1. Akhter S, Shefa J, Quader MA, Talukder K, Hussain AE, Kundu GK, Fatema K, Alam ST, Islam KA, Rahman MS, Rahman MM, Hasan Z, Mannan M. Autism spectrum disorder among 16- to 30-month-old children in Bangladesh: Observational cross-sectional study. Autism : the international journal of research and practice. 2022: 13623613221135297.

A nationwide survey was done in Bangladesh to assess autism spectrum disorder prevalence in 16- to 30-month-old children at urban-rural distribution and to determine the association with socioeconomic and demographic conditions. A three-stage cluster sampling method was used where districts from all divisions were selected in the first stage, census enumeration areas as blocks of households were selected in the second stage and households (within the blocks) were selected in the third stage. Thereby, it included 38,440 children from 37,982 households (71% rural, 29% urban) aged 16-30 months from 30 districts of eight divisions of Bangladesh. Screening was done with a ‘Red Flag’ tool and Modified Checklist for Toddlers and a final diagnosis using Diagnostic and Statistical Manual of Mental Disorders, 5th Edition for autism spectrum disorder. Autism spectrum disorder prevalence was 17 per 10,000 young children – in other words, one in 589 young children. Boys were found at higher risk of autism (one in 423 boys; one in 1026 girls). Prevalence of autism spectrum disorder was higher in urban environments than in rural ones – 25/10,000 and 14/10,000, respectively. More autism spectrum disorder children were found in advanced age groups of parents, especially mothers, and in households with a higher wealth quintile. This survey is significant as it covers both urban and rural areas and specifically targets very young children. The involvement of the Bangladesh Bureau of Statistics, as well as support from the entire healthcare system infrastructure, makes this survey more representative on a national level. Its results will form a database to support the development of an effective early intervention programme in Bangladesh. We hope it will prove useful for researchers, clinicians and frontline healthcare workers, and inform the decisions of policymakers and funders in Bangladesh.

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2. Behzadpoor S, Pouretemad H. Some comments on « intolerance of uncertainty » for explaining anxiety in children with autism. Asian journal of psychiatry. 2022; 79: 103333.

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3. Chezan LC, McCammon MN, Wolfe K, Drasgow E, Tabacu LM. Teachers’ Familiarity, Confidence, Training, and Use of Problem Behavior Interventions for Learners with Autism Spectrum Disorder in School Settings. Journal of developmental and physical disabilities. 2022: 1-25.

Our main purpose in this study was to investigate the levels of and the relationship between familiarity, confidence, training, and use of problem behavior interventions by special education teachers working with learners with autism spectrum disorder (ASD) in school settings. A total of 80 special education teachers in South Carolina and Virginia completed an online survey. Results indicate a positive correlation between teachers’ familiarity, confidence, training, and use of problem behavior interventions. Across all intervention categories, providing choices, prompting, modeling, and direct instruction received the highest rankings for familiarity, confidence, and use. In addition, our results reveal that familiarity and confidence in implementing these interventions differs across groups of special education teachers based on years of experience. The most frequently reported factors that limit the use of problem behavior interventions in school settings were competing responsibilities, the need to involve multiple people, the amount of time required, and the difficulty using interventions during typical routines. Implications for research and practice are discussed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10882-022-09885-2.

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4. Cumberland A, Hale N, Azhan A, Gilchrist CP, Chincarini G, Tolcos M. Excitatory and inhibitory neuron imbalance in the intrauterine growth restricted fetal guinea pig brain: Relevance to the developmental origins of schizophrenia and autism. Developmental neurobiology. 2022.

Neurodevelopmental disorders such as schizophrenia and autism are thought to involve an imbalance of excitatory and inhibitory signaling in the brain. Intrauterine growth restriction (IUGR) is a risk factor for these disorders, with IUGR onset occurring during critical periods of neurodevelopment. The aim of this study was to determine the impact of IUGR on excitatory and inhibitory neurons of the fetal neocortex and hippocampus. Fetal brains (n = 2) were first collected from an unoperated pregnant guinea pig at mid-gestation (32 days of gestation [dg]; term ∼67 dg) to visualize excitatory (Ctip2) and inhibitory (calretinin [CR] and somatostatin [SST]) neurons via immunohistochemistry. Chronic placental insufficiency (CPI) was then induced via radial artery ablation at 30 dg in another cohort of pregnant guinea pigs (n = 8) to generate IUGR fetuses (52 dg; n = 8); control fetuses (52 dg; n = 7) were from sham surgeries with no radial artery ablation. At 32 dg, Ctip2- and CR-immunoreactive (IR) cells had populated the cerebral cortex, whereas SST-IR cells had not, suggesting these neurons were yet to complete migration. At 52 dg, in IUGR versus control fetuses, there was a reduction in SST-IR cell density in the cerebral cortex (p = .0175) and hilus of the dentate gyrus (p = .0035) but not the striatum (p > .05). There was no difference between groups in the density of Ctip2-IR (cortex) or CR-IR (cortex, hippocampus) neurons (p > 0.05). Thus, we propose that an imbalance in inhibitory (SST-IR) and excitatory (Ctip2-IR) neurons in the IUGR fetal guinea pig brain could lead to excitatory/inhibitory dysfunction commonly seen in neurodevelopmental disorders such as autism and schizophrenia.

