1. Abu Diab M, Eiges R. {{The Contribution of Pluripotent Stem Cell (PSC)-Based Models to the Study of Fragile X Syndrome (FXS)}}. {Brain Sci}. 2019; 9(2).
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a deficiency in the fragile X mental retardation protein (FMRP) due to a CGG repeat expansion in the 5′-UTR of the X-linked FMR1 gene. When CGGs expand beyond 200 copies, they lead to epigenetic gene silencing of the gene. In addition, the greater the allele size, the more likely it will become unstable and exhibit mosaicism for expansion size between and within tissues in affected individuals. The timing and mechanisms of FMR1 epigenetic gene silencing and repeat instability are far from being understood given the lack of appropriate cellular and animal models that can fully recapitulate the molecular features characteristic of the disease pathogenesis in humans. This review summarizes the data collected to date from mutant human embryonic stem cells, induced pluripotent stem cells, and hybrid fusions, and discusses their contribution to the investigation of FXS, their key limitations, and future prospects.
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2. Aljehany MS, Bennett KD. {{A Comparison of Video Prompting to Least-to-Most Prompting among Children with Autism and Intellectual Disability}}. {J Autism Dev Disord}. 2019.
Students with autism spectrum disorder (ASD) and intellectual disability (ID) may experience challenges when learning tasks that are complex and require numerous steps. This difficulty can lead to employment issues for this population of learners. Therefore, researchers have explored methods to teach employment-related tasks to students with ASD and ID. Two such procedures are video prompting (VP) and least-to-most prompting. These procedures are frequently combined as an intervention package to boost student responding. The purpose of this study was to explore which of these interventions was more effective and efficient when used to teach office tasks to individuals with ASD and ID. Three adolescent students participated in this study. Using the adapted alternating treatments design, we found that VP was more effective and efficient for two participants, whereas least-to-most prompting was more effective but less efficient for the remaining participant. Implications for research and practice are discussed.
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3. Bitsika V, Arnold WA, Sharpley CF. {{The Role of Sensory Features in Mediating Associations Between Autism Symptoms and Anxiety in Boys with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2019.
To investigate possible correlates of generalised anxiety disorder (GAD) in young males with ASD, a test of the mediation effects of sensory features (SF) upon the association between ASD symptoms and GAD was conducted with 150 males aged 6 to 18 years. GAD data were obtained from parents of the boys and from the boys themselves; SF and ASD data were obtained from parents. Symptoms of ASD were found to influence elevated levels of parent-rated GAD indirectly through greater levels of sensory avoiding, and auditory-specific sensory behaviours correlated with parent-rated anxiety more strongly than other sensory modalities. There were no significant effects for the boys’ self-rated GAD.
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4. Bobrowska-Korczak B, Gatarek P, Rosiak A, Giebultowicz J, Kaluzna-Czaplinska J. {{Reduced levels of modified nucleosides in the urine of autistic children. Preliminary studies}}. {Analytical biochemistry}. 2019.
The aim of this study was to investigate and compare the levels of concentration of modified nucleosides in the urine of autistic and healthy children. The compounds have never been analyzed before. The levels of nucleosides in the urine of both groups were determined by validated high performance liquid chromatography coupled to mass spectrometry (LC-MS/MS) method using multiple reaction monitoring (MRM) mode. Chromatographic separation was achieved with HILIC column and tubercidin was used as the internal standard for the quantification of urinary nucleosides. The within run accuracy and precision ranged from 89 to 106% and from 0.8% to 4.9%, respectively. Lower levels of O-methylguanosine, 7-methylguanosine, 1-methyladenosine, 1-methylguanine, 7-methylguanine and 3-methyladenine in the urine of 22 children with autism, aged 3 to 16 were observed. The differences were not observed in 20 healthy volunteers, in a similar age group. These findings show that modified nucleosides there are metabolic disturbances and nutritional deficiencies in autistic children.
