1. INSAR President’s message. Autism research : official journal of the International Society for Autism Research. 2021; 14(12): 2711-2.

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2. Blaylock RL, Faria M. New concepts in the development of schizophrenia, autism spectrum disorders, and degenerative brain diseases based on chronic inflammation: A working hypothesis from continued advances in neuroscience research. Surgical neurology international. 2021; 12: 556.

This paper was written prompted by a poignant film about adolescent girl with schizophrenia who babysits for a younger girl in an isolated cabin. Schizophrenia is an illness that both authors are fascinated with and that they continue to study and investigate. There is now compelling evidence that schizophrenia is a very complex syndrome that involves numerous neural pathways in the brain, far more than just dopaminergic and serotonergic systems. One of the more popular theories in recent literature is that it represents a hypo glutaminergic deficiency of certain pathways, including thalamic ones. After much review of research and study in this area, we have concluded that most such theories contain a number of shortcomings. Most are based on clinical responses to certain drugs, particularly antipsychotic drugs affecting the dopaminergic neurotransmitters; thus, assuming dopamine release was the central cause of the psychotic symptoms of schizophrenia. The theory was limited in that dopamine excess could only explain the positive symptoms of the disorder. Antipsychotic medications have minimal effectiveness for the negative and cognitive symptoms associated with schizophrenia. It has been estimated that 20-30% of patients show either a partial or no response to antipsychotic medications. In addition, the dopamine hypothesis does not explain the neuroanatomic findings in schizophrenia.

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3. Borissov A, Bakolis I, Tekola B, Kinfe M, Ceccarelli C, Girma F, Abdurahman R, Zerihun T, Hanlon C, Hoekstra RA. Adaptation and validation of two autism-related measures of skills and quality of life in Ethiopia. Autism : the international journal of research and practice. 2021: 13623613211050751.

Although most children with autism and other neurodevelopmental disorders live in low- and middle-income countries, reliable tools to assess these conditions are often not available in these settings. In this study, we adapted two questionnaires developed in Western high-income contexts for use in Ethiopia – the Autism Treatment Evaluation Checklist and the Pediatric Quality of Life Inventory™ Family Impact Module. Both measures are completed by a child’s caregiver and both are relatively short and easy to complete. The Autism Treatment Evaluation Checklist is used to monitor the developmental issues of the child, while the Pediatric Quality of Life Inventory™ Family Impact Module measures the impact of the child’s condition on the caregiver. We translated both tools into the Ethiopian language Amharic, and adapted them to the local cultural context. Three hundred caregivers, half of whom were parents of children with neurodevelopmental disorders, and half were parents of children with physical health problems, completed the questionnaires through a face-to face interview, so that non-literate caregivers could also take part. Both tools performed adequately, measured what we aimed to measure and were reliable. Both the Autism Treatment Evaluation Checklist and Pediatric Quality of Life Inventory™ are suitable tools to assess children with developmental and other health problems in Ethiopia and their caregivers. We believe that more similar tools should be developed or adapted for use in low-income countries like Ethiopia, to gain a better understanding of developmental problems in those settings, and allowing clinicians and service providers to use these tools in their practice. Moreover, these tools can be used in future studies to evaluate interventions to improve support for families.

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4. Deshmukh AL, Caron MC, Mohiuddin M, Lanni S, Panigrahi GB, Khan M, Engchuan W, Shum N, Faruqui A, Wang P, Yuen RKC, Nakamori M, Nakatani K, Masson JY, Pearson CE. FAN1 exo- not endo-nuclease pausing on disease-associated slipped-DNA repeats: A mechanism of repeat instability. Cell reports. 2021; 37(10): 110078.

