1. Afsharnejad B, Falkmer M, Picen T, Black MH, Alach T, Fridell A, Coco C, Milne K, Perry J, Bölte S, Girdler S. « I Met Someone Like Me! »: Autistic Adolescents and Their Parents’ Experience of the KONTAKT® Social Skills Group Training. Journal of autism and developmental disorders. 2022; 52(4): 1458-77.

This study captured the experiences of 35 autistic adolescents and their parents after completing a 16-session variant of social skills group training KONTAKT® (ACTRN12617001117303). Semi-structured interviews explored participants’ and relatives’ perceptions of KONTAKT® and associated social outcomes. Adolescents were classified as either high (HR, n = 23) or low (LR, n = 12) responders based on the primary outcome effects during the previous trial. Thematic analysis revealed that both HR and LR participants their parents were satisfied with KONTAKT®, noting consistent patterns of improvement in adolescents’ social understanding, communication, relationships, and empowerment, although positive reports were more frequent among HR than LR groups. This study enhances the understanding of the impact of SSGT, which is key in improving their content, principles, and administration.

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2. Baig U, Mehdi SM, Imtiaz Afzal HM. Sleep disturbances in children with autism spectrum disorder in Lahore, Pakistan; a cross-sectional study. JPMA The Journal of the Pakistan Medical Association. 2021; 71(1(b)): 783-5.

OBJECTIVE: To assess the frequency of insomnia and other sleep disturbances among children with autism spectrum disorder. METHODS: The descriptive cross-sectional study was conducted in Lahore, Pakistan, from May to August 2019, after approval from the ethics committee of Sharif Medical and Dental College, Lahore. It comprised children aged 6-12 years pre-diagnosed with autism spectrum disorder who were enrolled from 3 institutions and an out-patient department of a tertiary care hospital. Sleep disturbance scale for children was used for data-collection, and the parents were asked to fill it out. Data was analysed using SPSS 23. RESULTS: Of the 93 subjects, 71(76.3%) were boys and 22(23.7%) were girls, and 58(62.4%) were aged 6-8 years. Overall, 37(39.8%) children had at least one type of sleeping disorder; the most common being insomnia 24(25.8%), and the least common being sleep breathing disorders 4(4.3%). CONCLUSIONS: Nearly 40% children with autism spectrum disorder had sleep disorders, and insomnia was the most common.

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3. Banday S, Pandita RK, Mushtaq A, Bacolla A, Mir US, Singh DK, Jan S, Bhat KP, Hunt CR, Rao G, Charaka VK, Tainer JA, Pandita TK, Altaf M. Autism-Associated Vigilin Depletion Impairs DNA Damage Repair. Molecular and cellular biology. 2021; 41(7): e0008221.

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders.

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4. Bucher M, Niebling S, Han Y, Molodenskiy D, Hassani Nia F, Kreienkamp HJ, Svergun D, Kim E, Kostyukova AS, Kreutz MR, Mikhaylova M. Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses. eLife. 2021; 10.

Members of the SH3- and ankyrin repeat (SHANK) protein family are considered as master scaffolds of the postsynaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this proof-of-principle study, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3 and demonstrate that both mutant proteins indeed show distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and distal structural disturbances result in altered synaptic targeting and changes of protein turnover at synaptic sites in rat primary hippocampal neurons.

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5. Coffield CN, Spitalnik DM, Harris JF, Jimenez ME. Exploring the Experiences of Families of Latino Children Newly Diagnosed With Autism Spectrum Disorder. Journal of developmental and behavioral pediatrics : JDBP. 2021; 42(9): 711-6.

OBJECTIVE: Understanding families’ experiences from their initial developmental concerns through the first several months after autism spectrum disorder (ASD) diagnosis might help explain persistent disparities in age of diagnosis for low-income Latino children and those whose parents speak a primary language other than English. We explored these experiences among Latino parents of children recently diagnosed with ASD to develop a richer understanding of this critical juncture. METHOD: We conducted semistructured interviews with Latino parents of children diagnosed with ASD in the previous 3 months who were receiving follow-up care through a large, hospital-based outpatient practice. Interviews were recorded, transcribed verbatim, translated, and analyzed using an iterative process. RESULTS: Twenty parents participated in a semistructured interview approximately 3 months after their child was diagnosed with ASD. All respondents were female and Latina, 90% spoke Spanish, and 95% of children received Medicaid. We identified the following 3 themes from their experiences: (1) When parents first shared their concerns about their child’s development with professionals, they felt unheard. (2) Parents were surprised that the diagnostic process for ASD relied on parental description of child development and behavior and observation of the child, not on medical tests. (3) Receiving an ASD diagnosis was a life-altering event for parents, and how that diagnosis was communicated by clinicians had a significant impact on families. CONCLUSION: Parents of young Latino children identified several barriers throughout the process of ASD identification and diagnosis that have important implications for improving clinician communication with families.

