1. Bergman NJ. {{Hypothesis on supine sleep, sudden infant death syndrome reduction and association with increasing autism incidence}}. {World J Clin Pediatr};2016 (Aug 8);5(3):330-342.
AIM: To identify a hypothesis on: Supine sleep, sudden infant death syndrome (SIDS) reduction and association with increasing autism incidence. METHODS: Literature was searched for autism spectrum disorder incidence time trends, with correlation of change-points matching supine sleep campaigns. A mechanistic model expanding the hypothesis was constructed based on further review of epidemiological and other literature on autism. RESULTS: In five countries (Denmark, United Kingdom, Australia, Israel, United States) with published time trends of autism, change-points coinciding with supine sleep campaigns were identified. The model proposes that supine sleep does not directly cause autism, but increases the likelihood of expression of a subset of autistic criteria in individuals with genetic susceptibility, thereby specifically increasing the incidence of autism without intellectual disability. CONCLUSION: Supine sleep is likely a physiological stressor, that does reduce SIDS, but at the cost of impact on emotional and social development in the population, a portion of which will be susceptible to, and consequently express autism. A re-evaluation of all benefits and harms of supine sleep is warranted. If the SIDS mechanism proposed and autism model presented can be verified, the research agenda may be better directed, in order to further decrease SIDS, and reduce autism incidence.
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2. Connor SA, Ammendrup-Johnsen I, Chan AW, Kishimoto Y, Murayama C, Kurihara N, Tada A, Ge Y, Lu H, Yan R, LeDue JM, Matsumoto H, Kiyonari H, Kirino Y, Matsuzaki F, Suzuki T, Murphy TH, Wang YT, Yamamoto T, Craig AM. {{Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2}}. {Neuron};2016 (Sep 7);91(5):1052-1068.
Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.
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3. de Sonneville LM, Hidding E, van Engeland H, Vorstman JA, Sijmens-Morcus ME, Swaab H. {{Executive functioning and its relation to ASD and ADHD symptomatology in 22q11.2 deletion syndrome}}. {Child Neuropsychol};2016 (Sep 9):1-19.
Children with 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial-syndrome) are at risk for the developmental disorders, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this study, the relation between executive functioning (EF) and the severity of ADHD and ASD symptoms is examined, since EF is known to be important in relation to emotional and behavioral problems. The participants consist of 58 children (38 females) with a mean age of 13.5 years (SD 2.6). Standardized assessment was used to evaluate the severity of ASD and ADHD symptomatology. The major aspects of EF, i.e., cognitive flexibility, inhibition, sustained attention, distractibility, working memory and reaction speed, were evaluated. The profile of EF in 22q11DS was found to be characterized by weaker performance compared to the norms on all subdomains of EF. Poor cognitive flexibility and inhibition, as well as high distractibility, were found to be related to more severe ASD symptoms, while poor quality of sustained attention and high distractibility were found to be related to more severe ADHD symptoms. It is concluded that children with 22q11DS experience impairments in EF, and that the degree of impairment on specific EF subdomains is related to the severity of ASD and/or ADHD symptomatology. These results may help in defining the mediating role of neurocognitive dysfunctions in the development of social and behavioral problems in 22q11DS.
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4. Flores-Pajot MC, Ofner M, Do MT, Lavigne E, Villeneuve PJ. {{Childhood autism spectrum disorders and exposure to nitrogen dioxide, and particulate matter air pollution: A review and meta-analysis}}. {Environ Res};2016 (Aug 25)
BACKGROUND AND OBJECTIVE: Genetic and environmental factors have been recognized to play an important role in autism. The possibility that exposure to outdoor air pollution increases the risk of autism spectrum disorder (ASD) has been an emerging area of research. Herein, we present a systematic review, and meta-analysis of published epidemiological studies that have investigated these associations. METHODS: We undertook a comprehensive search strategy to identify studies that investigated outdoor air pollution and autism in children. Overall, seven cohorts and five case-control studies met our inclusion criteria for the meta-analysis. We summarized the associations between exposure to air pollution and ASD based on the following critical exposure windows: (i) first, second and third trimester of pregnancy, (ii) entire pregnancy, and (iii) postnatal period. Random effects meta-analysis modeling was undertaken to derive pooled risk estimates for these exposures across the studies. RESULTS: The meta-estimates for the change in ASD associated with a 10mug/m3 increase in exposure in PM2.5 and 10 ppb increase in NO2 during pregnancy were 1.34 (95% CI:0.83, 2.17) and 1.05 (95% CI:0.99, 1.11), respectively. Stronger associations were observed for exposures received after birth, but these estimates were unstable as they were based on only two studies. O3 exposure was weakly associated with ASD during the third trimester of pregnancy and during the entire pregnancy, however, these estimates were also based on only two studies. CONCLUSION: Our meta-analysis support the hypothesis that exposure to ambient air pollution is associated with an increased risk of autism. Our findings should be interpreted cautiously due to relatively small number of studies, and several studies were unable to control for other key risk factors.
