1. Aziz MC, Schneider PN, Carvill GL. Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy. Developmental neuroscience. 2021; 43(3-4): 241-6.

Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic SCN1A variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.

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2. Barbaro J, Masi A, Gilbert M, Nair R, Abdullahi I, Descallar J, Dissanayake C, Eastwood J, Hasan I, Jalaludin B, Karlov L, Khan F, Kohlhoff J, Liaw ST, Lingam R, Mendoza Diaz A, Ong N, Tam CWM, Unwin K, Woolfenden S, Eapen V. A Multistate Trial of an Early Surveillance Program for Autism Within General Practices in Australia. Frontiers in pediatrics. 2021; 9: 640359.

Background: The early detection of developmental conditions such as autism is vital to ensure children can access appropriate and timely evidence-based supports, services, and interventions. Children who have undetected developmental conditions early in life are more likely to develop later health, developmental, learning, and behavioral issues, which in turn can have a cumulative effect over the life course. Methods: The current protocol describes a multi-site, cluster randomized control trial comparing a developmental surveillance pathway for autism to usual care, using opportunistic visits to general practitioners (GPs). Units of randomization are GP clinics across two Australian states (New South Wales and Victoria), with thirty clinics within each state, each of which will aim to recruit approximately forty children aged between ~18- and 24-months, for a total of ~2,400 participants. Children will be randomized to two clusters; namely, an autism surveillance pathway (ASP) or surveillance as usual (SaU). The screening process for the ASP arm involves primary and secondary screenings for developmental concerns for autism, using both parent and GP reports and observations. Children in both arms who show signs of developmental concerns for autism will be offered a full developmental assessment by the research team at 24 months of age to determine the efficacy of developmental surveillance in successfully identifying children with autism. Trial Registration: The trial is registered with ANZCTR (ACTRN12619001200178) and reporting of the trial results will be according to recommendations in the CONSORT Statement.

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3. Georgiou N, Delfabbro P, Balzan R. Autistic traits as a potential confounding factor in the relationship between schizotypy and conspiracy beliefs. Cognitive neuropsychiatry. 2021; 26(4): 273-92.

BACKGROUND: Conspiracy Theories (CT) are complex belief systems that view the world as being manipulated by multiple actors collaborating in the pursuit of malevolent goals. Although culture, education and sociological factors have been implicated in their development, psychological factors are recognized as important. Certain individual differences, including schizotypy and cognitive processing style, have been shown to make some individuals susceptible to CTs. However, the finding that schizotypy often co-occurs with autism spectrum disorder raises a question as to the relative and potentially confounding role of autistic traits in increasing vulnerability to CT beliefs. METHOD: A total of 508 adults were recruited from an international online panel. The study included measures of conspiracy beliefs, schizotypy and autistic traits as well as measures of information searching and cognitive style. RESULTS: The results confirmed that both autistic and schizotypy traits were positively associated with CT beliefs, but that schizotypy traits were the strongest predictor. Exploratory analyses of cognitive style measures indicated potential avenues for further investigation in relation in differences in cognitive processes that might underlie the development of CTs for in people with autistic traits as opposed to schizotypal traits. LIMITATIONS: The study was based on a self-report methodology and did not utilise a clinical sample. CONCLUSION: Both schizotypal and autistic traits are reliable predictors of conspiracy beliefs, but schizotypy appears to be the stronger predictor and that autistic traits are not a strong confounding factor in this relationship. However, autistic traits may pose an additional risk factor for CT beliefs.

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4. Goh JX, Aishworiya R, Ho RCM, Wang W, He HG. A qualitative study exploring experiences and support needs of parents of children with autism spectrum disorder in Singapore. Journal of clinical nursing. 2021; 30(21-22): 3268-80.