Ongoing inchworm-like CAG and CGG repeat expansions in brains, arising by aberrant processing of slipped DNAs, may drive Huntington’s disease, fragile X syndrome, and autism. FAN1 nuclease modifies hyper-expansion rates by unknown means. We show that FAN1, through iterative cycles, binds, dimerizes, and cleaves slipped DNAs, yielding striking exo-nuclease pauses along slip-outs: 5′-C↓A↓GC↓A↓G-3′ and 5′-C↓T↓G↓C↓T↓G-3′. CAG excision is slower than CTG and requires intra-strand A•A and T•T mismatches. Fully paired hairpins arrested excision, whereas disease-delaying CAA interruptions further slowed excision. Endo-nucleolytic cleavage is insensitive to slip-outs. Rare FAN1 variants are found in individuals with autism with CGG/CCG expansions, and CGG/CCG slip-outs show exo-nuclease pauses. The slip-out-specific ligand, naphthyridine-azaquinolone, which induces contractions of expanded repeats in vivo, requires FAN1 for its effect, and protects slip-outs from FAN1 exo-, but not endo-, nucleolytic digestion. FAN1’s inchworm pausing of slip-out excision rates is well suited to modify inchworm expansion rates, which modify disease onset and progression.

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5. Fan W, Jin X, Xu M, Xi Y, Lu W, Yang X, Guan MX, Ge W. FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism. Nucleic acids research. 2021; 49(22): 13108-21.

Mutations in genes encoding mitochondrial aminoacyl-tRNA synthetases are linked to diverse diseases. However, the precise mechanisms by which these mutations affect mitochondrial function and disease development are not fully understood. Here, we develop a Drosophila model to study the function of dFARS2, the Drosophila homologue of the mitochondrial phenylalanyl-tRNA synthetase, and further characterize human disease-associated FARS2 variants. Inactivation of dFARS2 in Drosophila leads to developmental delay and seizure. Biochemical studies reveal that dFARS2 is required for mitochondrial tRNA aminoacylation, mitochondrial protein stability, and assembly and enzyme activities of OXPHOS complexes. Interestingly, by modeling FARS2 mutations associated with human disease in Drosophila, we provide evidence that expression of two human FARS2 variants, p.G309S and p.D142Y, induces seizure behaviors and locomotion defects, respectively. Together, our results not only show the relationship between dysfunction of mitochondrial aminoacylation system and pathologies, but also illustrate the application of Drosophila model for functional analysis of human disease-causing variants.

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6. Harmelech T, Roth Y, Tendler A. Deep TMS H7 Coil: Features, Applications & Future. Expert review of medical devices. 2021; 18(12): 1133-44.

INTRODUCTION: Transcranial magnetic stimulation (TMS) uses magnetic pulses to induce electrical current in the underlying neuronal tissue. A variety of TMS coils exist on the market, differing primarily in configuration, orientation, and flexibility of the wire windings of the coil. Deep TMS(TM) utilizes H-Coils, flexible coils with different configurations for stimulating different brain regions implicated in different neuropsychiatric disorders. The H7 Coil, designed to target primarily the medial prefrontal cortex and the anterior cingulate cortex, is FDA-cleared for obsessive-compulsive disorder (OCD). It was chosen as the focus of this review since it recently showed promise in various neuropsychiatric populations in addition to growing understanding of its mechanism of action (MOA). AREAS COVERED: Here we assembled all peer-reviewed publications on the H7 Coil to showcase its efficacy in: (a) various OCD patient populations (e.g., different degrees of symptom severity, treatment resistance, comorbidities) (b) other neuropsychiatric populations (e.g., addiction, major depressive disorder and autism spectrum disorder). EXPERT OPINION: While substantial evidence pertaining to the H7 Coil’s efficacy as well as its MOA has accumulated, much work remains. In the final section of this review, we highlight areas of ongoing and future research that will further elucidate the coil’s MOA as well as its full efficacy potential.

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7. Hijab MHF, Al-Thani D, Banire B. A Multimodal Messaging App (MAAN) for Adults With Autism Spectrum Disorder: Mixed Methods Evaluation Study. JMIR formative research. 2021; 5(12): e33123.