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5. Denisova K, Lin Z. The importance of low IQ to early diagnosis of autism. Autism research : official journal of the International Society for Autism Research. 2022.

Some individuals can flexibly adapt to life’s changing demands while others, in particular those with Autism Spectrum Disorder (ASD), find it challenging. The origin of early individual differences in cognitive abilities, the putative tools with which to navigate novel information in life, including in infants later diagnosed with ASD remains unexplored. Moreover, the role of intelligence quotient (IQ) vis-à-vis core features of autism remains debated. We systematically investigate the contribution of early IQ in future autism outcomes in an extremely large, population-based study of 8000 newborns, infants, and toddlers from the US between 2 and 68 months with over 15,000 cross-sectional and longitudinal assessments, and for whom autism outcomes are ascertained or ruled out by about 2-4 years. This population is representative of subjects involved in the National Institutes of Health (NIH)-funded research, mainly on atypical development, in the US. Analyses using predetermined age bins showed that IQ scores are consistently lower in ASD relative to typically developing (TD) children at all ages (p < 0.001), and IQ significantly correlates with social, non-social, and total Calibrated Severity Scores (CSS) on the Autism Diagnostic Observation Schedule (ADOS) (p<0.01). Lower IQ is associated with greater autistic impairments. Note, verbal IQ (VIQ) is no better than the full-scale IQ to predict ASD cases. These findings raise new, compelling questions about potential atypical brain circuitry affecting performance in both verbal and nonverbal abilities and preceding an ASD diagnosis. This study is the first to establish prospectively that low early IQ is a major feature of ASD in early childhood. LAY SUMMARY: The role of IQ scores in autism remains debated. We systematically investigate the contribution of early IQ in an extremely large study of 8,000 children between 2 and 68 months with autism outcomes by about 2-4 years. We show that IQ scores are consistently lower in ASD relative to TD children. This study is the first to establish prospectively that low early IQ is a predictor for ASD diagnosis in early childhood.

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6. Ferenc K, Płatos M, Byrka K, Król ME. Looking through rainbow-rimmed glasses: Taking neurodiversity perspective is related to subjective well-being of autistic adults. Autism : the international journal of research and practice. 2022: 13623613221135818.

Autistic adults experience a high level of distress. Finding new ways to support their well-being is an important goal for researchers and clinicians. We assessed the way autistic adults view their autism, as a disorder or as a type of mind (neurodiversity), and the level they integrate with other autistic people, and we checked how those factors contribute to their well-being. People who see autism rather as a type of mind than as a disorder had higher self-esteem. People who view themselves as more similar to other autistic people felt more stressed, but this result was not accurate for people who view autism as a type of mind. Clinicians should be sensitive to the way autistic people understand autism and to what extent they identify with the autism community, because it may relate to their well-being.

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7. Gong L, Guo D, Gao Z, Wei K. Atypical development of social and nonsocial working memory capacity among preschoolers with autism spectrum disorders. Autism research : official journal of the International Society for Autism Research. 2022.

Individuals with autism spectrum disorders (ASD) have shown impaired performance in canonical and nonsocial working memory (WM). However, no study has investigated social WM and its early development. Using biological motion stimuli, our study assessed the development of social and nonsocial WM capacity among children with or without ASD across the age span between 4 and 6 (N = 150). While typically developing (TD) children show a rapid development from age 5 to 6, children with ASD showed a delayed development for both social and nonsocial WM capacity, reaching a significant group difference at age 6. Furthermore, we found a negative correlation between social (but not nonsocial) WM capacity and the severity of autistic symptoms among children with ASD. In contrast, there is a positive correlation between both types of WM capacity and intelligence among TD children but not among children with ASD. Our findings thus indicate that individuals with ASD miss the rapid development of WM capacity in early childhood and, particularly, their delayed social WM development might contribute to core symptoms that critically depend on social information processing.

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8. Gracia-Darder I, Llull Ramos A, Giacaman A, Gómez Bellvert C, Obrador-Hevia A, Jubert Esteve E, Martín-Santiago A. Report of a case of RAVEN, hair heterochromia and autism in the setting of FGFR2 mutation. Pediatric dermatology. 2022.