AIMS AND OBJECTIVE: To explore the experiences and support needs of parents of children with recently diagnosed autism spectrum disorder (ASD) in Singapore. BACKGROUND: Raising a child with ASD is challenging for parents, especially in the initial period following the diagnosis. Limited studies have focused on parents’ perspectives. DESIGN: A qualitative descriptive design study. METHODS: Thirteen parents were recruited from a developmental and behavioural paediatric outpatient clinic of a tertiary hospital in Singapore from October-December 2018. Adult parents, who were primary caregivers of 2-10-year-old children diagnosed with ASD in the preceding 3 months to 2 years, were recruited. Semi-structured individual face-to-face interviews were conducted based on an interview guide. Thematic analysis was used to analyse the data. Consolidated Criteria for Reporting Qualitative Studies (COREQ) checklist was used for reporting. RESULTS: Common themes were analysed using constant comparative method to generate results. Four themes emerged after 13 interviews: (1) adjusting psychologically, (2) changing lifestyle, (3) contending with hurdles to services and (4) needing informational, tangible and emotional support. CONCLUSIONS: Findings suggested a need for more formal support networks, targeted resource platforms and accessibility of services to help support parents better after receiving a diagnosis of ASD in their child. RELEVANCE TO CLINICAL PRACTICE: Enhancing current healthcare and social policies to improve the provision of standardised and targeted information to parents, establishing formal support networks, facilitating access to childcare services, and involving domestic helpers/nannies as dedicated caregivers and trainers could better support parents.

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5. Halsall J, Clarke C, Crane L. « Camouflaging » by adolescent autistic girls who attend both mainstream and specialist resource classes: Perspectives of girls, their mothers and their educators. Autism : the international journal of research and practice. 2021; 25(7): 2074-86.

There are a range of different types of schools that support children diagnosed with autism, including mainstream schools (where pupils are taught in general classrooms) and specialist schools (where pupils are exclusively taught alongside other children with special educational needs). An intermediary option involves resource bases attached to mainstream schools, which enable children to transition between mainstream and specialist educational settings. Autistic girls use a variety of strategies to negotiate the expectations and demands of school life. One of these strategies is known as camouflaging. This involves ‘hiding’ autism-based behaviours and developing ways to manage social situations, with the aim of fitting in with others. Research has shown that camouflaging can help to meet social expectations and friendships, but it can also result in challenges, including exhaustion and anxiety. In this study, we conducted detailed interviews with eight autistic girls, their parents and their school staff. The results showed that the girls tried to use camouflaging strategies to hide their autism and learning needs, especially within mainstream classrooms. Their camouflaging was often unsuccessful, which affected their relationships and sense of belonging. They also found camouflaging exhausting and distressing, which may (when combined with the demands of the classroom) affect their relationships, learning and mental health. This research provides important implications for supporting autistic girls who attend resource bases. These focus around increasing awareness of camouflaging and ways to support autistic girls, so they are included and able to fully participate and learn within school.

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6. Halstead E, Sullivan E, Zambelli Z, Ellis JG, Dimitriou D. The treatment of sleep problems in autistic adults in the United Kingdom. Autism : the international journal of research and practice. 2021; 25(8): 2412-7.

Sleep problems are one of the most common complaints by autistic adults. This study aimed to report the perspectives of autistic adults on treatment of their sleep problems; 288 autistic adults living in the United Kingdom completed an online survey which assessed their sleep quality. We also gathered data on experiences and preferences of sleep treatment with UK healthcare professionals and their experiences of self-management of their sleep; 58% of autistic adults never had a visit with a healthcare professional regarding their sleep problem, despite 90% meeting the criteria for poor sleep quality. Some of those who attended a consultation for their sleep were prescribed medication (72%), but 60% were not satisfied with the outcome. The participants also reported that sleep self-management was not effective (80%); 41% reported a preference for non-medication including education, advice and talking therapies for sleep treatment. This report highlights the need for a fundamental shift in treatment of sleep problems in autistic adults. The current treatments are not resolving sleep issues; hence, it is imperative to develop management strategies that considers autistic adults’ preferences, reduces sleep problems and thus improves quality of life for autistic adults.

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7. Lansdon LA, Fleming EA, Viso FD, Sullivan BR, Saunders CJ. Second patient with GNB2-related neurodevelopmental disease: Further evidence for a gene-disease association. European journal of medical genetics. 2021; 64(7): 104243.

