1. Albright J, Fok M, DeLucia EA, Scarpa A. A Qualitative Examination of the Impact of COVID-19 on Transition Services for Autistic Youth. Journal of autism and developmental disorders. 2023: 1-15.

The coronavirus (COVID-19) pandemic has caused widespread disturbances in many human and social service programs. Several studies have examined special education programming adaptations since the onset of the pandemic; however, there has yet to be documentation of pandemic-related changes to transition programming and the impact of these changes for autistic youth. The purpose of this qualitative study was to examine changes in transition programming for autistic youth amid the changing educational landscape. We conducted 12 interviews with caregivers (n = 5) and school providers (n = 7) about transition programming for autistic youth and the COVID-19 impact to these services. The pandemic had positive and negative effects on many aspects of transition programming, including student-focused planning, student development, interagency and interdisciplinary collaboration, family involvement, and program structure and attributes. Elucidation of the ways that the COVID-19 pandemic impacted transition programming from the perspectives of multiple stakeholders has important implications for school personnel and can help to inform the future directions for the field of transition programming research.

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2. Day TC, Gerber A, McNair ML, Reicher D, Lerner MD. Trajectories of internalizing symptoms among autistic and nonautistic youth during the COVID-19 pandemic. Autism research : official journal of the International Society for Autism Research. 2023.

The COVID-19 pandemic elicited increases in anxiety and depression in youth, and youth on the autism spectrum demonstrate elevations in such symptoms pre-pandemic. However, it is unclear whether autistic youth experienced similar increases in internalizing symptoms after the COVID-19 pandemic onset or whether decreases in these symptoms were present, as speculated in qualitative work. In the current study, longitudinal changes in anxiety and depression during the COVID-19 pandemic in autistic youth were assessed in comparison to nonautistic youth. A well-characterized sample of 51 autistic and 25 nonautistic youth (age(M)  = 12.8, range = 8.5-17.4 years, IQ > 70) and their parents completed the Revised Children’s Anxiety and Depression Scale (RCADS), a measure of internalizing symptoms, repeatedly, representing up to 7 measurement occasions from June to December 2020 (N ~ 419 occasions). Multilevel models were used to evaluate changes in internalizing symptoms over time. Internalizing symptoms did not differ between autistic and nonautistic youth in the summer of 2020. As reported by youth themselves, internalizing symptoms decreased in autistic youth, both overall and compared to nonautstic peers. This effect was driven by decreases in generalized anxiety, social anxiety, and depression symptoms in autistic youth. Reductions in generalized anxiety, social anxiety, and depression in autistic youth may be due to COVID-19 pandemic-specific differences in response to social, environmental, and contextual changes that unfolded in 2020. This highlights the importance of understanding unique protective and resilience factors that may be evident in autistic individuals in response to broad societal shifts such as those seen in response to COVID-19.

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3. Donnelly N, Cunningham A, Salas SM, Bracher-Smith M, Chawner S, Stochl J, Ford T, Raymond FL, Escott-Price V, van den Bree MBM. Identifying the neurodevelopmental and psychiatric signatures of genomic disorders associated with intellectual disability: a machine learning approach. Molecular autism. 2023; 14(1): 19.

BACKGROUND: Genomic conditions can be associated with developmental delay, intellectual disability, autism spectrum disorder, and physical and mental health symptoms. They are individually rare and highly variable in presentation, which limits the use of standard clinical guidelines for diagnosis and treatment. A simple screening tool to identify young people with genomic conditions associated with neurodevelopmental disorders (ND-GCs) who could benefit from further support would be of considerable value. We used machine learning approaches to address this question. METHOD: A total of 493 individuals were included: 389 with a ND-GC, mean age = 9.01, 66% male) and 104 siblings without known genomic conditions (controls, mean age = 10.23, 53% male). Primary carers completed assessments of behavioural, neurodevelopmental and psychiatric symptoms and physical health and development. Machine learning techniques (penalised logistic regression, random forests, support vector machines and artificial neural networks) were used to develop classifiers of ND-GC status and identified limited sets of variables that gave the best classification performance. Exploratory graph analysis was used to understand associations within the final variable set. RESULTS: All machine learning methods identified variable sets giving high classification accuracy (AUROC between 0.883 and 0.915). We identified a subset of 30 variables best discriminating between individuals with ND-GCs and controls which formed 5 dimensions: conduct, separation anxiety, situational anxiety, communication and motor development. LIMITATIONS: This study used cross-sectional data from a cohort study which was imbalanced with respect to ND-GC status. Our model requires validation in independent datasets and with longitudinal follow-up data for validation before clinical application. CONCLUSIONS: In this study, we developed models that identified a compact set of psychiatric and physical health measures that differentiate individuals with a ND-GC from controls and highlight higher-order structure within these measures. This work is a step towards developing a screening instrument to identify young people with ND-GCs who might benefit from further specialist assessment.