A newborn presented with extensive rounded and velvety epidermal nevus (RAVEN) with a genetic study of the cutaneous lesions revealing a heterozygous mutation in FGFR2 (p.Cys382Arg). By 2 years of age, the patient developed hair heterochromia and autism spectrum disorder. Although RAVEN was initially associated with fibroblast growth factor 3 (FGFR3) mutations, three cases of RAVEN have been identified with mutations in FGFR2 (p.Ser252Trp) and one case of linear keratinocytic epidermal nevi has been identified with the same mutation as the mutation identified in our patient. This strongly supports the pathogenic role of these mutations.

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9. Granak S, Tuckova K, Kutna V, Vojtechova I, Bajkova L, Petrasek T, Ovsepian SV. Developmental dynamics of the impact of constitutive mTORC1 hyperactivity and environmental enrichment on structural synaptic plasticity and behaviour in a rat model of autism spectrum disorder. The European journal of neuroscience. 2022.

Autism spectrum disorder (ASD) is a neurodevelopmental condition causing a range of social and communication impairments. Although the role of multiple genes and environmental factors has been reported, the impact of the interplay between genes and environment on the onset and progression of the disease remains elusive. We housed wild-type (Tsc2+/+) and tuberous sclerosis 2 deficient (Tsc2+/-) Eker rats (ASD model) in individually ventilated cages or enriched conditions and conducted a series of behavioural tests followed by the histochemical analysis of dendritic spines and plasticity in three age groups (days 45, 90, and 365). The elevated plus-maze test revealed a reduction of anxiety by enrichment, while the mobility of young and adult Eker rats in the open field was lower compared to wild-type. In the social interaction test, an enriched environment reduced social contact in the youngest group and increased anogenital exploration in 90- and 365-day-old rats. Self-grooming was increased by environmental enrichment in young and adult rats and decreased in aged Eker rats. Dendritic spine counts revealed an increased spine density in the cingulate gyrus in adult Ekers irrespective of housing conditions, whereas spine density in hippocampal pyramidal neurons was comparable across all genotypes and groups. Morphometric analysis of dendritic spines revealed age-related changes in spine morphology and density which were responsive to animal genotype and environment. Taken together, our findings suggest that under TSC2 haploinsufficiency and mTORC1 hyperactivity, the expression of behavioural signs and neuroplasticity in Eker rats can be differentially influenced by the developmental stage and environment.

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10. Hayot G, Massonot M, Keime C, Faure E, Golzio C. Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance. Life science alliance. 2023; 6(1).

Individuals with mutations in CHD8 present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, using a stable constitutive chd8 mutant zebrafish model, we found that the loss of chd8 leads to a reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube, and that their early migration capability was altered. At later stages, although the intestinal colonization by NCCs was complete, we found the decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in the absence of chd8 Furthermore, transcriptomic analyses revealed an altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. The tissue examination of chd8 mutants revealed a thinner intestinal epithelium accompanied by an accumulation of neutrophils and the decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with a perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between chd8, NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.

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11. Hocking DR, Loesch DZ, Stimpson P, Tassone F, Atkinson A, Storey E. Relationships of Motor Changes with Cognitive and Neuropsychiatric Features in FMR1 Male Carriers Affected with Fragile X-Associated Tremor/Ataxia Syndrome. Brain sciences. 2022; 12(11).

The premutation expansion of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome has been linked to a range of clinical and subclinical features. Nearly half of men with FMR1 premutation develop a neurodegenerative disorder; Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). In this syndrome, cognitive executive decline and psychiatric changes may co-occur with major motor features, and in this study, we explored the interrelationships between these three domains in a sample of adult males affected with FXTAS. A sample of 23 adult males aged between 48 and 80 years (mean = 62.3; SD = 8.8), carrying premutation expansions between 45 and 118 CGG repeats, and affected with FXTAS, were included in this study. We employed a battery of cognitive assessments, two standard motor rating scales, and two self-reported measures of psychiatric symptoms. When controlling for age and/or educational level, where appropriate, there were highly significant correlations between motor rating score for ICARS gait domain, and the scores representing global cognitive decline (ACE-III), processing speed (SDMT), immediate memory (Digit Span), and depression and anxiety scores derived from both SCL90 and DASS instruments. Remarkably, close relationships of UPDRS scores, representing the contribution of Parkinsonism to FXTAS phenotypes, were exclusive to psychiatric scores. Highly significant relationships between CGG repeat size and most scores for three phenotypic domains suggest a close tracking with genetic liability. These findings of relationships between a constellation of phenotypic domains in male PM carriers with FXTAS are reminiscent of other conditions associated with disruption to cerebro-cerebellar circuits.

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12. Högstedt E, Igelström K, Korhonen L, Käcker P, Marteinsdottir I, Björk M. ‘It’s like it is designed to keep me stressed’-Working sustainably with ADHD or autism. Scandinavian journal of occupational therapy. 2022: 1-12.