G-proteins are ubiquitously expressed heterotrimeric proteins consisting of α, β and γ subunits and mediate G-protein coupled receptor signalling cascades. The β subunit is encoded by one of five highly similar paralogs (GNB1-GNB5, accordingly). The developmental importance of G-proteins is highlighted by the clinical relevance of variants in genes such as GNB1, which cause severe neurodevelopmental disease (NDD). Recently the candidacy of GNB2 was raised in association with NDD in an individual with a de novo variant affecting a codon conserved across paralogs and recurrently mutated in GNB1-related disease, c.229G>A p.(Gly77Arg), in association with global developmental delay, intellectual disability and dysmorphic features. Here, we report a patient with strikingly similar facial features and NDD in association with a de novo GNB2 variant affecting the same codon, c.229G>T p.(Gly77Trp). In addition, this individual has epilepsy and overgrowth. Our report is the second to implicate a de novo GNB2 variant with a severe yet variable NDD.

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8. Lapostolle A, Delion T, Arnaud S, Manceau P, Degos B. Thrombocytopenia and agranulocytosis in a FXTAS choreic patient treated with tetrabenazine. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2021; 42(8): 3475-7.

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9. Lebreton K, Malvy J, Bon L, Hamel-Desbruères A, Marcaggi G, Clochon P, Guénolé F, Moussaoui E, Bowler DM, Bonnet-Brilhault F, Eustache F, Baleyte JM, Guillery-Girard B. Local Processing Bias Impacts Implicit and Explicit Memory in Autism. Frontiers in psychology. 2021; 12: 622462.

Autism spectrum disorder (ASD) is characterized by atypical perception, including processing that is biased toward local details rather than global configurations. This bias may impact on memory. The present study examined the effect of this perception on both implicit (Experiment 1) and explicit (Experiment 2) memory in conditions that promote either local or global processing. The first experiment consisted of an object identification priming task using two distinct encoding conditions: one favoring local processing (Local condition) and the other favoring global processing (Global condition) of drawings. The second experiment focused on episodic (explicit) memory with two different cartoon recognition tasks that favored either local (i.e., processing specific details) or a global processing (i.e., processing each cartoon as a whole). In addition, all the participants underwent a general clinical cognitive assessment aimed at documenting their cognitive profile and enabling correlational analyses with experimental memory tasks. Seventeen participants with ASD and 17 typically developing (TD) controls aged from 10 to 16 years participated to the first experiment and 13 ASD matched with 13 TD participants were included for the second experiment. Experiment 1 confirmed the preservation of priming effects in ASD but, unlike the Comparison group, the ASD group did not increase his performance as controls after a globally oriented processing. Experiment 2 revealed that local processing led to difficulties in discriminating lures from targets in a recognition task when both lures and targets shared common details. The correlation analysis revealed that these difficulties were associated with processing speed and inhibition. These preliminary results suggest that natural perceptual processes oriented toward local information in ASD may impact upon their implicit memory by preventing globally oriented processing in time-limited conditions and induce confusion between explicit memories that share common details.

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10. Li K, Fang Z, Zhao G, Li B, Chen C, Xia L, Wang L, Luo T, Wang X, Wang Z, Zhang Y, Jiang Y, Pan Q, Hu Z, Guo H, Tang B, Liu C, Sun Z, Xia K, Li J. Cross-Disorder Analysis of De Novo Mutations in Neuropsychiatric Disorders. Journal of autism and developmental disorders. 2022; 52(3): 1299-313.

The clinical similarity among different neuropsychiatric disorders (NPDs) suggested a shared genetic basis. We catalogued 23,109 coding de novo mutations (DNMs) from 6511 patients with autism spectrum disorder (ASD), 4,293 undiagnosed developmental disorder (UDD), 933 epileptic encephalopathy (EE), 1022 intellectual disability (ID), 1094 schizophrenia (SCZ), and 3391 controls. We evaluated that putative functional DNMs contribute to 38.11%, 34.40%, 33.31%, 10.98% and 6.91% of patients with ID, EE, UDD, ASD and SCZ, respectively. Consistent with phenotype similarity and heterogeneity in different NPDs, they show different degree of genetic association. Cross-disorder analysis of DNMs prioritized 321 candidate genes (FDR < 0.05) and showed that genes shared in more disorders were more likely to exhibited specific expression pattern, functional pathway, genetic convergence, and genetic intolerance.