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5. Haessler F, Gaese F, Huss M, Kretschmar C, Brinkman M, Peters H, Elstner S, Colla M, Pittrow D. {{Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study}}. {BMC Psychiatry};2016;16(1):318.
BACKGROUND: As data on the phenotype, characteristics and management of patients with Fragile X Syndrome (FXS) are limited, we aimed to collect such data in Germany in experienced centres involved in the treatment of such patients. METHODS: EXPLAIN-FXS is a prospective observational (non-interventional) study (registry) performed between April 2013 and January 2016 at 18 sites in Germany. Requirements for patient participation included confirmed diagnosis of FXS by genetic testing (>200 CGG repeats) and written informed consent. Patients were followed for up to 2 years. RESULTS: Seventy-five patients (84.0 % males, mean age 16.7 +/- 14.5 years, ranging from 2 – 82 years) were analysed. The mean 6-item score, determined according to Giangreco (J Pediatr 129:611-614, 1996), was 6.9 +/- 2.5 points. At least one neurological finding each was noted in 53 patients (69.7 %). Specifically, ataxia was noted in 5 patients (6.6 %), lack of fine motor skills in 40 patients, (52.6 %), muscle tonus disorder in 4 patients (5.3 %), and other neurological disorders in 39 patients (51.3 %). Spasticity was not noted in any patient. Seizures were reported in 6 patients (8.1 %), anxiety disorders in 22 patients (30.1 %), depression in 7 patients (9.6 %), ADHD/ADD in 36 patients (49.3 %), impairment of social behavior in 39 patients (53.4 %), and other comorbidities in 23 patients (31.5 %). The mean Aberrant Behaviour Checklist Community Edition (ABC-C) score on behavioral symptoms, obtained in 71 patients at first documentation, was 48.4 +/- 27.8 (median 45.0, range 5-115). The mean visual analogue scale (VAS) score, obtained in 59 patients at first documentation, was 84.9 +/- 14.6 points (median 90; range 50 – 100). CONCLUSIONS: This report describes the largest cohort of patients with FXS in Europe. The reported observations indicate a substantial burden of disease for patients and their caregivers. Based on these observations, an early expert psychiatric diagnosis is recommended for suspected FXS patients. Further recommendations include multimodal and multi-professional management that is tailored to the individual patient’s needs. TRIAL REGISTRATION: The ClinTrials.gov identifier is NCT01711606 . Registered on 18 October 2012.
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6. Liu S, Qiu S, Lu Y, Kanu JS, Li R, Bai Y, Zhu X, Lei J, Xu N, Yu Y, Liu Y, Jiang H. {{The rs251684 Variant of PLA2G4C Is Associated with Autism Spectrum Disorder in the Northeast Han Chinese Population}}. {Genet Test Mol Biomarkers};2016 (Sep 9)
AIM: To investigate the association between autism spectrum disorder (ASD) and the phospholipase A2 group IVC (PLA2G4C) and phospholipase A2 group XIIA (PLA2G12A) polymorphisms in the Northeast Han Chinese population. MATERIALS AND METHODS: A total of 68 family trios (children diagnosed with ASD and their unaffected parents) were enrolled. Five single-nucleotide polymorphisms (SNPs) (rs9226, rs1045376, rs251684, rs2307279, and rs156631) in PLA2G4C and four SNPs (rs6533451, rs2285714, rs2285713, and rs11728699) in PLA2G12A were selected and genotyped. The association between the SNPs and ASD was analyzed using the transmission disequilibrium test. RESULTS: Our results showed a significant association between ASD and the rs251684 variant of PLA2G4C (transmitted/nontransmitted = 36/21, chi2 = 3.947, p = 0.047), but no association between ASD and the other eight SNPs investigated (all p > 0.05). Moreover, we found no preference in the transmission of haplotypes constructed for either PLA2G4C or PLA2G12A. CONCLUSION: The rs251684 polymorphism of PLA2G4C may be associated with ASD risk.
