1. Ceylan AC, Citli S, Erdem HB, Sahin I, Acar Arslan E, Erdogan M. {{Importance and usage of chromosomal microarray analysis in diagnosing intellectual disability, global developmental delay, and autism; and discovering new loci for these disorders}}. {Molecular cytogenetics}. 2018; 11: 54.
Background: Chromosomal microarray analysis is a first-stage test that is used for the diagnosis of intellectual disability and global developmental delay. Chromosomal microarray analysis can detect well-known microdeletion syndromes. It also contributes to the identification of genes that are responsible for the phenotypes in the new copy number variations. Results: Chromosomal microarray analysis was conducted on 124 patients with intellectual disability and global developmental delay. Multiplex ligation-dependent probe amplification was used for the confirmation of chromosome 22q11.2 deletion/duplication. 26 pathogenic and likely pathogenic copy number variations were detected in 23 patients (18.55%) in a group of 124 Turkish patients with intellectual disability and global developmental delay. Chromosomal microarray analysis revealed pathogenic de novo Copy number variations, such as a novel 2.9-Mb de novo deletion at 18q22 region with intellectual disability and autism spectrum disorder, and a 22q11.2 region homozygote duplication with new clinical features. Conclusion: Our data expand the spectrum of 22q11.2 region mutations, reveal new loci responsible from autism spectrum disorder and provide new insights into the genotype-phenotype correlations of intellectual disability and global developmental delay.
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2. Demetriou EA, Song CY, Park SH, Pepper KL, Naismith SL, Hermens DF, Hickie IB, Thomas EE, Norton A, White D, Guastella AJ. {{Autism, Early Psychosis, and Social Anxiety Disorder: a transdiagnostic examination of executive function cognitive circuitry and contribution to disability}}. {Translational psychiatry}. 2018; 8(1): 200.
The disability burden in clinical cohorts with social impairment is significant, leading to poor functional outcomes. Some of this impairment has been linked to executive dysfunction. In this study, a transdiagnostic approach was taken to identify executive function (EF) processes in young adults that may underpin social impairment and to evaluate their contribution to disability. Comparisons were made between three prominent disorders that are characterized by social impairments, Autism Spectrum Disorder (ASD), Early Psychosis (EP) and Social Anxiety Disorder (SAD), as well as a neurotypically developing group (TYP). We examined whether overall disability could be predicted by neuropsychological and self-report assessments of EF. Our study showed that ASD participants demonstrated impaired performance on most domains of EF compared to the TYP group (mental flexibility, sustained attention and fluency) while the EP group showed impairment on sustained attention and attentional shifting. The SAD participants showed EF impairment on self-report ratings, even though their objective performance was intact. Self-reports of EF explained a significant percentage (17%) of disability in addition to the variance explained by other predictors, and this was particularly important for ASD. This is the first study to compare EF measures across clinical groups of social impairment and suggests unique cognitive-circuitry that underpins disability within groups. Impairments in EF were broad in ASD and predicted disability, EP impairments were specific to attentional processes and SAD impairments likely relate to negative self-monitoring. Self-report, as opposed to performance-based EF, provided best capacity to predict disability. These findings contribute to transdiagnostic circuitry models and intervention strategies.
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3. Frantz MC, Pellissier LP, Pflimlin E, Loison S, Gandia J, Marsol C, Durroux T, Mouillac B, Becker JAJ, Le Merrer J, Valencia C, Villa P, Bonnet D, Hibert M. {{LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism}}. {Journal of medicinal chemistry}. 2018.
Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V1a and V2 vasopressin receptor subtypes (V1a-R and V2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure-affinity and structure-efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.
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4. Goel A, Cantu DA, Guilfoyle J, Chaudhari GR, Newadkar A, Todisco B, de Alba D, Kourdougli N, Schmitt LM, Pedapati E, Erickson CA, Portera-Cailliau C. {{Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible}}. {Nature neuroscience}. 2018; 21(10): 1404-11.