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5. Dreaver J, Thompson C, Girdler S, Adolfsson M, Black MH, Falkmer M. {{Success Factors Enabling Employment for Adults on the Autism Spectrum from Employers’ Perspective}}. {J Autism Dev Disord}. 2019.
Employment outcomes for individuals with autism spectrum disorder (ASD) are poor and there is limited understanding on how best to support individuals with ASD in the workplace. Stakeholders involved in the employment of adults with ASD, including employers and employment service providers have unique insights into the factors influencing employment for this population. Organisational and individual factors facilitating successful employment for adults with ASD across Australia and Sweden were explored, including the supports and strategies underpinning employment success from an employers’ perspective. Three themes including Knowledge and Understanding of ASD, Work Environment and Job Match emerged, suggesting that a holistic approach was key to supporting success, with employer knowledge and understanding of ASD underpinning their ability to facilitate employment.
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6. Gohel D, Sripada L, Prajapati P, Singh K, Roy M, Kotadia D, Tassone F, Charlet-Berguerand N, Singh R. {{FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS]}}. {Biochimica et biophysica acta Molecular basis of disease}. 2019.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats (premutation) in FMR1. These CGG repeats are Repeat Associated non-ATG (RAN) translated into a small and pathogenic protein, FMRpolyG. The cellular and molecular mechanisms of FMRpolyG toxicity are unclear. Various mitochondrial dysfunctions have been observed in FXTAS patients and animal models. However, the causes of these mitochondrial alterations are not well understood. In the current study, we investigated interaction of FMRpolyG with mitochondria and its role in modulating mitochondrial functions. Beside nuclear inclusions, FMRpolyG also formed small cytosolic aggregates that interact with mitochondria both in cell and mouse model of FXTAS. Importantly, expression of FMRpolyG reduces ATP levels, mitochondrial transmembrane potential, mitochondrial supercomplexes assemblies and activities and expression of mitochondrial DNA encoded transcripts in cell and animal models of FXTAS, as well as in FXTAS patient brain tissues. Overall, these results suggest that FMRpolyG alters mitochondrial functions, bioenergetics and initiates cell death. The further study in this direction will help to establish the role of mitochondria in FXTAS conditions.
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7. Morrison KE, Pinkham AE, Kelsven S, Ludwig K, Penn DL, Sasson NJ. {{Psychometric evaluation of social cognitive measures for adults with autism}}. {Autism Res}. 2019.
Although social cognition is frequently identified as a target in clinical trials and psychosocial interventions for adults with autism spectrum disorder (ASD), these efforts are hampered by a lack of consensus and validation of social cognitive measures. The current study provides psychometric evaluation of 11 frequently used measures encompassing different subdomains of social cognition. Adults with autism (N = 103) and typically developing controls (N = 95) completed 11 commonly used social cognitive tasks spanning the domains of emotion processing, social perception, and mentalizing/theory of mind. We examined each measure’s internal reliability and sensitivity to group differences, how performance related to general intellectual ability, and alignment of measures with a proposed two-factor structure of social cognition in ASD. Controls outperformed the ASD group on 8 of the 11 social cognitive tasks, with the largest group differences occurring on two mentalizing measures, The awareness of social inference task (TASIT) and hinting task. In ASD, all tasks demonstrated strong internal consistency and avoided ceiling and floor effects. Social cognitive performance was also related to, but not redundant with, intellectual functioning. We also found support for a two-factor structure of social cognition, with basic social perception and emotional processing aligning into a lower-order social perception factor, while mentalizing tasks aligned into a higher-order social appraisal factor. In sum, eight tasks showed adequate to strong psychometric properties. The psychometric data, effect size estimates, and correlations between measures reported here can be used for study planning for social cognitive interventions in autism. Autism Res 2019, 999: 1-13. (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: We examined 11 tasks that measure how adults with autism perceive and interpret social information. Eight of the tasks were reliable and showed lower performance in adults with autism compared to typically-developing controls. Task performance was related to but distinguishable from IQ. These measures evaluated here may be useful in assessing the effectiveness of interventions and treatments to improve social abilities in adults with autism.