BACKGROUND: Individuals with autism spectrum disorder (ASD) often exhibit difficulties in social and communication skills. For more than 30 years, specialists, parents, and caregivers have used techniques, such as applied behavioral analysis, augmentative and alternative communication, and the picture exchange communication system to support the social and communication skills of people with ASD. Even though there are many techniques devised to enhance communication, these techniques are not considered in existing social media apps for people with ASD. OBJECTIVE: This study aimed to investigate the effect of adding accessibility features, such as text-to-speech (TTS), speech-to-text (STT), and communication symbols (CS), to a messaging app (MAAN). We hypothesized that these accessibility features can enhance the social and communication skills of adults with ASD. We also hypothesized that usage of this app can reduce social loneliness in adults with ASD. METHODS: Semistructured interviews were conducted with 5 experts working in fields related to ASD to help design the app. Seven adults with ASD participated in the study for a period of 10 to 16 weeks. Data logs of participants’ interactions with the app were collected. Additionally, 6 participants’ parents and 1 caregiver were asked to complete a short version of the Social and Emotional Loneliness Scale for Adults (SELSA-S) questionnaire to compare pre-post study results. The Mobile Application Rating Scale: user version questionnaire was also used to evaluate the app’s usability. Following the study, interviews were conducted with participants to discuss their experiences with the app. RESULTS: The SELSA-S questionnaire results showed no change in the family subscale; however, the social loneliness subscale showed a difference between prestudy and poststudy. The Wilcoxon signed-rank test indicated that poststudy SELSA-S results were statistically significantly higher than prestudy results (z=-2.047; P=.04). Point-biserial correlation indicated that the SELSA-S rate of change was strongly related to usage of the TTS feature (r=0.708; P=.04) and CS feature (r=-0.917; P=.002), and moderately related to usage of the STT feature (r=0.428; P=.17). Lastly, we adopted grounded theory to analyze the interview data, and the following 5 categories emerged: app support, feature relevance, user interface design, overall feedback, and recommendations. CONCLUSIONS: This study discusses the potential for improving the communication skills of adults with ASD through special features in mobile messaging apps. The developed app aims to support the inclusion and independent life of adults with ASD. The study results showed the importance of using TTS, STT, and CS features to enhance social and communication skills, as well as reduce social loneliness in adults with ASD.

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8. Johnson AJ, Howell BR. Dietary diversity contributes to microbiome associations in autism. Cell metabolism. 2021; 33(12): 2311-3.

Research exploring the links between the microbiome and autism has inadequately considered the contribution of diet diversity. Recently in Cell, Yap et al. addressed the contribution of restrictive dietary patterns to microbiome diversity in autism and found that decreased dietary diversity shapes the microbiome more than previously appreciated.

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9. Kim E, Paik D, Ramirez RN, Biggs DG, Park Y, Kwon HK, Choi GB, Huh JR. Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4(+) T cells. Immunity. 2022; 55(1): 145-58.e7.

Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4(+) T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.

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10. Magalhães JM, Rodrigues TA, Neta MMR, Damasceno C, Sousa K, Arisawa EÂ LS. Experiences of family members of children diagnosed with autism spectrum disorder. Revista gaucha de enfermagem. 2021; 42: e20200437.

OBJECTIVE: To describe, in the mothers’ perception, the experiences lived by families in the care of children with autism spectrum disorder. METHOD: Qualitative study, carried out with 20 mothers of children diagnosed with autistic disorder accompanied by an institution in Teresina-Piauí, Brazil. Semi-structured interviews were conducted between February and March 2019 and subjected to content analysis. RESULTS: Five central ideas related to the stages experienced by family members after the diagnosis were identified, ranging from denial to acceptance. Family members and caregivers experience feelings of sadness and mourning for the discovery of the impossibility of curing the syndrome, revealing the need for care for this family. The search for help and adaptations of the routine are constant experiences. CONCLUSION: Caring for children who live with autistic disorder involves learning ranging from structural to emotional aspects, such as dealing with limitations and impossibility of cure, pointing out to the need for family care.