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6. Collins BE, Merritt JK, Erickson KR, Neul JL. Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome. Genes, brain, and behavior. 2022; 21(1): e12739.

Rett syndrome is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in MECP2, encoding transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Although no disease-modifying therapies exist at this time, some proposed therapeutic strategies aim to supplement the mutant allele with a wild-type allele producing typical levels of functional MeCP2, such as gene therapy. Because MECP2 is a dosage-sensitive gene, with both loss and gain of function causing disease, these approaches must achieve a narrow therapeutic window to be both safe and effective. While MeCP2 supplementation rescues RTT-like phenotypes in mouse models, the tolerable threshold of MeCP2 is not clear, particularly for partial loss-of-function mutations. We assessed the safety of genetically supplementing full-length human MeCP2 in the context of the R294X allele, a common partial loss-of-function mutation retaining DNA-binding capacity. We assessed the potential for adverse effects from MeCP2 supplementation of a partial loss-of-function mutant and the potential for dominant negative interactions between mutant and full-length MeCP2. In male hemizygous R294X mice, MeCP2 supplementation rescued RTT-like behavioral phenotypes and did not elicit behavioral evidence of excess MeCP2. In female heterozygous R294X mice, RTT-specific phenotypes were similarly rescued. However, MeCP2 supplementation led to evidence of excess MeCP2 activity in a motor coordination assay, suggesting that the underlying motor circuitry is particularly sensitive to MeCP2 dosage in females. These results show that genetic supplementation of full-length MeCP2 is safe in males and largely so females. However, careful consideration of risk for adverse motor effects may be warranted for girls and women with RTT.

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7. Cybulski L, Ashcroft DM, Carr MJ, Garg S, Chew-Graham CA, Kapur N, Webb RT. Temporal trends in annual incidence rates for psychiatric disorders and self-harm among children and adolescents in the UK, 2003-2018. BMC psychiatry. 2021; 21(1): 229.

BACKGROUND: There has been growing concern in the UK over recent years that a perceived mental health crisis is affecting children and adolescents, although published epidemiological evidence is limited. METHODS: Two population-based UK primary care cohorts were delineated in the Aurum and GOLD datasets of the Clinical Practice Research Datalink (CPRD). We included data from 9,133,246 individuals aged 1-20 who contributed 117,682,651 person-years of observation time. Sex- and age-stratified annual incidence rates were estimated for attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) (age groups: 1-5, 6-9, 10-12, 13-16, 17-19), depression, anxiety disorders (6-9, 10-12, 13-16, 17-19), eating disorders and self-harm (10-12, 13-16, 17-19) during 2003-2018. We fitted negative binomial regressions to estimate incidence rate ratios (IRRs) to examine change in incidence between the first (2003) and final year (2018) year of observation and to examine sex-specific incidence. RESULTS: The results indicated that the overall incidence has increased substantially in both boys and girls in between 2003 and 2018 for anxiety disorders (IRR 3.51 95% CI 3.18-3.89), depression (2.37; 2.03-2.77), ASD (2.36; 1.72-3.26), ADHD (2.3; 1.73-3.25), and self-harm (2.25; 1.82-2.79). The incidence for eating disorders also increased (IRR 1.3 95% CI 1.06-1.61), but less sharply. The incidence of anxiety disorders, depression, self-harm and eating disorders was in absolute terms higher in girls, whereas the opposite was true for the incidence of ADHD and ASD, which were higher among boys. The largest relative increases in incidence were observed for neurodevelopmental disorders, particularly among girls diagnosed with ADHD or ASD. However, in absolute terms, the incidence was much higher for depression and anxiety disorders. CONCLUSION: The number of young people seeking help for psychological distress appears to have increased in recent years. Changes to diagnostic criteria, reduced stigma, and increased awareness may partly explain our results, but we cannot rule out true increases in incidence occurring in the population. Whatever the explanation, the marked rise in demand for healthcare services means that it may be more challenging for affected young people to promptly access the care and support that they need.