To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1(-/-)) mouse model of Fragile X syndrome. Using a go/no-go task and in vivo two-photon calcium imaging, we find that impaired visual discrimination in Fmr1(-/-) mice correlates with marked deficits in orientation tuning of principal neurons and with a decrease in the activity of parvalbumin interneurons in primary visual cortex. Restoring visually evoked activity in parvalbumin cells in Fmr1(-/-) mice with a chemogenetic strategy using designer receptors exclusively activated by designer drugs was sufficient to rescue their behavioral performance. Strikingly, human subjects with Fragile X syndrome exhibit impairments in visual discrimination similar to those in Fmr1(-/-) mice. These results suggest that manipulating inhibition may help sensory processing in Fragile X syndrome.
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5. Hughes HK, Rose D, Ashwood P. {{The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders}}. {Current neurology and neuroscience reports}. 2018; 18(11): 81.
PURPOSE OF REVIEW: There is a growing body of evidence indicating the gut microbiota influence neurodevelopment and behavior. The purposes of this review are to provide an overview of studies analyzing the microbiota and their metabolites in autism spectrum disorders (ASD) and to discuss the possible mechanisms of action involved in microbial influence on the brain and behavior. RECENT FINDINGS: The microbiota-gut-brain (MGB) axis has been extensively studied in animal models, and it is clear that alterations in the composition of microbiota alter neurological and behavioral outcomes. However, findings in human studies are less abundant. Although there are several studies so far showing altered microbiota (dysbiosis) in ASD, the results are heterogeneous and often contradictory. Intervention studies such as fecal microbiota transplant therapies show promise and lend credence to the involvement of the microbiota in ASD. A role for the microbiota in ASD is likely; however, further studies elucidating microbial or metabolomic signatures and mechanisms of action are needed. Future research should focus on intervention studies that can identify specific metabolites and immune mediators that improve with treatment to help identify etiologies and pathological mechanisms of ASD.
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6. Jachyra P, Anagnostou E, Knibbe TJ, Petta C, Cosgrove S, Chen L, Capano L, Moltisanti L, McPherson AC. {{« Girls don’t have big tummies »: The experiences of weight-related discussions for children with autism spectrum disorders}}. {Autism : the international journal of research and practice}. 2018: 1362361318793020.
Children with autism spectrum disorders appear to be at a higher risk of having obesity than their typically developing peers. Although it has been recommended that healthcare providers speak to children with autism spectrum disorders about the potential health risks of unhealthy weight, no previous research has explored how healthcare providers communicate with them about this topic. The purpose of this study was to explore children’s perspectives and experiences of discussing weight-related topics in healthcare consultations. Eight children were interviewed, and an interpretive phenomenological analysis informed the research approach and analysis of the data. Results indicated that weight-related discussions with healthcare providers were often met with trepidation, anxiety, anger, and frustration. Children also expressed that they experienced weight stigma in clinical visits and everyday interactions. Weight stigma was often (unwittingly) projected by healthcare providers during appointments and had debilitating effects on children. Finally, higher weights emerged as a repetitive/restricted interest, and children reported body image challenges regarding their higher weights. Frameworks and tools that are specific to the needs and abilities of children with autism spectrum disorders are needed for healthcare providers to foster positive conversations about weight-related topics in an effort to promote lifelong wellness.
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7. Kentrou V, de Veld DM, Mataw KJ, Begeer S. {{Delayed autism spectrum disorder recognition in children and adolescents previously diagnosed with attention-deficit/hyperactivity disorder}}. {Autism : the international journal of research and practice}. 2018: 1362361318785171.
Phenotypic elements of autism spectrum disorder can be masked by attention-deficit/hyperactivity disorder symptoms, potentially leading to a misdiagnosis or delaying an autism spectrum disorder diagnosis. This study explored differences in the age of autism spectrum disorder diagnosis between participants with previously diagnosed attention-deficit/hyperactivity disorder versus autism spectrum disorder-only respondents. Children and adolescents, but not adults, initially diagnosed with attention-deficit/hyperactivity disorder received an autism spectrum disorder diagnosis an average of 1.8 years later than autism spectrum disorder-only children, although the findings regarding the adult sample should be interpreted with caution. Gender differences were also explored, revealing that the delay in receiving an autism diagnosis was 1.5 years in boys and 2.6 years in girls with pre-existing attention-deficit/hyperactivity disorder, compared with boys and girls without prior attention-deficit/hyperactivity disorder. No significant gender differences were observed in the adult sample. We argue that overlapping symptoms between autism spectrum disorder and attention-deficit/hyperactivity disorder might delay a formal diagnosis of autism either by leading to a misdiagnosis of attention-deficit/hyperactivity disorder or by making it difficult to identify the presence of co-occurring autism spectrum disorder conditions once an initial diagnosis of attention-deficit/hyperactivity disorder has been obtained. Current findings highlight the need to recruit multidimensional and multidisciplinary screening procedures to assess for potential emerging autism spectrum disorder hallmarks in children and adolescents diagnosed or presenting with attention-deficit/hyperactivity disorder symptoms.