BACKGROUND: Adults with attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) face multiple challenges in obtaining and maintaining employment. AIMS: To identify and describe how adults with ADHD or ASD experienced their ability to work and what factors affected their ability to find a sustainable work situation over time. METHODS: Individual in-depth interviews were performed with 20 purposively sampled participants with ADHD/ASD. Data were analysed inductively using reflexive thematic analysis. RESULTS: Three themes were identified, describing (1) one’s own cognitive abilities and challenges, (2) enablement by flexibility and acceptance in the work environment, and (3) accumulated stress that makes the work situation unsustainable over time. CONCLUSIONS: Over time, a lack of continuity and predictability of support measures caused great stress and exhaustion, with severe consequences for working life and in life in general. Adaptations needed to be individually tailored and include nonoccupational factors. SIGNIFICANCE: The study shows that adults with ADHD/ASD need long-term interventions that flexibly adapt to individual needs, as they vary over time. The findings suggest that occupational therapists and other health care providers, employers, employment services and other involved agencies should pay a greater deal of attention to stability and predictability over time.

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13. Huebschman JL, Monterrey CA, Foster DM, Omoregie CC, Cakir AE, Sevilla-Gutierrez A, Chow EC, Essoh A, Guo Y, Smith LN. The role of the dorsal striatum in a mouse model for fragile X syndrome: Behavioral and dendritic spine assessment. Brain research. 2022; 1795: 148060.

Fragile X syndrome (FXS), a leading monogenic cause of autism spectrum disorders (ASDs), typically occurs as the result of a mutation silencing the Fmr1 gene, preventing production of the fragile X messenger ribonucleoprotein (FMRP). FXS is characterized, in part, by hyperactivity, impaired behavioral flexibility, and the development of repetitive, or stereotyped, behaviors. While these phenotypes are influenced by striatal activity, few studies have examined FXS or FMRP in the context of striatal function. Here, we report enhanced repetitive behaviors in Fmr1 knockout (KO) compared to wild type (WT) mice according to multiple measures, including quantity and intensity of stereotypic behaviors in an open field and nose poking activity in an unbaited hole board test. However, using a baited version of the hole board assay, we see that KO mice do show some behavioral flexibility in that they make changes in their nose poking behavior following familiarization with an appetitive bait. By contrast, repeated exposure to cocaine (15 mg/kg) promotes repetitive behavior in both WT and KO mice, in a manner mostly independent of genotype. Branch length alterations in medium spiny neurons (MSNs) of the dorsolateral striatum (DLS) are similar between WT cocaine-treated and KO saline-treated mice, possibly suggesting shared synaptic mechanisms. Overall, we suggest that scoring open field behavior is a sensitive measure for repetitive sensory-motor behaviors in Fmr1 KO mice. In addition, our findings show that synaptic contacts onto MSNs in the DLS should be examined in conjunction with measures of stereotypical behavior.

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14. Ifrim MF, Janusz-Kaminska A, Bassell GJ. Development of single-molecule ubiquitination mediated fluorescence complementation to visualize protein ubiquitination dynamics in dendrites. Cell reports. 2022; 41(7): 111658.

The ubiquitination/proteasome system is important for the spatiotemporal control of protein synthesis and degradation at synapses, while dysregulation may underlie autism spectrum disorders (ASDs). However, methods allowing direct visualization of the subcellular localization and temporal dynamics of protein ubiquitination are lacking. Here we report the development of Single-Molecule Ubiquitin Mediated Fluorescence Complementation (SM-UbFC) as a method to visualize and quantify the dynamics of protein ubiquitination in dendrites of live neurons in culture. Using SM-UbFC, we demonstrate that the rate of PSD-95 ubiquitination is elevated in dendrites of FMR1 KO neurons compared with wild-type controls. We further demonstrate the rapid ubiquitination of the fragile X messenger ribonucleoprotein, FMRP, and the AMPA receptor subunit, GluA1, which are known to be key events in the regulation of synaptic protein synthesis and plasticity. SM-UbFC will be useful for future studies on the regulation of synaptic protein homeostasis.

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15. Jeon SJ, Kwon H, Bae HJ, Gonzales EL, Kim J, Chung HJ, Kim DH, Ryu JH, Shin CY. Agmatine relieves behavioral impairments in Fragile X mice model. Neuropharmacology. 2022; 219: 109234.