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8. Jonsdottir SL, Saemundsen E, Jonsson BG, Rafnsson V. Validation of the Modified Checklist for Autism in Toddlers, Revised with Follow-up in a Population Sample of 30-Month-Old Children in Iceland: A Prospective Approach. Journal of autism and developmental disorders. 2022; 52(4): 1507-22.

The Modified Checklist for Autism in Toddlers, Revised with Follow-up was validated on a population sample in Reykjavik, Iceland. The participants (N = 1585) were screened in well-child care at age 30 months and followed up for at least 2 years to identify autism cases. The sensitivity, specificity, positive and negative predictive values were 0.62, 0.99, 0.72, and 0.99, respectively. True-positive children were diagnosed 10 months earlier than false-negative children. Autism symptom severity and the proportions of children with verbal and performance IQs/DQs < 70 were similar between groups. Although the sensitivity was suboptimal, the screening contributed to lowering the age at diagnosis for many children. Adding autism-specific screening to the well-child care program should be considered.

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9. Kyselicová K, Belica I, Vidošovičová M, Janšáková K, Neščáková E, Špajdel M, Navarová S, Ostatníková D. Autism spectrum disorder and new perspectives on the reliability of second to fourth digit ratio. Developmental psychobiology. 2021; 63(6): e22122.

The second to fourth digit ratio (2D:4D) is according to previous studies a likely biomarker for prenatal testosterone exposure and its effect on the human brain. It was found to be linked to autism spectrum disorders (ASD). Recently, 2D:4D raised a lot of questions with regard to its stability and autism-related behaviors. Here, we present a cross-sectional study of 2D:4D in boys (N = 91, mean age 7.63) and adults (N = 36 mean age 22.8) with ASD as well as neurotypical students, 506 participants in total. Digit ratio was assessed by taking measurements from digital scans, compared between groups and correlated with the autism quotient. Significant differences were found in the digit ratio of children and adults. Both girls and boys had 2D:4D ratio lower than women and men, both on the right (p = 0.000 in females, p = 0.000 in males) and left hand (p = 0.018 in females, p = 0.011 in males). No significant differences were found in digit ratios between neurotypical subjects and those with ASD nor was there a relationship with the reported autistic traits, which leads us to question the reliability of 2D:4D and its relation to ASD.

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10. Lee GK, Curtiss SL, Kuo HJ, Chun J, Lee H, Nimako DD. The Role of Acceptance in the Transition to Adulthood: A Multi-Informant Comparison of Practitioners, Families, and Youth with Autism. Journal of autism and developmental disorders. 2022; 52(4): 1444-57.

This study investigated the role of acceptance during the transition process among autistic young adults, parents, and practitioners. Six focus groups were run and thematic analysis was used to identify four themes: Youth on the autism spectrum discussed transition as a time where Self-Advocacy and Self-Acceptance were salient. Both youth and parents discussed the Lack of Understanding and Acceptance they experience. Particularly, youth highlighted the lack of understanding of sensory needs and parents underscored the lack of understanding by medical professionals. In contrast, practitioners highlighted the presence of Community Openness. Both practitioners and parents discussed Finding Personal Support through Acceptance. Self-acceptance and acceptance of autism are imperative for autistic young adults and families to achieve well-being.

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11. Loncarevic A, Maybery MT, Whitehouse AJO. The associations between autistic and communication traits in parents and developmental outcomes in children at familial risk of autism at 6 and 24 months of age. Infant behavior & development. 2021; 63: 101570.

BACKGROUND: Several studies have explored relationships between parent broader autism phenotype and offspring communication, and have reported that autistic-like traits in parents are related to offspring communication difficulties and autism severity. However, past research has focused on studying such associations in childhood and we know very little about them in infancy. With accumulating evidence that interventions administered during infancy may be most effective in reducing ASD symptoms, it is imperative to examine whether relationships between parent autistic-like traits and child communication appear even earlier during this critical period of life. METHOD: This longitudinal study collected data from infant siblings of autistic children (N = 32) and infants with no family history of autism (N = 45) to explore how autistic-like traits in parents related to child developmental outcomes during infancy. RESULTS: Parental communication difficulties and autistic-like traits were found to be associated with a range of child behaviours in the first two years of life, including social-emotional difficulties at 6 and 24 months, lower communication and emerging cognition at 24 months, and increased autistic behaviours at 24 months. CONCLUSIONS: Based on the results, it appears that some of the difficulties seen in parents are relayed to children genetically. These findings contribute to ASD research concerning early communication development in children and heritability of ASD traits and may have important implications in monitoring child development. Furthermore, since the current study found a significant association between autistic traits in parents and child social-emotional behaviour as early as 6 months of age, it provides evidence of the value of assessing interventions that target infancy.