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4. Hermans RA, Sassen SDT, Kloosterboer SM, Reichart CG, Kouijzer MEJ, de Kroon MMJ, Bastiaansen D, van Altena D, van Schaik RHN, Nasserinejad K, Hillegers MHJ, Koch BCP, Dierckx B, de Winter BCM. Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder: linking blood levels to weight gain and effectiveness. British journal of clinical pharmacology. 2023.

AIM: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between PK parameters and BMI in children and adolescents with ASD and behavioral problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and drug effectiveness. METHODS: Twenty-four children and adolescents (15 males, 9 females) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and drug effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analyzed to predict outcomes using generalized and linear mixed-effects models. RESULTS: For both aripiprazole and de-hydro-aripiprazole, one-compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations best predicted higher BMI z-scores (P < .001) and higher Hb1Ac levels (p=0.03) during follow-up. No significant association was found between sum concentrations and effectiveness. CONCLUSION: Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioral problems.

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5. Jasim S, Perry A. Repetitive and restricted behaviors and interests in autism spectrum disorder: relation to individual characteristics and mental health problems. BMC psychiatry. 2023; 23(1): 356.

BACKGROUND: Although repetitive and restricted behaviors and interests (RRBIs) may interfere with well-being and functioning in autistic individuals, research on their relation to sex, age, cognitive level, and mental health problems remains unclear. Much of the research to date has used broad categorizations rather than specific categorizations of RRBIs to examine the difference in RRBIs between individuals. The purpose of this study was to explore, in different groups of individuals, the presence of specific RRBI subtypes, and to examine the association of specific RRBI subtypes with symptoms of internalizing and externalizing behaviors. METHODS: Secondary data analyses were conducted using the Simons Simplex Collection dataset, which included 2,758 participants (aged 4 to 18). Families of autistic children completed the Repetitive Behavior Scale-Revised (RBS-R) and the Child Behavior Checklist. RESULTS: Across all RBS-R subtypes, results revealed no sex differences. Older children showed higher rates of Ritualistic/Sameness behaviors than younger children and adolescents, whereas younger and older children showed more Stereotypy than adolescents. Additionally, lower cognitive level groups showed higher rates of RBS-R subtypes except for Ritualistic/Sameness. After controlling for age and cognitive level, RBS-R subtypes accounted for a substantial amount of variance in internalizing and externalizing behaviors (23% and 25%, respectively). Specifically, Ritualistic/Sameness and Self-Injurious Behavior both predicted internalizing and externalizing behaviors, whereas Stereotypy only predicted internalizing behavior. CONCLUSIONS: These findings have key clinical implications that emphasize not only the consideration of sex, age, and cognitive level, but also specific RRBIs and co-occurring mental health problems, when assessing for ASD and designing individualized interventions.

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6. Karaca M, Tahtasakal R, Dana H, Sahin M, Pirencioglu SN, Tughan E, Dal F, Demirci E, Sener EF. Decreased levels of alpha synuclein in families with autism spectrum disorder and relationship between the disease severity. Brain research. 2023: 148410.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorders that begin in early childhood. Mutations in α-synuclein (SNCA) gene have been shown to result in the accumulation of α-synuclein, which occurs in many neurodegenerative diseases. Our aim was to determine the changes in the expression profile and protein level of this gene by comparing the autistic children with their healthy siblings, their mothers and healthy controls in order to elucidate the possible contribution of the SNCA gene to the etiology of ASD. 50 autistic patients, their mothers, siblings and 25 healthy controls and their mothers were enrolled to determine SNCA gene expression and serum α-synuclein levels. It was determined that α-synuclein serum levels decreased in the autistic patients. Similarly, it was found that SNCA gene expression and serum α-synuclein levels were significantly decreased in the mothers of the patients. Significant negative correlation was observed between the SNCA gene and protein expression amounts in the 6-8 age of the patients. This family-based study is the first in the literature, with both gene expression and serum levels of α-synuclein. The relationship between ASD severity and α-synuclein level needs to be confirmed in larger-scale studies.

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7. Levy SM, Witte TH. An Analysis of Social and Coping Alcohol Use Motives for College Students with Autistic Traits. Substance use & misuse. 2023: 1-8.

Background: Little is known about alcohol use among college students with autism spectrum disorder (ASD), despite the increasing prevalence of college students with this diagnosis and/or with no formal diagnosis but who would meet criteria. Of concern, previous research suggests that individuals with ASD may be particularly vulnerable to the coping and social facilitation effects of alcohol use. Objectives: The present study examined the associated between autistic traits and alcohol use motives (social, coping, conformity, enhancement) in a sample of college students. Symptoms of social anxiety were assessed as a moderator and thought to enhance the associations between autistic traits and social and coping motives. Results: Findings revealed that both autistic traits and social anxiety were significantly and positively correlated with coping and conformity drinking motives. Additionally, a significantly negative correlation emerged between autistic traits and social drinking motives for participants with low social anxiety, and a similar pattern emerged for enhancement drinking motives. Conclusions: These findings suggest that college students with autistic traits may experience daily encounters or emotions that are alleviated by the mood-altering effects of alcohol; however, the specific feelings, emotions, or experiences that these individuals are looking to seek relief from remain understudied.