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8. Lamy M, Erickson CA. {{Pharmacological management of behavioral disturbances in children and adolescents with autism spectrum disorders}}. {Current problems in pediatric and adolescent health care}. 2018.
Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition that, based on recent CDC estimates affects an estimated 1 in 59 American children. Behavioral treatments remain the mainstay of treatment for the core symptoms of ASD including communication deficits, social interaction deficits and repetitive behavior. However, youth with ASD may also have severe behavioral challenges including irritability, aggression, and hyperactivity. Currently there are only two medications (risperidone and aripiprazole) approved by the FDA for the treatment of irritability associated with ASD in children. Psychiatric comorbidities are common in youth with ASD, affecting up to 70% of affected children and adolescents. Given the burden of co-occurring disorders, medications are often employed to target symptoms such as irritability, anxiety, and hyperactivity. Other common co-occurring conditions including gastrointestinal disorders and sleep disorders may be improved with pharmacologic management. Evidence for the efficacy of many commonly used psychotropic medications in ASD is limited by the lack of large placebo-controlled trials in youth with ASD. This paper reviews the current literature regarding use of medications to address co-occurring conditions in children and adolescents with ASD as well as areas of emerging research.
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9. Loper PL, Jr. {{The Electronic Health Record and Acquired Physician Autism}}. {JAMA pediatrics}. 2018.
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10. Lundin A, Kosidou K, Dalman C. {{Measuring Autism Traits in the Adult General Population with the Brief Autism-Spectrum Quotient, AQ-10: Findings from the Stockholm Public Health Cohort}}. {Journal of autism and developmental disorders}. 2018.
BACKGROUND: The autism-spectrum quotient scale was developed to study autism as a spectrum. Few studies have examined the psychometric properties of the 10 item AQ (AQ-10). We examine the AQ-10 measurement ability and convergent validity in a population health survey (n = 44,722). METHODS: The item severity and item discrimination was assessed using item response theory. Convergent validity was assessed by regressing on ADHD, psychological distress (PD) and having an education in the sciences. RESULTS: Whilst unidimensional, the AQ-10 had some poorly fitting items. Item discrimination ranged from very low to very high. The scale correlated as hypothesised with the regress expected when factoring in ADHD, PD and possessing an eduction in the sciences. CONCLUSION: The AQ-10 has adequate validity in the present sample and may be used in s as a measure of autistic traits. In Conclusion, The AQ-10 has adequate validity to be used in health surveys as a measure of autistic traits, although some items may perform poorly.
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11. Morello N, Schina R, Pilotto F, Phillips M, Melani R, Plicato O, Pizzorusso T, Pozzo-Miller L, Giustetto M. {{Loss of Mecp2 Causes Atypical Synaptic and Molecular Plasticity of Parvalbumin-Expressing Interneurons Reflecting Rett Syndrome-Like Sensorimotor Defects}}. {eNeuro}. 2018; 5(5).
Rett syndrome (RTT) is caused in most cases by loss-of-function mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MECP2). Understanding the pathological processes impacting sensory-motor control represents a major challenge for clinical management of individuals affected by RTT, but the underlying molecular and neuronal modifications remain unclear. We find that symptomatic male Mecp2 knockout (KO) mice show atypically elevated parvalbumin (PV) expression in both somatosensory (S1) and motor (M1) cortices together with excessive excitatory inputs converging onto PV-expressing interneurons (INs). In accordance, high-speed voltage-sensitive dye imaging shows reduced amplitude and spatial spread of synaptically induced neuronal depolarizations in S1 of Mecp2 KO mice. Moreover, motor learning-dependent changes of PV expression and structural synaptic plasticity typically occurring on PV(+) INs in M1 are impaired in symptomatic Mecp2 KO mice. Finally, we find similar abnormalities of PV networks plasticity in symptomatic female Mecp2 heterozygous mice. These results indicate that in Mecp2 mutant mice the configuration of PV(+) INs network is shifted toward an atypical plasticity state in relevant cortical areas compatible with the sensory-motor dysfunctions characteristics of RTT.