BACKGROUND: Fragile X syndrome (FXS) is the most common heritable form of neurodevelopmental disorder, which is caused by the loss of fragile X mental retardation protein (FMRP) expression. Despite the unceasing efforts to develop therapeutic agents against FXS based on the pathophysiological changes observed in animal models of FXS and human patients, therapeutic candidates including mGluR signaling modulators have failed to provide sufficient effects. Based on the recent successful demonstration of an endogenous polyamine, agmatine, to improve the autism-like symptoms in the valproic acid animal model of autism, we investigated the effects of agmatine against FXS symptoms using Fmr1 knockout (KO) mice. METHODS: We used male Fmr1 KO mice for behavioral tests such as marble burying, open-field test, memory tasks, social interaction tests and startle response to confirm the symptoms of FXS. We also checked the electrophysiological profile of neural activity in agmatine-treated Fmr1 KO mice. RESULTS: Agmatine reversed the compulsion, learning and memory deficits, hyperactivity, aberrant social interaction, and communication deficit in Fmr1 KO mice while it normalized the aberrant LTP and LTD in the hippocampus. CONCLUSIONS: The results highlight the potential of agmatine’s novel disease-ameliorating effects in FXS, which warrants further studies to ascertain whether these findings translate into clinical effects in FXS patients.

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16. Kilroy E, Gerbella M, Cao L, Molfese P, Butera C, Harrison L, Jayashankar A, Rizzolatti G, Aziz-Zadeh L. Specific tractography differences in autism compared to developmental coordination disorder. Scientific reports. 2022; 12(1): 19246.

About 85% of children with autism spectrum disorder (ASD) experience comorbid motor impairments, making it unclear whether white matter abnormalities previously found in ASD are related to social communication deficits, the hallmark of ASD, or instead related to comorbid motor impairment. Here we aim to understand specific white matter signatures of ASD beyond those related to comorbid motor impairment by comparing youth (aged 8-18) with ASD (n = 22), developmental coordination disorder (DCD; n = 16), and typically developing youth (TD; n = 22). Diffusion weighted imaging was collected and quantitative anisotropy, radial diffusivity, mean diffusivity, and axial diffusivity were compared between the three groups and correlated with social and motor measures. Compared to DCD and TD groups, diffusivity differences were found in the ASD group in the mid-cingulum longitudinal and u-fibers, the corpus callosum forceps minor/anterior commissure, and the left middle cerebellar peduncle. Compared to the TD group, the ASD group had diffusivity differences in the right inferior frontal occipital/extreme capsule and genu of the corpus callosum. These diffusion differences correlated with emotional deficits and/or autism severity. By contrast, children with DCD showed unique abnormality in the left cortico-spinal and cortico-pontine tracts.Trial Registration All data are available on the National Institute of Mental Health Data Archive: https://nda.nih.gov/edit_collection.html?id=2254 .

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17. Kim NS, Ringeling FR, Zhou Y, Nguyen HN, Temme SJ, Lin YT, Eacker S, Dawson VL, Dawson TM, Xiao B, Hsu KS, Canzar S, Li W, Worley P, Christian KM, Yoon KJ, Song H, Ming GL. CYFIP1 Dosages Exhibit Divergent Behavioral Impact via Diametric Regulation of NMDA Receptor Complex Translation in Mouse Models of Psychiatric Disorders. Biological psychiatry. 2022; 92(10): 815-26.

BACKGROUND: Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. METHODS: We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. RESULTS: Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. CONCLUSIONS: CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

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18. Lee J, Lee TS, Lee S, Jang J, Yoo S, Choi Y, Park YR. Correction: Development and Application of a Metaverse-Based Social Skills Training Program for Children With Autism Spectrum Disorder to Improve Social Interaction: Protocol for a Randomized Controlled Trial. JMIR research protocols. 2022; 11(11): e43864.

[This corrects the article DOI: 10.2196/35960.].

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19. Lin E, Lunsky Y, Chung H, Durbin A, Volpe T, Dobranowski K, Benadict MB, Balogh R. Amenable deaths among adults with intellectual and developmental disabilities including Down syndrome: An Ontario population-based cohort study. Journal of applied research in intellectual disabilities : JARID. 2022.

BACKGROUND: Rates of death and avoidable deaths are reportedly higher among people with intellectual and developmental disabilities. This study contributes to our understanding of how mortality and intellectual and development disabilities are associated. METHOD: General population and intellectual and developmental disabilities adult cohorts were defined using linked administrative data. All-cause and amenable deaths between 2010 and 2015 were reported for these cohorts and subcohorts with and without Down syndrome. Cox proportional hazards models evaluated the impact of potential contributors to amenable deaths. RESULTS: Adults with intellectual and developmental disabilities had higher all-cause (6.1 vs. 1.6%) and amenable death percentages (21.4 vs. 14.1%) than general population comparators. Within intellectual and developmental disabilities, those with Down syndrome had higher all-cause (12.0 vs. 6.0%) but lower amenable death percentages (19.2 vs. 21.8%) than those without. CONCLUSIONS: Results suggest that interventions to reduce amenable deaths target provider-care-recipient interactions and coordination across care and support sectors.