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11. Malkin L, Abbot-Smith K. How set switching affects the use of context-appropriate language by autistic and neuro-typical children. Autism : the international journal of research and practice. 2021; 25(8): 2418-22.

The way autistic individuals use language often gives the impression that they are not considering how much information listeners need in a given context. The same child can give too much information in one context (e.g. saying ‘the big cup’ with only one cup present) and too little information in another context (e.g. entering a room and announcing ‘the red one’ when the listener has no prior knowledge regarding what this refers to). We asked whether many autistic children particularly struggle to tailor their language appropriately in situations where this means changing how they have previously described something. That is, if a speaker has recently described an object as ‘the cup’, the need to switch to describing it as ‘the big cup’ could hinder the speaker’s ability to use language in a context-appropriate way. We found that switching descriptions indeed makes it more difficult for children to use language in a context-appropriate way, but that this effect did not play out differently for autistic versus neuro-typical children. Autistic children were, however, less likely to provide a context-appropriate amount of information overall than were neuro-typical peers. The combination of these effects meant that when object re-description was required, autistic children only produced an appropriate description half the time. In contrast, without a requirement to re-describe, autistic children could indeed take listener informational needs into account. Applied professionals should consider whether a requirement to change the way the child has previously said something may hinder a child’s ability to communicate effectively.

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12. McLaughlin CS, Grosman HE, Guillory SB, Isenstein EL, Wilkinson E, Trelles MDP, Halpern DB, Siper PM, Kolevzon A, Buxbaum JD, Wang AT, Foss-Feig JH. Reduced engagement of visual attention in children with autism spectrum disorder. Autism : the international journal of research and practice. 2021; 25(7): 2064-73.

Limited eye contact and difficulty tracking where others are looking are common in people with autism spectrum disorder. It is unclear, however, whether these are specifically social differences; it is possible that they are a result of broader alterations in engaging and disengaging visual attention. We used eye-tracking technology with children with autism spectrum disorder (n = 35) and typical development (n = 32), showing them both social and nonsocial imaging to test their visual attention. Children with autism spectrum disorder had a significant difference in how long it took them to look from an image in the middle to one on the side, depending on whether the middle image stayed on the screen or flashed off before the one on the side appeared. This difference was present for both social and nonsocial images, and was related to cognitive ability for only the children with autism spectrum disorder. Our findings suggest that children with autism spectrum disorder have differences in general processes of engaging visual attention that are not specifically social in nature, and that these processes may relate to cognitive ability in autism spectrum disorder. Affected processes of visual engagement in autism spectrum disorder may contribute to symptoms like reduced eye contact, but social-specific symptoms of autism spectrum disorder likely do not stem from reduced visual engagement alone.

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13. Ritter C, Hewitt K, McMorris CA. Psychotropic Polypharmacy Among Children and Youth with Autism: A Systematic Review. Journal of child and adolescent psychopharmacology. 2021; 31(4): 244-58.

Objectives: Majority of youth with autism are taking two or more medications (psychotropic or nonpsychotropic) simultaneously, also known as polypharmacy. Yet the efficacy and the potential outcomes of polypharmacy in this population are widely unknown. This systematic literature review described the trends of polypharmacy among autistic youth, and identified factors associated with polypharmacy. Methods: Sixteen studies were included, encompassing over 300,000 youth with autism. Results: Rates of polypharmacy varied quite substantially across studies, ranging from 6.8% to 87% of autistic youth. Having psychiatric comorbidities, self-injurious behaviors, and physical aggression, as well as being male and older, were associated with higher rates of polypharmacy. Conclusion: Findings emphasize the importance of further research to determine appropriate practices related to the monitoring of adverse side effects, and the long-term impact of polypharmacy among autistic youth.

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14. Sharifi O, Yasui DH. The Molecular Functions of MeCP2 in Rett Syndrome Pathology. Frontiers in genetics. 2021; 12: 624290.

MeCP2 protein, encoded by the MECP2 gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As MECP2 gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with Mecp2 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.

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