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12. Nadeem A, Ahmad SF, Al-Harbi NO, Attia SM, Alshammari MA, Al-Zahrani KS, Bakheet SA. {{Increased oxidative stress in the cerebellum and peripheral immune cells leads to exaggerated autism-like repetitive behavior due to deficiency of antioxidant response in BTBR T+tf/J mice}}. {Progress in neuro-psychopharmacology & biological psychiatry}. 2018.
Autism is a neurodevelopmental disorder that affects social cognitive abilities resulting in communication or sensory deficits, and stereotyped behaviors in millions of people worldwide. Oxidant-antioxidant imbalance contributes significantly to the neurobehavioral dysregulations and severity of symptoms in patients with autism, however it has not been explored earlier whether it affects autism-like behavior directly. Therefore, we investigated oxidant-antioxidant balance in peripheral immune cells (neutrophils and CD3+ T cells) and cerebellum of BTBR T+tf/J (BTBR) mice which show autism-like behavior and the social C57BL/6J (C57) mice. Further, we utilized buthionine sulfoximine (BSO), a glutathione depleting agent to assess the impact of oxidant-antioxidant dysregulation on autism-like behavior. Our study shows that BTBR mice have increased lipid/protein oxidation products in cerebellum and neutrophils/CD3+ T cells along with increased NADPH oxidase (NOX2) and inducible nitric oxide synthase (iNOS) expression. This was concurrent with lower levels of glutathione and enzymatic antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the cerebellum and peripheral immune cells. BSO administration led to further lowering of glutathione with a concurrent upregulation of iNOS, and NOX2 in cerebellum and peripheral immune cells. However, there was deficiency of an adaptive antioxidant response which was associated with exaggerated repetitive behaviors in BTBR mice. On the other hand, C57 mice also had increased oxidative stress after BSO treatment, however there was an enzymatic antioxidant response both in cerebellum and periphery. Overall, this study suggests that BTBR mice have increased oxidative stress with a deficient enzymatic antioxidant response that is associated with autism-like repetitive behaviors.
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13. Raghavan R, Zuckerman B, Hong X, Wang G, Ji Y, Paige D, DiBari J, Zhang C, Fallin MD, Wang X. {{Fetal and Infancy Growth Pattern, Cord and Early Childhood Plasma Leptin, and Development of Autism Spectrum Disorder in the Boston Birth Cohort}}. {Autism research : official journal of the International Society for Autism Research}. 2018.
Leptin is a proinflammatory cytokine that plays an important role in energy homeostasis. Emerging evidence suggests that leptin levels are altered in children with autism spectrum disorder (ASD); however, this has not been studied prospectively. Rapid growth during infancy and early childhood has been implicated in ASD, but the evidence is inconsistent. As leptin is involved in growth and is a potential risk factor for ASD, we explored the associations between (a) cord, early childhood leptin and ASD; and (b) birth weight for gestational age, early childhood weight gain, and ASD. We also assessed the mediating role of leptin in the relationship between weight gain during infancy and ASD. This study was conducted in a sample of 822 subjects from the Boston Birth Cohort. ASD was defined from diagnostic codes in electronic medical records. Extremely rapid weight gain during infancy was associated with a greater ASD risk and this persisted after adjusting for potential confounders (aOR: 3.11; 95% CI: 1.37, 7.07). Similarly, children that had higher plasma leptin levels, prior to ASD diagnosis, had an increased ASD risk in both unadjusted and adjusted models (aOR: 7.87; 95% CI: 2.06, 30.04). Further, early childhood leptin indirectly mediated the relationship between rapid weight gain and ASD. No associations were found between birth weight for gestational age, cord leptin and risk of ASD. Our findings provide a basis to further explore whether the combination of early life growth pattern and a biomarker such as leptin can predict ASD earlier. LAY SUMMARY: Is early life growth and a biomarker leptin related to ASD risk? To answer this question, we followed 822 children from birth and found that those who gained weight very quickly in infancy, had higher leptin levels in early childhood, had a greater chance of later ASD diagnosis. More research is needed to see if infant’s weight gain pattern along with a biomarker (such as leptin) can be used to identify children with ASD sooner.