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20. Lin PY, Chen YL, Hsiao RC, Chen HL, Yen CF. Risks of attention-deficit/hyperactivity disorder, autism spectrum disorder, and intellectual disability in children delivered by caesarean section: A population-based cohort study. Asian journal of psychiatry. 2022; 80: 103334.

This population-based study investigated the risks of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disabilities among children delivered by Cesarean section (CS) in comparison with those who were delivered by vaginal delivery (VD). The Taiwan Maternal and Child Health Database from 2004 to 2016 registered 675,718 and 1,208,983 children delivered by CS and by VD, respectively. The results of Cox proportional hazards regression model demonstrated that children delivered by CS had significantly higher risks of ADHD, ASD, and intellectual disability than those delivered by VD after the confounding effects of maternal and child factors were controlled for.

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21. Maisterrena A, Matas E, Mirfendereski H, Balbous A, Marchand S, Jaber M. The State of the Dopaminergic and Glutamatergic Systems in the Valproic Acid Mouse Model of Autism Spectrum Disorder. Biomolecules. 2022; 12(11).

Autism Spectrum Disorder (ASD) is a progressive neurodevelopmental disorder mainly characterized by deficits in social communication and stereotyped behaviors and interests. Here, we aimed to investigate the state of several key players in the dopamine and glutamate neurotransmission systems in the valproic acid (VPA) animal model that was administered to E12.5 pregnant females as a single dose (450 mg/kg). We report no alterations in the number of mesencephalic dopamine neurons or in protein levels of tyrosine hydroxylase in either the striatum or the nucleus accumbens. In females prenatally exposed to VPA, levels of dopamine were slightly decreased while the ratio of DOPAC/dopamine was increased in the dorsal striatum, suggesting increased turn-over of dopamine tone. In turn, levels of D1 and D2 dopamine receptor mRNAs were increased in the nucleus accumbens of VPA mice suggesting upregulation of the corresponding receptors. We also report decreased protein levels of striatal parvalbumin and increased levels of p-mTOR in the cerebellum and the motor cortex of VPA mice. mRNA levels of mGluR1, mGluR4, and mGluR5 and the glutamate receptor subunits NR1, NR2A, and NR2B were not altered by VPA, nor were protein levels of NR1, NR2A, and NR2B and those of BDNF and TrkB. These findings are of interest as clinical trials aiming at the dopamine and glutamate systems are being considered.

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22. Malow BA, Veatch OJ, Niu X, Fitzpatrick KA, Hucks D, Maxwell-Horn A, Davis LK. A practical approach to identifying autistic adults within the electronic health record. Autism research : official journal of the International Society for Autism Research. 2022.

The electronic health record (EHR) provides valuable data for understanding physical and mental health conditions in autism. We developed an approach to identify charts of autistic young adults, retrieved from our institution’s de-identified EHR database. Clinical notes within two cohorts were identified. Cohort 1 charts had at least one International Classification of Diseases (ICD-CM) autism code. Cohort 2 charts had only autism key terms without ICD-CM codes, and at least four notes per chart. A natural language processing tool parsed medical charts to identify key terms associated with autism diagnoses and mapped them to Unified Medical Language System Concept Unique Identifiers (CUIs). Average scores were calculated for each set of charts based on captured CUIs. Chart review determined whether patients met criteria for autism using a classification rubric. In Cohort 1, of 418 patients, 361 were confirmed to have autism by chart review. Sensitivity was 0.99 and specificity was 0.68 with positive predictive value (PPV) of 0.97. Specificity improved to 0.81 (sensitivity was 0.95; PPV was 0.98) when the number of notes was limited to four or more per chart. In Cohort 2, 48 of 136 patients were confirmed to have autism by chart review. Sensitivity was 0.95, specificity was 0.73, and PPV was 0.70. Our approach, which included using key terms, identified autism charts with high sensitivity, even in the absence of ICD-CM codes. Relying on ICD-CM codes alone may result in inclusion of false positive cases and exclusion of true cases with autism.

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23. Naples A, Tenenbaum EJ, Jones RN, Righi G, Sheinkopf SJ, Eigsti IM. Exploring communicative competence in autistic children who are minimally verbal: The Low Verbal Investigatory Survey for Autism (LVIS). Autism : the international journal of research and practice. 2022: 13623613221136657.