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11. Markenscoff-Papadimitriou E, Binyameen F, Whalen S, Price J, Lim K, Ypsilanti AR, Catta-Preta R, Pai EL, Mu X, Xu D, Pollard KS, Nord AS, State MW, Rubenstein JL. Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes. Cell reports. 2021; 37(10): 110089.

Deleterious genetic variants in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Although it is a high-confidence ASD risk gene, the neurodevelopmental functions of POGZ remain unclear. Here we reveal the genomic binding of POGZ in the developing forebrain at euchromatic loci and gene regulatory elements (REs). We profile chromatin accessibility and gene expression in Pogz(-/-) mice and show that POGZ promotes the active chromatin state and transcription of clustered synaptic genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies loci with ADNP, another high-confidence ASD risk gene, and provide evidence that POGZ regulates other neurodevelopmental disorder risk genes as well. Our results reveal a neurodevelopmental function of an ASD risk gene and identify molecular targets that may elucidate its function in ASD.

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12. Mazon C, Etchegoyhen K, Saint-Supery I, Amestoy A, Bouvard M, Consel C, Sauzéon H. Fostering parents-professional collaboration for facilitating the school inclusion of students with ASD: design of the « ToGather » web-based prototype. Educational technology research and development : ETR & D. 2022; 70(1): 231-62.

In recent years, many psycho-educational technologies were studied to address the school-related difficulties encountered by students with autism spectrum disorder (ASD). However, most of them remain individual-centered and do not consider the social environment. To fill this gap, this study reports on the user-centered design of a web-based support tool, which aims to support communication and coordination between parents, school staff and health professionals of middle and high school students with ASD, in the context of elaborating, implementing, and following an Individualized Education Plan. The study followed a two-step design process: (1) a need analysis for identifying information domains deemed important by the stakeholders; (2) through a participative iterative design process, a panel of professionals and parents provided ideas and feedbacks on the design, which was integrated in subsequent prototype versions of the « ToGather » app. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11423-021-10073-w.

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13. Nishizawa H, Motobayashi M, Akahane M, Wakui K, Kitazawa N, Inaba Y, Fukushima Y, Kosho T. Neuropsychological and neurophysiological features of WAGR syndrome: Detailed comprehensive evaluation of a patient with severe intellectual disability and autism spectrum disorder. Brain & development. 2022; 44(3): 229-33.

BACKGROUND: Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome is a contiguous gene deletion syndrome caused by a de novo deletion including the 11p13 region. Although autism spectrum disorder (ASD) is frequently observed in patients with WAGR syndrome, few reports have comprehensively described its characteristics. We herein present the detailed neuropsychological and neurophysiological findings of a patient with WAGR syndrome complicated with severe psychomotor developmental delay and ASD. CASE PRESENTATION: The patient is presently a 6-year-old boy. Microarray analysis revealed a 7.1 Mb loss at 11p14.3-p13 and a 9.3 Mb loss at 11p13-p12, which encompassed the PAX6, WT1, and PRRG4 genes. His behavioral features were characteristic even among the ASD population: severe hypoesthesia to touch, pain, and temperature in addition to remarkable sensory seeking posing a high risk of serious accident. Sensory Profile analysis objectively identified a strong preference for sensory stimulation. Furthermore, his somatosensory evoked potential (SSEP) showed a mild delay in central conduction time, suggesting partial brain stem dysfunction-induced hypoalgesia. DISCUSSION: This first attempt to characterize sensory dysfunction using Sensory Profile and SSEP in WAGR syndrome may contribute to understanding its neuropsychological features and improve the quality of rehabilitation and socioeducational support in affected children.

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14. Oztenekecioglu B, Mavis M, Osum M, Kalkan R. Genetic and Epigenetic Alterations in Autism Spectrum Disorder. Global medical genetics. 2021; 8(4): 144-8.