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14. Schulz SE, Stevenson RA. {{Sensory hypersensitivity predicts repetitive behaviours in autistic and typically-developing children}}. {Autism : the international journal of research and practice}. 2018: 1362361318774559.
The objective of this study was to examine the relationship between sensory hypersensitivity and restricted interests and repetitive behaviours associated with autism spectrum disorder and their typically-developing peers. Furthermore, the aims included the examination of the relationship across sensory modalities and various types of restricted interests and repetitive behaviours. Data were collected from the parents of 114 children: 49 of whom were diagnosed with autism spectrum disorder and 65 typically-developing children. Parents completed the Sensory Profile 2 – Child Version and the Repetitive Behaviours Questionnaire, Second Edition. The results suggested that sensory hypersensitivity is strongly related to the core autism spectrum disorder symptom of repetitive behaviours. This relationship was not specific to autism spectrum disorder; repetitive behaviours significantly increased with sensory hypersensitivity in typically-developing individuals as well. This effect was consistent across all modalities in both autism spectrum disorder and typically developing groups; group differences were observed in the oral and tactile modalities. Furthermore, sensory hypersensitivity was significantly predictive of repetitive behaviours in all participants, autism spectrum disorder and typically-developing, and importantly, autism spectrum disorder diagnosis did not add any predictive influence above and beyond sensory hypersensitivity. Finally, sensory hypersensitivity was significantly predictive of all subdomains of repetitive behaviours, including repetitive motor movements, rigidity and adherence to routine, preoccupation with restricted patterns of interest and unusual sensory interests, and diagnosis added no predictive ability beyond sensory hypersensitivity.
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15. Tillmann J, Swettenham J. {{Contrasting the Effects of Task Difficulty and Perceptual Load on Auditory Detection Sensitivity in Individuals with Autism}}. {Journal of autism and developmental disorders}. 2018.
To test a central assumption of the increased perceptual capacity account in individuals with Autism Spectrum Disorder (ASD), the effects of perceptual load and target-stimulus degradation on auditory detection sensitivity were contrasted. Fourteen adolescents with ASD and 16 neurotypical controls performed a visual letter search task under three conditions: low perceptual load, high perceptual load and low perceptual load with a degraded target while simultaneously detecting an auditory tone in noise. For both participants with ASD and neurotypical controls, increasing perceptual load and target degradation increased task difficulty as indexed by reaction times and accuracy. However, only increasing perceptual load reduced subsequent auditory detection sensitivity. The study confirms that perceptual load, and not task difficulty, modulates selective attention in ASD.
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16. Varman DR, Soria-Ortiz MB, Martinez-Torres A, Reyes-Haro D. {{GABArho3 expression in lobule X of the cerebellum is reduced in the valproate model of autism}}. {Neuroscience letters}. 2018.
Autism spectrum disorder (ASD) is a group of developmental disorders characterized by social interaction deficits, communication impairments, and stereotyped and repetitive behaviors. Additionally, impairments in the GABAergic circuitry have been associated with ASD. Several studies have shown that dysfunction of the cerebellum is a hallmark of ASD, and postmortem studies in humans reported a reduced density of Purkinje cells (PCs) together with an abnormal expression of GABA-A subunits, among which GABArho3 is expressed in early postnatal development, forms homomeric receptors with high affinity to the agonist (GABA EC50 ~ 3 muM) and desensitize very little upon activation. Thus, we tested if the expression of GABArho3 was modified by prenatal exposure to valproate (VPA), a well-known murine model of autism. The latency to find the nest increased in VPA-treated mice when compared to controls at postnatal day 8 (P8). Immunofluorescence studies showed a reduced expression of GABArho3 in Purkinje cells (PCs) and ependymal glial cells (EGCs) from lobule X of VPA-treated mice. Finally, the expression of GABArho3 increases linearly throughout normal development of the cerebellum, but this pattern is disrupted in the VPA model of autism. We conclude that the expression of GABArho3 is reduced in PCs and EGCs from lobule X of the cerebellum in the VPA model of autism. Thus, GABArho3 may be a relevant marker for ASD etiology.
