heterozygous state: a novel deletion c.1075delTTC (p.S359) and a known one c.1157del44 (p.L386Q fs X2) in the C-terminal region of MeCP2.
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3. Gallagher S, Whiteley J. {{Social support is associated with blood pressure responses in parents caring for children with developmental disabilities}}. {Res Dev Disabil};2012 (Jul 6);33(6):2099-2105.
The present study tested whether parents caring for children with developmental disabilities would have higher blood pressure compared to parents of typically developing children (controls). It also examined the psychosocial factors underlying this observation. Thirty-five parents of children with developmental disability and thirty controls completed standard measures of perceived stress, child challenging behaviours and social support and wore an ambulatory blood pressure (BP) monitor throughout the day, for one day. Relative to controls, parents caring for children with developmental disabilities reported poorer psychosocial functioning and had a higher mean systolic BP. Of the psychosocial predictors, only social support was found to be predictive. Moreover, variations in social support accounted for some of the between group differences with the beta for parental group attenuated from .42 to .34 in regression analyses. It appears that social support may influence blood pressure responses in parental caregivers. Finally, our findings underscore the importance of providing psychosocial interventions to improve the health of family caregivers.
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4. Greimel E, Nehrkorn B, Schulte-Ruther M, Fink GR, Nickl-Jockschat T, Herpertz-Dahlmann B, Konrad K, Eickhoff SB. {{Changes in grey matter development in autism spectrum disorder}}. {Brain Struct Funct};2012 (Jul 10)
Results on grey matter (GM) structural alterations in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about age effects on brain-structure abnormalities in ASD beyond childhood. Here, we aimed to examine regional GM volumes in a large sample of children, adolescents, and adults with ASD. Magnetic resonance imaging scans were obtained in 47 male ASD subjects and 51 matched healthy controls aged 8-50 years. We used whole-brain voxel-based morphometry to first assess group differences in regional GM volume across age. Moreover, taking a cross-sectional approach, group differences in age effects on regional GM volume were investigated. Compared to controls, ASD subjects showed reduced GM volumes in the anterior cingulate cortex, posterior superior temporal sulcus, and middle temporal gyrus. Investigation of group differences in age effects on regional GM volume revealed complex, region-specific alterations in ASD. While GM volumes in the amygdala, temporoparietal junction, septal nucleus and middle cingulate cortex increased in a negative quadratic fashion in both groups, data indicated that GM volume curves in ASD subjects were shifted to the left along the age axis. Moreover, while GM volume in the right precentral gyrus decreased linearly with age in ASD individuals, GM volume development in controls followed a U-shaped pattern. Based on a large sample, our voxel-based morphometry results on group differences in regional GM volumes help to resolve inconclusive findings from previous studies in ASD. Results on age-related changes of regional GM volumes suggest that ASD is characterized by complex alterations in lifetime trajectories of several brain regions that underpin social-cognitive and motor functions.
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5. Grether JK, Qian Y, Croughan MS, Wu YW, Schembri M, Camarano L, Croen LA. {{Is Infertility Associated with Childhood Autism?}}. {J Autism Dev Disord};2012 (Jul 10)
Concerns persist about a possible link between infertility and risk of autism spectrum disorders (ASD). Interpretation of existing studies is limited by racial/ethnic homogeneity of study populations and other factors. Using a case-control design, we evaluated infertility history and treatment documented in medical records of members of Kaiser Permanente Northern California. Among singletons (349 cases, 1,847 controls), we found no evidence to support an increase in risk of ASD associated with infertility. Among multiple births (21 cases, 54 controls), we found an increased risk associated with infertility history and with infertility evaluations and treatment around the time of index pregnancy conception; however, small sample size and lack of detailed data on treatments preclude firm interpretation of results for multiple births.
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6. Kim KY, Jung YW, Sullivan GJ, Chung L, Park IH. {{Cellular reprogramming: a novel tool for investigating autism spectrum disorders}}. {Trends Mol Med};2012 (Jul 6)
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in reciprocal social interaction and communication, as well as the manifestation of stereotyped behaviors. Despite much effort, ASDs are not yet fully understood. Advanced genetics and genomics technologies have recently identified novel ASD genes, and approaches using genetically engineered murine models or postmortem human brain have facilitated understanding ASD. Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) provides unprecedented opportunities in generating human disease models. Here, we present an overview of applying iPSCs in developing cellular models for understanding ASD. We also discuss future perspectives in the use of iPSCs as a source of cell therapy and as a screening platform for identifying small molecules with efficacy for alleviating ASD.
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7. Mondal K, Ramachandran D, Patel VC, Hagen KR, Bose P, Cutler DJ, Zwick ME. {{Excess Variants in AFF2 Detected by Massively Parallel Sequencing of Males with Autism Spectrum Disorder}}. {Hum Mol Genet};2012 (Jul 5)
Autism spectrum disorder (ASD) is a heterogeneous disorder with substantial heritability, most of which is unexplained. ASD has a population prevalence of one percent and affects four times as many males as females. Patients with fragile X E (FRAXE) intellectual disability, which is caused by a silencing of the X-linked gene AFF2, display a number of ASD-like phenotypes. Duplications and deletions at the AFF2 locus have also been reported in cases with moderate ID and ASD. We hypothesized that other rare X-linked sequence variants at the AFF2 locus might contribute to ASD. We sequenced the AFF2 genomic region in 202 male ASD probands and found that 2.5% of males sequenced had missense mutations at highly conserved evolutionary sites. When compared to the frequency of missense mutations in 5545 X chromosomes from unaffected controls, we saw a statistically significant enrichment in patients with ASD (OR: 4.9; p < 0.014). In addition, we identified rare AFF2 3′ UTR variants at conserved sites which alter gene expression in a luciferase assay. These data suggest that rare variation in AFF2 may be a previously unrecognized ASD susceptibility locus and may help explain some of the male excess of ASD.