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8. Matthiesen M, Khlaifia A, Steininger CFD, Jr., Dadabhoy M, Mumtaz U, Arruda-Carvalho M. Maturation of nucleus accumbens synaptic transmission signals a critical period for the rescue of social deficits in a mouse model of autism spectrum disorder. Molecular brain. 2023; 16(1): 46.

Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although social deficits are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J and the idiopathic ASD mouse model BTBR T(+)Itpr3(tf)/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. BTBR NAc MSNs display increased spontaneous excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs compared to C57BL/6J mice. BTBR mice also show increased optically evoked medial prefrontal cortex-NAc paired pulse ratios at P15 and P30. These early changes in synaptic transmission are consistent with a potential critical period, which could maximize the efficacy of rescue interventions. To test this, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established intervention for ASD-like behavior. Rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but did not affect social interaction in adulthood.

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9. Nyrenius J, Eberhard J, Ghaziuddin M, Gillberg C, Billstedt E. The ‘lost generation’ in adult psychiatry: psychiatric, neurodevelopmental and sociodemographic characteristics of psychiatric patients with autism unrecognised in childhood. BJPsych open. 2023; 9(3): e89.

BACKGROUND: Patients with ‘underlying’ autism spectrum disorder (ASD) constitute a significant minority in adult out-patient psychiatry. Diagnoses of previously unrecognised ASD are increasing in adults. Characteristics of patients with autism within adult out-patient psychiatry have not been sufficiently explored, and there have not been any systematic comparisons of characteristics between patients with and those without autism within adult out-patient psychiatric populations. AIMS: To examine psychiatrically relevant characteristics in autistic adult psychiatric out-patients, and to compare the characteristics with non-autistic adult psychiatric out-patients. METHOD: We assessed 90 patients who were referred to a Swedish psychiatric out-patient clinic and screened for ASD during 2019-2020. Sixty-three patients met the DSM-5 criteria for ASD or ‘subthreshold’ ASD. The 27 who did not meet the criteria for ASD were used as a comparison group. Assessments were made with structured and well-validated instruments, including parent ratings of developmental history. RESULTS: No differences were found between the groups regarding self-reported sociodemographic variables. The ASD group showed a higher number of co-occurring psychiatric disorders than the non-ASD group (t((88)) = 5.17, 95% CI 1.29-2.91, d = 1.19). Functional level was lower in the ASD group (t((88)) = -2.66, 95% CI -9.46 to -1.27, d = -0.73), and was predicted by the number of co-occurring psychiatric disorders. CONCLUSIONS: The results underscore the need for thorough assessment of psychiatric disorders in autistic patients in adult psychiatric services. ASD should be considered as a possible ‘underlying’ condition in adult psychiatry, and there is no easy way of ruling out ASD in this population.

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10. Openshaw RL, Thomson DM, Bristow GC, Mitchell EJ, Pratt JA, Morris BJ, Dawson N. 16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability. Communications biology. 2023; 6(1): 557.

Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism.

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11. Ravel JM, Renaud M, Muller J, Becker A, Renard É, Remen T, Lefort G, Dexheimer M, Jonveaux P, Leheup B, Bonnet C, Lambert L. Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study. Genome medicine. 2023; 15(1): 39.

BACKGROUND: Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported. METHODS: This retrospective study examined 1641 CGH arrays performed over 8 years (2010-2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria. RESULTS: Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size. CONCLUSIONS: This study’s high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.

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12. Tsompanidis A, Warrier V, Baron-Cohen S. The genetics of autism and steroid-related traits in prenatal and postnatal life. Frontiers in endocrinology. 2023; 14: 1126036.