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7. Martin A, Quintin EM, Hall SS, Reiss AL. {{The Role of Executive Function in Independent Living Skills in Female Adolescents and Young Adults With Fragile X Syndrome}}. {Am J Intellect Dev Disabil};2016 (Sep);121(5):448-460.
Fragile X syndrome (FXS) is associated with executive function (EF) and independent living skills (ILS) deficits. We examined the role of childhood EF in ILS during adolescence/early adulthood in females with FXS and two comparison groups in the same age range (matched for IQ [IQ/Age group] and with another genetic condition, Turner syndrome [TS group]). EF and ILS were significantly higher for the FXS group than the IQ/Age group but did not differ from the TS group. For the FXS group, age and EF were significant predictors of ILS during adolescence/early adulthood, but there were no statistically significant longitudinal associations between EF and ILS. Our findings suggest that impairments in EF may have a significant effect on ILS in FXS.
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8. Provenzano G, Corradi Z, Monsorno K, Fedrizzi T, Ricceri L, Scattoni ML, Bozzi Y. {{Comparative Gene Expression Analysis of Two Mouse Models of Autism: Transcriptome Profiling of the BTBR and En2 (-/-) Hippocampus}}. {Front Neurosci};2016;10:396.
Autism spectrum disorders (ASD) are characterized by a high degree of genetic heterogeneity. Genomic studies identified common pathological processes underlying the heterogeneous clinical manifestations of ASD, and transcriptome analyses revealed that gene networks involved in synapse development, neuronal activity, and immune function are deregulated in ASD. Mouse models provide unique tools to investigate the neurobiological basis of ASD; however, a comprehensive approach to identify transcriptional abnormalities in different ASD models has never been performed. Here we used two well-recognized ASD mouse models, BTBR T(+) Itpr3 (tf) /J (BTBR) and Engrailed-2 knockout (En2 (-/-)), to identify conserved ASD-related molecular signatures. En2 (-/-) mice bear a mutation within the EN2 transcription factor homeobox, while BTBR is an inbred strain with unknown genetic defects. Hippocampal RNA samples from BTBR, En2 (-/-) and respective control (C57Bl/6J and En2 (+/+)) adult mice were assessed for differential gene expression using microarrays. A total of 153 genes were similarly deregulated in the BTBR and En2 (-/-) hippocampus. Mouse phenotype and gene ontology enrichment analyses were performed on BTBR and En2 (-/-) hippocampal differentially expressed genes (DEGs). Pathways represented in both BTBR and En2 (-/-) hippocampal DEGs included abnormal behavioral response and chemokine/MAP kinase signaling. Genes involved in abnormal function of the immune system and abnormal synaptic transmission/seizures were significantly represented among BTBR and En2 (-/-) DEGs, respectively. Interestingly, both BTBR and En2 (-/-) hippocampal DEGs showed a significant enrichment of ASD and schizophrenia (SCZ)-associated genes. Specific gene sets were enriched in the two models: microglial genes were significantly enriched among BTBR DEGs, whereas GABAergic/glutamatergic postsynaptic genes, FMRP-interacting genes and epilepsy-related genes were significantly enriched among En2 (-/-) DEGs. Weighted correlation network analysis (WGCNA) performed on BTBR and En2 (-/-) hippocampal transcriptomes together identified six modules significantly enriched in ASD-related genes. Each of these modules showed a specific enrichment profile in neuronal and glial genes, as well as in genes associated to ASD comorbidities such as epilepsy and SCZ. Our data reveal significant transcriptional similarities and differences between the BTBR and En2 (-/-) hippocampus, indicating that transcriptome analysis of ASD mouse models may contribute to identify novel molecular targets for pharmacological studies.