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8. Sato J, Kato A, Takeda S, Nishikawa H. {{Case report: Atrioventricular block after transcatheter atrial septal closure using the Figulla(R) Flex II ASD occluder}}. {Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions}. 2019.
We report a 7-year-old male patient who developed severe atrioventricular block after transcatheter closure of the atrial septal defect with an Occlutech Figulla(R) Flex II ASD occluder (FSO). He had a small aortic rim and the defect measuring 22.3 mm by balloon sizing. When a 24 mm FSO was deployed, he developed Wenckebach second-degree heart block; however, it recovered to sinus rhythm. Hence, the device was implanted. The rhythm deteriorated to a fixed 2:1 heart block within 7 hr. He underwent surgical retrieval of the device and closure of the defect. Intraoperative findings demonstrated the right atrium disk compressing the triangle of Koch, resulting in a small hematoma. The rhythm recovered completely by 7 days after the surgery. Care must be taken when a relatively large device is deployed in a patient with small rims as even « soft and flexible » device like the FSO can injure the endocardium.
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9. Sears JC, Choi WJ, Broadie K. {{Fragile X mental retardation protein positively regulates PKA anchor Rugose and PKA activity to control actin assembly in learning/memory circuitry}}. {Neurobiology of disease}. 2019.
Recent work shows Fragile X Mental Retardation Protein (FMRP) drives the translation of very large proteins (>2000 aa) mediating neurodevelopment. Loss of function results in Fragile X syndrome (FXS), the leading heritable cause of intellectual disability (ID) and autism spectrum disorder (ASD). Using the Drosophila FXS disease model, we discover FMRP positively regulates the translation of the very large A-Kinase Anchor Protein (AKAP) Rugose (>3000 aa), homolog of ASD-associated human Neurobeachin (NBEA). In the central brain Mushroom Body (MB) circuit, where Protein Kinase A (PKA) signaling is necessary for learning/memory, FMRP loss reduces Rugose levels and targeted FMRP over-expression elevates Rugose levels. Using a new in vivo transgenic PKA activity reporter (PKA-SPARK), we find FMRP loss reduces PKA activity in MB Kenyon Cells whereas FMRP overexpression elevates PKA activity. Consistently, loss of Rugose reduces PKA activity, but Rugose overexpression has no independent effect. A well-established PKA output is regulation of F-actin cytoskeleton dynamics. In the FXS disease model, F-actin is aberrantly accumulated in MB lobes and single MB Kenyon cells. Consistently, Rugose loss results in similar F-actin accumulation. Moreover, targeted FMRP, Rugose and PKA overexpression all result in increased F-actin accumulation in the MB circuit. These findings uncover a FMRP-Rugose-PKA mechanism regulating actin cytoskeleton. This study reveals a novel FMRP mechanism controlling neuronal PKA activity, and demonstrates a shared mechanistic connection between FXS and NBEA associated ASD disease states, with a common link to PKA and F-actin misregulation in brain neural circuits. SIGNIFICANCE STATEMENT: Autism spectrum disorder (ASD) arises from a wide array of genetic lesions, and it is therefore critical to identify common underlying molecular mechanisms. Here, we link two ASD states; Neurobeachin (NBEA) associated ASD and Fragile X syndrome (FXS), the most common inherited ASD. Using established Drosophila disease models, we find Fragile X Mental Retardation Protein (FMRP) positively regulates translation of NBEA homolog Rugose, consistent with a recent advance showing FMRP promotes translation of very large proteins associated with ASD. FXS exhibits reduced cAMP induction, a potent activator of PKA, and Rugose/NBEA is a PKA anchor. Consistently, we find brain PKA activity strikingly reduced in both ASD models. We discover this pathway regulation controls actin cytoskeleton dynamics in brain neural circuits.