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8. Saunders J, Gandal MJ, Roberts TP, Siegel SJ. {{NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders}}. {Behav Brain Res};2012 (Jul 5)
Autism is a highly disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors. There are few effective biological treatments for this disorder, partly due to the lack of translational biomarkers. However, recent data suggest that autism has reliable electrophysiological endophenotypes, along with evidence that some deficits may be caused by NMDA receptor (NMDAR) dysfunction. Similarly, the NMDAR antagonist MK801 has been used in behavioral animal models of autism. Since MK801 has also been used as a model of schizophrenia, this paper examines the independent and overlapping ways in which MK801 recreates the electrophysiogical changes present in both diseases. Mouse EEG was recorded in response to auditory stimuli after either vehicle or MK801 and the dose-response relationship for each measure was determined. ERP component amplitude and latency analysis was performed along with time-frequency analysis of gamma frequency inter-trial coherence and evoked power. Evoked gamma power and ITC were decreased by MK801 at the highest dose. P1, N1 latency and gamma baseline power were increased in dose dependent fashion following MK801. There were no amplitude changes in P1 or N1. MK801 caused alterations in evoked gamma activity, gamma ITC, gamma baseline power, P1 and N1 latency similar to findings in autism. These data provide evidence indicating that NMDAR dysfunction may contribute to deficits specific to autism and some that overlap with other disorders such as schizophrenia. Such observations could be important for developing novel therapeutics, as electrophysiological endophenotypes associate with functional measures and may provide early biomarkers for efficacy in clinical trials.
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9. Tavassoli T, Auyeung B, Murphy LC, Baron-Cohen S, Chakrabarti B. {{Variation in the autism candidate gene GABRB3 modulates tactile sensitivity in typically developing children}}. {Mol Autism};2012 (Jul 6);3(1):6.
ABSTRACT: BACKGROUND: Autism spectrum conditions have a strong genetic component. Atypical sensory sensitivities are one of the core but neglected features of autism spectrum conditions. GABRB3 is a well-characterised candidate gene for autism spectrum conditions. In mice, heterozygous Gabrb3 deletion is associated with increased tactile sensitivity. However, no study has examined if tactile sensitivity is associated with GABRB3 genetic variation in humans. To test this, we conducted two pilot genetic association studies in the general population, analysing two phenotypic measures of tactile sensitivity (a parent-report and a behavioural measure) for association with 43 SNPs in GABRB3. FINDINGS: Across both tactile sensitivity measures, three SNPs (rs11636966, rs8023959 and rs2162241) were nominally associated with both phenotypes, providing a measure of internal validation. Parent-report scores were nominally associated with six SNPs (P <0.05). Behaviourally measured tactile sensitivity was nominally associated with 10 SNPs (three after Bonferroni correction). CONCLUSIONS: This is the first human study to show an association between GABRB3 variation and tactile sensitivity. This provides support for the evidence from animal models implicating the role of GABRB3 variation in the atypical sensory sensitivity in autism spectrum conditions. Future research is underway to directly test this association in cases of autism spectrum conditions.
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10. Yang Y, Wang C, Wang F, Zhu L, Liu H, He X. {{Novel chromosomal translocation t(11;9)(p15;p23) involving deletion and duplication of 9p in a girl associated with autism and mental retardation}}. {Gene};2012 (Jul 10);502(2):154-158.
We describe a 5-year-old girl presented with autism and mental retardation features. Conventional karyotyping revealed a novel unidirectional translocation t(11;9)(p15;p23). HumanCytoSNP-12 Chip analysis identified a 13Mb deletion from 9p24.3 to 9p23 and a 12.5Mb duplication from 9p23 to 9p21.2. The karyotype was described as 45,XX,psu dic(11; 9)(p15;p23), which was reported for the first time here. The deleted region, extending from 9p24.3 to 9p23, overlaps with the candidate region for monosomy 9p syndrome and contains a potential autism spectrum disorders (ASD) locus. The duplication region extending from 9p23 to 9p21.2 was previously identified as a critical region for the 9p duplication syndrome. These results suggested that the apparently balanced de novo translocations could produce cryptic deletions or duplications, and the precise mapping of the abnormal area may improve clinical management.
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11. Zakareia FA, Al-Ayadhi LY, Al-Drees AA. {{Study of dual angiogenic/neurogenic growth factors among Saudi autistic children and their correlation with the severity of this disorder}}. {Neurosciences (Riyadh)};2012 (Jul);17(3):213-218.
OBJECTIVE: To investigate the role of 2 angiogenic/neurogenic growth factors, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) in Saudi children with autism. METHODS: The study included a total of 60 children that included 20 controls and 40 patients with a confirmed diagnosis of autism. The study was conducted in the Department of Physiology, Faculty of Medicine, King Saud University, and in the Autism Research and Treatment Center, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between May 2010 and April 2011. Collected blood plasma samples were analyzed for VEGF and PDGF. RESULTS: The levels of VEGF showed a non-significant change in autistic children compared with the control children (p=0.065). The levels of PDGF were significantly higher in autistic children compared with the control children (p=0.01). Furthermore, this increase was significantly more pronounced in children with severe autism as compared with children with mild autism (p=0.001), and it was not correlated to the severity of the disorder. CONCLUSION: A rise in PDGF may contribute to the pathophysiology of the disorder, either alone or in synergy with other neurotrophic factors to induce an angiogenic-neuroprotective effect. Plasma VEGF has no causative or compensatory contribution to the pathology of this disorder.