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9. Puts NA, Wodka EL, Harris AD, Crocetti D, Tommerdahl M, Mostofsky SH, Edden RA. {{Reduced GABA and altered somatosensory function in children with autism spectrum disorder}}. {Autism Res};2016 (Sep 9)
Sensory (e.g., touch) abnormalities are common in children with autism spectrum disorder (ASD). In previous work we have shown that children with ASD have altered sensitivity to touch. This altered sensitivity is specific to tasks that involve filtering and habituation to touch. GABA is the main inhibitory neurotransmitter in the human brain, and plays a key role in encoding touch. Previous studies suggest that the GABA system is altered in ASD. Using magnetic resonance spectroscopy (MRS), it is now possible to measure GABA levels in the human brain. Recent MRS work suggests that GABA levels are reduced in ASD. In this study we investigated whether brain GABA levels are altered in ASD and whether changes in brain GABA levels can predict differences in tactile sensitivity. Our results suggest that GABA levels are reduced in sensorimotor areas, but not in occipital visual areas. Lower GABA levels are associated with less « filtering » of touch information, and are not associated with habituation in ASD, whereas they are in typically developing children. Further research is necessary to elucidate the specific GABAergic mechanisms altered in ASD. Our results suggest that reduced brain GABA levels could underlie altered tactile function in ASD, and that altered GABA function in ASD disrupts the link between GABA and behavior. Understanding the link between brain GABA and tactile behavior is an important step in understanding brain behavior links in ASD, potentially leading to future therapies to reduce the severity of sensory symptoms.
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10. Sperdin HF, Schaer M. {{Aberrant Development of Speech Processing in Young Children with Autism: New Insights from Neuroimaging Biomarkers}}. {Front Neurosci};2016;10:393.
From the time of birth, a newborn is continuously exposed and naturally attracted to human voices, and as he grows, he becomes increasingly responsive to these speech stimuli, which are strong drivers for his language development and knowledge acquisition about the world. In contrast, young children with autism spectrum disorder (ASD) are often insensitive to human voices, failing to orient and respond to them. Failure to attend to speech in turn results in altered development of language and social-communication skills. Here, we review the critical role of orienting to speech in ASD, as well as the neural substrates of human voice processing. Recent functional neuroimaging and electroencephalography studies demonstrate that aberrant voice processing could be a promising marker to identify ASD very early on. With the advent of refined brain imaging methods, coupled with the possibility of screening infants and toddlers, predictive brain function biomarkers are actively being examined and are starting to emerge. Their timely identification might not only help to differentiate between phenotypes, but also guide the clinicians in setting up appropriate therapies, and better predicting or quantifying long-term outcome.
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11. Vivanti G, Hocking DR, Fanning P, Dissanayake C. {{Social affiliation motives modulate spontaneous learning in Williams syndrome but not in autism}}. {Mol Autism};2016;7(1):40.
BACKGROUND: Children with autism spectrum disorder (ASD) and those with Williams syndrome (WS) have difficulties with learning, though the nature of these remains unclear. METHODS: In this study, we used novel eye-tracking and behavioral paradigms to measure how 36 preschoolers with ASD and 21 age- and IQ-matched peers with WS attend to and learn novel behaviors (1) from the outcomes of their own actions (non-social learning), (2) through imitation of others’ actions (social learning), and across situations in which imitative learning served either an instrumental function or fulfilled social affiliation motives. RESULTS: The two groups demonstrated similar abilities to learn from the consequences of their own actions and to imitate new actions that were instrumental to the achievement of a tangible goal. Children with WS, unlike those with ASD, increased their attention and imitative learning performance when the model acted in a socially engaging manner. CONCLUSIONS: Learning abnormalities in ASD appear to be linked to the social rather than instrumental dimensions of learning.
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12. Zuckerman KE, Lindly OJ, Sinche B. {{Parent Beliefs About the Causes of Learning and Developmental Problems Among Children With Autism Spectrum Disorder: Results From a National Survey}}. {Am J Intellect Dev Disabil};2016 (Sep);121(5):432-447.
This study aimed to assess variation in parent beliefs about causes of learning and developmental problems in U.S. children with autism spectrum disorder, using data from a nationally representative survey. Results showed that beliefs about a genetic/hereditary cause of learning/developmental problems were most common, but nearly as many parents believed in exposure causes. Forty present of parents had no definite causal beliefs. On multivariate analysis, parents who were non-White, publicly insured or poor were more likely than other parents to endorse exposure causes, or less likely to endorse genetic causes, compared to other parents. Further research should assess how these beliefs modify health care quality or services use.