Approximately one in three autistic children is unable to communicate with language; this state is often described as minimally verbal. Despite the tremendous clinical implications, we cannot predict whether a minimally verbal child is simply delayed (but will eventually develop spoken language) or will continue to struggle with verbal language, and might therefore benefit from learning an alternative form of communication. This is important for clinicians to know, to be able to choose the most helpful interventions, such as alternative forms of communication. In addition, the field lacks a standard definition of « minimally verbal. » Even when we do agree on what the term means (e.g. fewer than 20 words), describing a child based on their lack of words does not tell us whether that child is communicating in other ways or how they are using those 20 words. To address these concerns, we developed the Low Verbal Investigatory Survey (LVIS), a one-page parent-report measure designed to help us characterize how minimally verbal autistic children are communicating. Parents of 147 children (aged 1-8 years) completed the LVIS. Here, we ask (1) whether the survey measures what it was designed to measure, that is, communicative ability in children without much spoken language, and (2) how the LVIS relates to cognitive and language ability, and symptoms of autism. Results suggest that this survey, which takes only 5 min to complete, is a good estimate of the child’s communication skills. Furthermore, LVIS survey scores are correlated with other measures of language and cognitive abilities as well as autism symptomatology. The LVIS has the potential to save time and money in both clinical and research efforts to assess communication skills in minimally verbal autistic children.

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24. Ng CSM, Ng SSL. A qualitative study on the experience of stigma for Chinese parents of children with autism spectrum disorder. Scientific reports. 2022; 12(1): 19550.

Experiencing stigma related to having a child with autism spectrum disorder (ASD) can be difficult and is detrimental to parent well-being. Since the research on stigmatized experiences among parents of children with ASD in non-Western communities is limited, this qualitative study examined the experiences, reactions and impacts of stigma on parents of children with ASD in Hong Kong. In-depth interviews were conducted with 54 Chinese parents/caregivers of children with ASD aged between 35 and 73 years old. Data were analyzed using an inductive approach. The participants reported stigma which stemmed from negative labelling of their children by schools and healthcare professionals, bullying by peers, stereotypes of ASD and stigma linked to autistic children’s behavior in the community. The reactions of participants towards stigmatization were classified into internalizing reactions including apologizing, ignoring and concealing ASD and externalizing reactions such as fighting back. The participants also reported impacts of stigma on both personal and emotional levels. The results point to the urgent need for the government to allocate resources and make concerted efforts to reduce stigma by educating the community to foster more positive attitudes towards individuals with ASD and offer support and counselling services to parents.

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25. Strom NI, Smit DJA, Silzer T, Iyegbe C, Burton CL, Pool R, Lemire M, Crowley JJ, Hottenga JJ, Ivanov VZ, Larsson H, Lichtenstein P, Magnusson P, Rück C, Schachar RJ, Wu HM, Meier SM, Crosbie J, Arnold PD, Mattheisen M, Boomsma DI, Mataix-Cols D, Cath D. Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals. Translational psychiatry. 2022; 12(1): 479.

Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26-48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a « gene discovery zone ». To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.

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26. Tevis C, Matson JL, Callahan M. Developmental Functioning of Toddlers At-Risk for Autism With and Without Down Syndrome. Developmental neurorehabilitation. 2022: 1-9.

PURPOSE: Due to the difficulties in differentiating between impairments associated with intellectual disability and ASD symptomology, DS often leads to delayed or misdiagnoses of ASD. METHOD: An ANOVA was run to investigate the effects of ASD risk and DS on overall developmental functioning across three groups: ASD+, DS-, and DS+ (n = 138). A MANOVA was run to investigate the differences of group on five developmental subdomains. RESULTS: The results revealed significant group differences in the overall developmental functioning and each developmental subdomain. Children in the DS+ group demonstrated significantly lower overall developmental functioning, as well as lower adaptive, cognitive, motor, and communication skills compared to their peers; however, children in the DS- group demonstrated significantly better social skills compared to their peers in the ASD+ group. DISCUSSION: These findings support the need for early screening and identification of ASD among those with DS.

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27. Trivedi P, Pandey M, Kumar Rai P, Singh P, Srivastava P. A meta-analysis of differentially expressed and regulatory genes with their functional enrichment analysis for brain transcriptome data in autism spectrum disorder. Journal of biomolecular structure & dynamics. 2022: 1-7.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent challenges in social interactions and repetitive behavioral patterns. It is a significant problem emerging worldwide, as one in 100 children is affected by this disorder globally. In this study, a meta-analysis was performed for the identification of differentially expressed genes (DEGs) along with the expression analysis of regulatory genes. Functional enrichment analysis was an integral part of current findings to notify the significant pathways of this complex disorder. The study was conducted with two RNA-Seq datasets, viz., GSE64018 and GSE62098, for ASD patients and control samples from the GEO database. The identification of up-regulatory and down-regulatory genes was performed by the interaction analysis of transcription factors (TF) and DEGs. As an outcome of the meta-analysis, 2543 DEGs were identified as common across both of the datasets in which 1402 DEGs exhibited upregulation and 1130 genes have shown downregulation. In network analysis, upregulatory genes have shown strong interaction while downregulatory genes exhibit weak or null interaction. Further, in the enrichment analysis of screened upregulatory DEGs, three major significant pathways were identified namely the ATP synthesis pathway, FAS signaling pathway, and the Huntington’s disease pathway. The common expression of CYC 1 gene in all the identified pathways has indicated that it is an important key regulator gene for the majorly associated pathways. The study concludes that all the potential DEGs were found to show their related high expression in neurobiological regulations specifically with ASD.Communicated by Ramaswamy S. Sarma.