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12. Molinini RM, Koziol NA, Marcinowski EC, Hsu LY, Tripathi T, Harbourne RT, McCoy SW, Lobo MA, Bovaird JA, Dusing SC. Early motor skills predict the developmental trajectory of problem solving in young children with motor delays. Developmental psychobiology. 2021; 63(6): e22123.

INTRODUCTION: The purpose of this study was to quantify the relationship between early motor skills, such as sitting, and the development of problem-solving skills in children with motor delays. METHODS: Motor (Gross Motor Function Measure) and problem-solving (Assessment of Problem-Solving in Play) skills of 134 children 7-16 months adjusted age at baseline with motor delay were assessed up to 5 times over 12 months. Participants were divided into two groups: mild and significant motor delay. RESULTS: Motor and problem-solving scores had large (r’s = 0.53-0.67) and statistically significant (p’s > .01) correlations at all visits. Baseline motor skills predicted baseline and change in problem solving over time. The associations between motor and problem-solving skills were moderated by level of motor delay, with children with significant motor delay generally having stronger associations compared to those with mild motor delay. CONCLUSIONS: These findings suggest that overall baseline motor skills are predictive of current and future development of problem-solving skills and that children with significant motor delay have a stronger and more stable association between motor and problem-solving skills over time. This highlights that children with motor delays are at risk for secondary delays in problem solving, and this risk increases as degree of motor delay increases.

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13. Nie G, Ullal A, Zheng Z, Swanson AR, Weitlauf AS, Warren ZE, Sarkar N. An Immersive Computer-Mediated Caregiver-Child Interaction System for Young Children With Autism Spectrum Disorder. IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society. 2021; 29: 884-93.

Autism Spectrum Disorder (ASD) affects 1 in 54 children in the United States. A core social communication skill negatively impacted by ASD is joint attention (JA), which influences the development of language, cognitive, and social skills from infancy onward. Although several technology-based JA studies have shown potential, they primarily focus on response to joint attention (RJA). The other important component of JA, the initiation of joint attention (IJA), has received less attention from a technology-based intervention perspective. In this work, we present an immersive Computer-mediated Caregiver-Child Interaction (C3I) system to help children with ASD practice IJA skills. C3I is a novel computerized intervention system that integrates a caregiver in the teaching loop, thereby preserving the advantages of both human and computer-administered intervention. A feasibility study with 6 dyads (caregiver-child with ASD) was conducted. A near significant increase with medium effect size on IJA performance was observed. Meanwhile, physiology-based stress analysis showed that C3I did not increase stress of the caregivers over the course of the study. To the best of our knowledge, this is the first autonomous system designed for teaching IJA skills to children with ASD incorporating caregivers within the loop to enhance the potential for generalization in real-world.

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14. Rossow T, MacLennan K, Tavassoli T. The relationship between sensory reactivity differences and mental health symptoms in preschool-age autistic children. Autism research : official journal of the International Society for Autism Research. 2021; 14(8): 1645-57.

There is growing evidence for an association between sensory reactivity and mental health in autism. This study set out to explore the relationship between sensory reactivity and mental health in preschool-aged autistic children. In total 54 preschool-aged children with an Autism Spectrum Condition took part. Sensory and mental health symptoms were obtained from the Sensory Processing Scale Inventory, Sensory Assessment of Neurodevelopmental Differences and the Behavioral Assessment System for Children-3. Correlational analyses showed a relationship between sensory reactivity and mental health symptoms in autistic preschool-aged children. Results also indicate divergence in sensory-mental health profiles between autistic preschool-aged children who are verbal and those who use few to no words. For the first time this study has revealed a relationship between sensory hyper-reactivity, as well as sensory seeking, and mental health symptoms outside of anxiety in autism. Of note, this relationship between sensory hyper-reactivity and internalizing symptoms appears to be driven by those with few to no words. This has implications for both research and clinical interventions, in particular for our understanding of the factors underlying mental health symptoms in different autistic phenotypes, as well as the possible role of functional communication in mitigating the development of mental health symptoms. LAY SUMMARY: The present study found that in autistic preschoolers, externalizing mental health symptoms, such as hyperactivity, are related to sensory seeking (seeking out or being fascinated with sensory stimuli), and internalizing mental health symptoms, such as depression, are related to sensory hyper-reactivity (sensitivity to sensory stimuli). Our results also show that whilst the relationships between externalizing symptoms and sensory seeking is seen across participants, the relationship between internalizing symptoms and sensory hyper-reactivity was only seen in autistic preschoolers who used few to no words. This has important implications for the assessment of sensory differences as part of more rigorous mental health assessments, especially in autistic people who use few to no words.