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10. Vaughan S, McGlone F, Poole H, Moore DJ. {{A Quantitative Sensory Testing Approach to Pain in Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2019.
Sensory abnormalities in autism has been noted clinically, with pain insensitivity as a specified diagnostic criterion. However, there is limited research using psychophysically robust techniques. Thirteen adults with ASD and 13 matched controls completed an established quantitative sensory testing (QST) battery, supplemented with measures of pain tolerance and central modulation. The ASD group showed higher thresholds for light touch detection and mechanical pain. Notably, the ASD group had a greater range of extreme scores (the number of z-scores outside of the 95% CI > 2), dynamic mechanical allodynia and paradoxical heat sensation; phenomena not typically seen in neurotypical individuals. These data support the need for research examining central mechanisms for pain in ASD and greater consideration of individual difference.
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11. Hegarty JP, Gengoux GW, Berquist KL, Millan ME, Tamura SM, Karve S, Rosenthal MD, Phillips JM, Hardan AY. {{A pilot investigation of neuroimaging predictors for the benefits from pivotal response treatment for children with autism}}. {Journal of psychiatric research}. 2019; 111: 140-4.
Children with autism spectrum disorder (ASD) frequently exhibit language delays and functional communication deficits. Pivotal response treatment (PRT) is an effective intervention for targeting these skills; however, similar to other behavioral interventions, response to PRT is variable across individuals. Thus, objective markers capable of predicting treatment response are critically-needed to identify which children are most likely to benefit from this intervention. In this pilot study, we investigated whether structural neuroimaging measures from language regions in the brain are associated with response to PRT. Children with ASD (n=18) who were receiving PRT to target their language deficits were assessed with MRI at baseline. T1-weighted images were segmented with FreeSurfer and morphometric measures of the primary language regions (inferior frontal (IFG) and superior temporal (STG) gyri) were evaluated. Children with ASD and language deficits did not exhibit the anticipated relationships between baseline structural measures of language regions and baseline language abilities, as assessed by the number of utterances displayed during a structured laboratory observation (SLO). Interestingly, the level of improvement on the SLO was correlated with baseline asymmetry of the IFG, and the size of the left STG at baseline was correlated with the level of improvement on standardized parental questionnaires. Although very preliminary, the observed associations between baseline structural properties of language regions and improvement in language abilities following PRT suggest that neuroimaging measures may be able to help identify which children are most likely to benefit from specific language treatments, which could help improve precision medicine for children with ASD.
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12. Carias KV, Wevrick R. {{Clinical and genetic analysis of children with a dual diagnosis of Tourette syndrome and autism spectrum disorder}}. {Journal of psychiatric research}. 2019; 111: 145-53.
Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder that causes children to make repeated, brief involuntary movements or sounds. TS can be co-morbid with other neurodevelopmental disorders, including autism spectrum disorder (ASD). Clusters of biologically related genes have been associated with neurodevelopmental disorders, suggesting shared pathologies. However, the genetic contribution to TS remains poorly defined. We asked whether children with both TS and ASD differed clinically from children with ASD alone, and identified potentially deleterious genetic events in children with TS and ASD. We compared clinical data from 119 children with ASD and TS to 2603 children with ASD, all from the Simons Simplex Collection. We performed gene set enrichment analysis on de novo genetic events in children with both TS and ASD to identify candidate genes and pathways, and compared these genes and pathways with those previously identified in TS. Children with TS and ASD were diagnosed at an older age, had higher IQ scores, and had more restricted and repetitive behavior than children with ASD but not TS. Gene Ontology analysis revealed that proteins important for specific biological pathways, including regulation of calcium ion-dependent exocytosis, basement membrane organization, and visual behavior and learning, and specific cellular pathways, including basal lamina and ciliary transition zone, are enriched among genes with de novo mutations in children with TS and ASD. Clinical and genetic analysis of cohorts of affected children can help to determine the underlying pathophysiology of TS and other neurodevelopmental disorders.