BACKGROUND: Autism likelihood is a largely heritable trait. Autism prevalence has a skewed sex ratio, with males being diagnosed more often than females. Steroid hormones play a mediating role in this, as indicated by studies of both prenatal biology and postnatal medical conditions in autistic men and women. It is currently unclear if the genetics of steroid regulation or production interact with the genetic liability for autism. METHODS: To address this, two studies were conducted using publicly available datasets, which focused respectively on rare genetic variants linked to autism and neurodevelopmental conditions (study 1) and common genetic variants (study 2) for autism. In Study 1 an enrichment analysis was conducted, between autism-related genes (SFARI database) and genes that are differentially expressed (FDR<0.1) between male and female placentas, in 1(st) trimester chorionic villi samples of viable pregnancies (n=39). In Study 2 summary statistics of genome wide association studies (GWAS) were used to investigate the genetic correlation between autism and bioactive testosterone, estradiol and postnatal PlGF levels, as well as steroid-related conditions such as polycystic ovaries syndrome (PCOS), age of menarche, and androgenic alopecia. Genetic correlation was calculated based on LD Score regression and results were corrected for multiple testing with FDR. RESULTS: In Study 1, there was significant enrichment of X-linked autism genes in male-biased placental genes, independently of gene length (n=5 genes, p<0.001). In Study 2, common genetic variance associated with autism did not correlate to the genetics for the postnatal levels of testosterone, estradiol or PlGF, but was associated with the genotypes associated with early age of menarche in females (b=-0.109, FDR-q=0.004) and protection from androgenic alopecia for males (b=-0.135, FDR-q=0.007). CONCLUSION: The rare genetic variants associated with autism appear to interact with placental sex differences, while the common genetic variants associated with autism appear to be involved in the regulation of steroid-related traits. These lines of evidence indicate that the likelihood for autism is partly linked to factors mediating physiological sex differences throughout development.

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13. Valicenti-McDermott M, Barresi I, Rosenthal M, Seijo R. Screening for Hearing Impairment in School-Age Children and Adolescents With Developmental Disabilities in an Ethnically Diverse Community. Clinical pediatrics. 2023: 99228231176344.

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14. Wu YX, Li ZX, Lyu XZ, Wang M, Huang TY, Cheng JH, Meng RR. [Scoping review of progress in cohort studies of autism spectrum disorder]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi. 2023; 44(5): 837-44.

Objective: To understand the status of autism spectrum disorder (ASD) cohort studies and explore the feasibility of constructing ASD disease-specific cohorts based on real-world data (RWD). Methods: ASD cohort studies published by December 2022 were collected by literature retrieval from major Chinese and English databases. And the characteristics of the cohort were summarized. Results: A total of 1 702 ASD cohort studies were included, and only 60 (3.53%) were from China. A total of 163 ASD-related cohorts were screened, of which 55.83% were birth cohorts, 28.22% were ASD-specific cohorts, and 4.91% were ASD high-risk cohorts. Most cohorts used RWD such as hospital registries or conducted community-based field surveys to obtain participant information and identified patients with ASD by scales or clinical diagnoses. The contents of the studies included ASD incidence and prognostic risk factors, ASD comorbidity patterns and the impact of ASD on self-health and their offspring’s health. Conclusions: ASD cohort studies in developed countries have been in the advanced stage, while the Chinese studies are still in their infancy. RWD provides the data basis for ASD-specific cohort construction and offers new opportunities for research, but work such as case validation is still needed to ensure the scientific nature of cohort construction.

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15. Xi K, Cai SQ, Yan HF, Tian Y, Cai J, Yang XM, Wang JM, Xing GG. CSMD3 Deficiency Leads to Motor Impairments and Autism-Like Behaviors via Dysfunction of Cerebellar Purkinje Cells in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023; 43(21): 3949-69.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Mutations of CUB and sushi multiple domains 3 (CSMD3) gene have been reported in individuals with ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain unexplored. Here, using male CSMD3 knock-out (CSMD3 (-/-)) mice, we found that genetic deletion of CSMD3 produced core autistic-like symptoms (social interaction deficits, restricted interests, and repetitive and stereotyped behaviors) and motor dysfunction in mice, indicating that the CSMD3 gene can be considered as a candidate for ASD. Moreover, we discovered that the ablation of CSMD3 in mice led to abnormal cerebellar Purkinje cell (PC) morphology in Crus I/II lobules, including aberrant developmental dendritogenesis and spinogenesis of PCs. Furthermore, combining in vivo fiber photometry calcium imaging and ex vivo electrophysiological recordings, we showed that the CSMD3 (-/-) mice exhibited an increased neuronal activity (calcium fluorescence signals) in PCs of Crus I/II lobules in response to movement activity, as well as an enhanced intrinsic excitability of PCs and an increase of excitatory rather than inhibitory synaptic input to the PCs, and an impaired long-term depression at the parallel fiber-PC synapse. These results suggest that CSMD3 plays an important role in the development of cerebellar PCs. Loss of CSMD3 causes abnormal PC morphology and dysfunction in the cerebellum, which may underlie the pathogenesis of motor deficits and core autistic-like symptoms in CSMD3 (-/-) mice. Our findings provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD. Recently, a novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains (CSMDs) has been identified as a candidate gene for ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain largely unknown. Here, we unravel that loss of CSMD3 results in abnormal morphology, increased intrinsic excitabilities, and impaired synaptic plasticity in cerebellar PCs, subsequently leading to motor deficits and ASD-like behaviors in mice. These results provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.

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