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28. Velani B, Sawhney I, Alexander RT, Shardlow S, Zia A. Implementing proposed reforms of the Mental Health Act for people with intellectual disability and autism: the perspective of multidisciplinary professionals in intellectual disability teams. BJPsych open. 2022; 8(6): e197.

BACKGROUND: A recent government white paper sets out proposals for reforms to the Mental Health Act 1983 (MHA). Some of these proposals affect people with intellectual disabilities and/or autism. AIMS: To explore both positive and unintended negative effects of the proposed reforms by gathering the perspectives of healthcare workers from multiple disciplines, working with intellectual disability and/or autism in community and in-patient settings. METHOD: A 14-question electronic questionnaire, comprising free-text, multiple choice and five-point Likert scale responses, was sent out via email between April and July 2021, to all multidisciplinary team professionals working in specialist intellectual disability community and in-patient teams in Hertfordshire Partnership University NHS Foundation Trust. RESULTS: There were 45 responders, of whom 53% worked in in-patient settings and 47% in out-patient teams. Respondents comprised healthcare professionals from multiple disciplines, 80% of which were non-medical. Most responders agreed with the general principles of the proposed reforms. However, 80% felt there would be potentially unintended consequences, and 76% thought that substantial investment in community services was required in advance of the proposed reforms. CONCLUSIONS: The proposed MHA reforms may have unintended consequences for people with intellectual disabilities and/or autism. The findings of this study raised key concerns that need to be explored further and addressed before the MHA reforms are implemented. These include community provision, safeguards and use of the Mental Capacity Act, the potential for under or overdiagnosis of mental illness, and effects associated with the criminal justice system.

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29. Wang T, Kim CN, Bakken TE, Gillentine MA, Henning B, Mao Y, Gilissen C, Nowakowski TJ, Eichler EE. Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders. Proceedings of the National Academy of Sciences of the United States of America. 2022; 119(46): e2203491119.

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.

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30. Wilson AC, Gunn S. What parents want in an autism diagnostic report: An interview-based study of parents accessing a neurodevelopmental assessment service. Clinical child psychology and psychiatry. 2022: 13591045221138703.

Diagnostic reports are a key outcome of autism assessment services. However, there is limited evidence regarding what key stakeholders, including families, want to see in reports. In this project, 30 parents whose young person had recently received a diagnosis of autism from a Neurodevelopmental Assessment Service in the North East of England took part in a telephone-based interview to explore what they want from a report. Interviews were analysed using thematic analysis. Ten key recommendations for reports were identified. Parents indicated that they want a detailed, balanced, sensitively written report. They highlighted that reports needed to be accessible and clearly structured. In this respect, it might be helpful to include a parent-driven summary of key points at the top, clear signposting of the structure of the report, and a description of what happened in the assessment process. Parents also valued practical, personalised recommendations based on the young person’s strengths and difficulties. Future research might explore perspectives on reports in families accessing other services, in other client groups (e.g., families of pre-schoolers diagnosed with autism), and with different stakeholders, including schools, referrers and autistic people.

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31. Wilson RB, Thompson AR, Rowse G, Smith R, Dugdale AS, Freeth M. Autistic women’s experiences of self-compassion after receiving their diagnosis in adulthood. Autism : the international journal of research and practice. 2022: 13623613221136752.

Knowledge of autistic individuals’ experiences of self-compassion is very limited. This study investigated autistic women’s experiences of self-compassion after receiving their diagnosis in adulthood. Eleven autistic women were interviewed about their experiences of receiving their diagnosis in adulthood and their experiences of self-compassion. Systematic analysis of the interview transcripts revealed common themes in the participants’ experiences. Participants reported that their autism diagnosis helped them to better understand themselves, particularly when reflecting on problematic past experiences. After receiving an autism diagnosis, participants described being able to relate to themselves with greater self-kindness compared to previous self-criticism; this included allowing themselves to assert their needs and engage in self-care activities. Participants spoke about having difficult social experiences, including feeling pressure to conform to expectations in society and often feeling misunderstood. The findings highlight the barriers autistic women face obtaining their diagnoses and demonstrate the need for autism training for professionals to support early identification. Findings from this study suggest that interventions aimed at developing self-compassion could support and enhance autistic women’s well-being.

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32. Yang K, Cheng C, Yuan Y, Zhang Y, Shan S, Qiu Z. Extension of the Lifespan of a Mouse Model of Rett Syndrome by Intracerebroventricular Delivery of MECP2. Neuroscience bulletin. 2022.

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