It is extremely important to understand the causes of autism spectrum disorder (ASD) which is a neurodevelopmental disease. Treatment and lifelong support of autism are also important to improve the patient’s life quality. In this article, several findings were explained to understand the possible causes of ASD. We draw, outline, and describe ASD and its relation with the epigenetic mechanisms. Here, we discuss, several different factors leading to ASD such as environmental, epigenetic, and genetic factors.

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15. Srancikova A, Reichova A, Bacova Z, Bakos J. Gene expression levels of DNA methyltransferase enzymes in Shank3-deficient mouse model of autism during early development. Endocrine regulations. 2021; 55(4): 234-7.

Objectives. The balance between DNA methylation and demethylation is crucial for the brain development. Therefore, alterations in the expression of enzymes controlling DNA methylation patterns may contribute to the etiology of neurodevelopmental disorders, including autism. SH3 and multiple ankyrin repeat domains 3 (Shank3)-deficient mice are commonly used as a well-characterized transgenic model to investigate the molecular mechanisms of autistic symptoms. DNA methyltransferases (DNMTs), which modulate several cellular processes in neurodevelopment, are implicated in the pathophysiology of autism. In this study, we aimed to describe the gene expression changes of major Dnmts in the brain of Shank3-deficient mice during early development. Methods and Results. The Dnmts gene expression was analyzed by qPCR in 5-day-old homo-zygous Shank3-deficient mice. We found significantly lower Dnmt1 and Dnmt3b gene expression levels in the frontal cortex. However, no such changes were observed in the hippocampus. However, significant increase was observed in the expression of Dnmt3a and Dnmt3b genes in the hypothalamus of Shank3-deficient mice. Conclusions. The present data indicate that abnormalities in the Shank3 gene are accompanied by an altered expression of DNA methylation enzymes in the early brain development stages, therefore, specific epigenetic control mechanisms in autism-relevant models should be more extensively investigated.

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16. Srikanth S, Cascio L, Pauly R, Jones K, Sorrow S, Cubillan R, Chen CF, Skinner CD, Champaigne K, Stevenson RE, Schwartz CE, Boccuto L. A new test for autism spectrum disorder: Metabolic data from different cell types. Data in brief. 2021; 39: 107598.

Experiments employing the Phenotype Mammalian Microarray (PM-M) technology were performed on lymphoblastoid cell lines (LCLs) from individuals with autism spectrum disorder (ASD) and age-matched controls. We used the custom-made PM-M plate designed to assess differential utilization of the amino acid tryptophan. Multiple parameters such as the sample size, incubation time, and cell concentration have been tested, leading to optimized protocols and minimized background noise by variable selection while controlling for false discoveries. The assay generated data based on the production of nicotinamide adenine dinucleotide (NADH) in the presence of different compounds containing tryptophan and showed clear differences between ASD and control samples.

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17. Tao X, Che Y, Li C, Ruan W, Xu J, Yu Y, Yang F, Wang J, Li H. Novel SNX13 Frameshift Variant in an Individual with Developmental Delay. Cytogenetic and genome research. 2021; 161(10-11): 514-9.

Recently, an increasing number of genes have been associated with global developmental delay (GDD) and intellectual disability (ID). The sorting nexin (SNX) protein family plays multiple roles in protein trafficking and intracellular signaling. SNXs have been reported to be associated with several disorders, including Alzheimer disease and Down syndrome. Despite the growing evidence of an association of SNXs with neurodegeneration, SNX13 deficiency has not been associated with GDD or ID. In this study, we present the case of a 4-year-old boy with brain dysplasia and GDD, including language delay, cognitive delay, and dyskinesia. Exome sequencing revealed a 1-bp homozygous deletion in SNX13 (NM_015132.5: exon8: c.742_743del; p.Tyr248Leufs*20), which caused a frameshift and predicted early termination. Sanger sequencing confirmed that the variant was inherited from his parents respectively. Our findings associate SNX13 variation with GDD for the first time and provide a new GDD candidate gene.

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