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15. Sandbank M, Chow J, Bottema-Beutel K, Woynaroski T. Evaluating evidence-based practice in light of the boundedness and proximity of outcomes: Capturing the scope of change. Autism research : official journal of the International Society for Autism Research. 2021; 14(8): 1536-42.

Evidence-based practice (EBP) reviews abound in early childhood autism intervention research. These reviews seek to describe and evaluate the evidence supporting the use of specific educational and clinical practices, but give little attention to evaluating intervention outcomes in terms of the extent to which they reflect change that extends beyond the exact targets and contexts of intervention. We urge consideration of these outcome characteristics, which we refer to as « proximity » and « boundedness, » as key criteria in evaluating and describing the scope of change effected by EBPs, and provide an overview and illustration of these concepts as they relate to early childhood autism intervention research. We hope this guidance will assist future researchers in selecting and evaluating intervention outcomes, as well as in making important summative determinations of the evidence base for this population. LAY SUMMARY: Recent reviews have come to somewhat different conclusions regarding the evidence base for interventions geared toward autistic children, perhaps because such reviews vary in the degree to which they consider the types of outcome measures used in past studies testing the effects of treatments. Here, we provide guidance regarding characteristics of outcome measures that research suggests are particularly important to consider when evaluating the extent to which an intervention constitutes « evidence-based practice. ».

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16. Sasayama D, Kuge R, Toibana Y, Honda H. Trends in Autism Spectrum Disorder Diagnoses in Japan, 2009 to 2019. JAMA network open. 2021; 4(5): e219234.

This cohort study examines the geographical variations in the incidence of autism spectrum disorder (ASD) and calculates the nationwide cumulative incidence of ASD in Japan.

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17. Varma M, Paskov KM, Chrisman BS, Sun MW, Jung JY, Stockham NT, Washington PY, Wall DP. A maximum flow-based network approach for identification of stable noncoding biomarkers associated with the multigenic neurological condition, autism. BioData mining. 2021; 14(1): 28.

BACKGROUND: Machine learning approaches for predicting disease risk from high-dimensional whole genome sequence (WGS) data often result in unstable models that can be difficult to interpret, limiting the identification of putative sets of biomarkers. Here, we design and validate a graph-based methodology based on maximum flow, which leverages the presence of linkage disequilibrium (LD) to identify stable sets of variants associated with complex multigenic disorders. RESULTS: We apply our method to a previously published logistic regression model trained to identify variants in simple repeat sequences associated with autism spectrum disorder (ASD); this L(1)-regularized model exhibits high predictive accuracy yet demonstrates great variability in the features selected from over 230,000 possible variants. In order to improve model stability, we extract the variants assigned non-zero weights in each of 5 cross-validation folds and then assemble the five sets of features into a flow network subject to LD constraints. The maximum flow formulation allowed us to identify 55 variants, which we show to be more stable than the features identified by the original classifier. CONCLUSION: Our method allows for the creation of machine learning models that can identify predictive variants. Our results help pave the way towards biomarker-based diagnosis methods for complex genetic disorders.

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18. Zhang L, Yan G, Benson V. The influence of emotional face distractors on attentional orienting in Chinese children with autism spectrum disorder. PloS one. 2021; 16(5): e0250998.

The current study examined how emotional faces impact on attentional control at both involuntary and voluntary levels in children with and without autism spectrum disorder (ASD). A non-face single target was either presented in isolation or synchronously with emotional face distractors namely angry, happy and neutral faces. ASD and typically developing children made more erroneous saccades towards emotional distractors relative to neutral distractors in parafoveal and peripheral conditions. Remote distractor effects were observed on saccade latency in both groups regardless of distractor type, whereby time taken to initiate an eye movement to the target was longest in central distractor conditions, followed by parafoveal and peripheral distractor conditions. The remote distractor effect was greater for angry faces compared to happy faces in the ASD group. Proportions of failed disengagement trials from central distractors, for the first saccade, were higher in the angry distractor condition compared with the other two distractor conditions in ASD, and this effect was absent for the typical group. Eye movement results suggest difficulties in disengaging from fixated angry faces in ASD. Atypical disengagement from angry faces at the voluntary level could have consequences for the development of higher-level socio-communicative skills in ASD.

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