1. Adebayo OL, Dewenter I, Rinne L, Golubiani G, Solomonia R, Müller M. Retraction notice to « Intensified mitochondrial hydrogen peroxide release occurs in all brain regions, affects male as well as female Rett mice, and constitutes a life-long burden » [Arch. Biochem. Biophys. 696 (15 December 2020) 10866]. Archives of biochemistry and biophysics. 2022; 732: 109467.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and Authors. Professor Michael Müller approached the journal explaining that he had encountered an issue in the way the spectrofluorometric data analyses was performed. The normalization of the fluorescence curves to their respective starting points (as explained in Figure 1A) overestimated the changes in Mecp2-mutant mice, which usually started at lower levels. This overestimation applies to Figure 3 A-D as well as Table 2 and Table 3 and altered the outcomes of the study. Both the EiC and the authors agreed that a corrigendum would not be appropriate due to the change in conclusion and that the paper should therefore be retracted. The authors apologise for any confusion this paper may have resulted in.

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2. Arteaga-Henríquez G, Lugo-Marín J, Gisbert L, Setién-Ramos I, Martínez-Gallo M, Pujol-Borrell R, Ramos-Quiroga JA. Activation of the Monocyte/Macrophage System and Abnormal Blood Levels of Lymphocyte Subpopulations in Individuals with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. International journal of molecular sciences. 2022; 23(22).

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a so far unknown etiology. Increasing evidence suggests that a state of systemic low-grade inflammation may be involved in the pathophysiology of this condition. However, studies investigating peripheral blood levels of immune cells, and/or of immune cell activation markers such as neopterin are lacking and have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing total and differential white blood cell (WBC) counts, blood levels of lymphocyte subpopulations and of neopterin between individuals with ASD and typically developing (TD) controls (PROSPERO registration number: CRD CRD42019146472). Online searches covered publications from 1 January 1994 until 1 March 2022. Out of 1170 publication records identified, 25 studies were finally included. Random-effects meta-analyses were carried out, and sensitivity analyses were performed to control for potential moderators. Results: Individuals with ASD showed a significantly higher WBC count (k = 10, g = 0.29, p = 0.001, I(2) = 34%), significantly higher levels of neutrophils (k = 6, g = 0.29, p = 0.005, I(2) = 31%), monocytes (k = 11, g = 0.35, p < 0.001, I(2) = 54%), NK cells (k = 7, g = 0.36, p = 0.037, I(2) = 67%), Tc cells (k = 4, g = 0.73, p = 0.021, I(2) = 82%), and a significantly lower Th/Tc cells ratio (k = 3, g = -0.42, p = 0.008, I(2) = 0%), compared to TD controls. Subjects with ASD were also characterized by a significantly higher neutrophil-to-lymphocyte ratio (NLR) (k = 4, g = 0.69, p = 0.040, I(2) = 90%), and significantly higher neopterin levels (k = 3, g = 1.16, p = 0.001, I(2) = 97%) compared to TD controls. No significant differences were found with respect to the levels of lymphocytes, B cells, Th cells, Treg cells, and Th17 cells. Sensitivity analysis suggested that the findings for monocyte and neutrophil levels were robust, and independent of other factors, such as medication status, diagnostic criteria applied, and/or the difference in age or sex between subjects with ASD and TD controls. Taken together, our findings suggest the existence of a chronically (and systemically) activated inflammatory response system in, at least, a subgroup of individuals with ASD. This might have not only diagnostic, but also, therapeutic implications. However, larger longitudinal studies including more homogeneous samples and laboratory assessment methods and recording potential confounding factors such as body mass index, or the presence of comorbid psychiatric and/or medical conditions are urgently needed to confirm the findings.

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3. Berry-Kravis E, Hagerman R, Budimirovic D, Erickson C, Heussler H, Tartaglia N, Cohen J, Tassone F, Dobbins T, Merikle E, Sebree T, Tich N, Palumbo JM, O’Quinn S. A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX). Journal of neurodevelopmental disorders. 2022; 14(1): 56.

BACKGROUND: Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. DESIGN: CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. METHODS: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-C(FXS)) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. RESULTS: A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). CONCLUSIONS: In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. TRIAL REGISTRATION: The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

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4. Bloch C, Tepest R, Jording M, Vogeley K, Falter-Wagner CM. Intrapersonal synchrony analysis reveals a weaker temporal coherence between gaze and gestures in adults with autism spectrum disorder. Scientific reports. 2022; 12(1): 20417.

The temporal encoding of nonverbal signals within individuals, referred to as intrapersonal synchrony (IaPS), is an implicit process and essential feature of human communication. Based on existing evidence, IaPS is thought to be a marker of nonverbal behavior characteristics in autism spectrum disorders (ASD), but there is a lack of empirical evidence. The aim of this study was to quantify IaPS in adults during an experimentally controlled real-life interaction task. A sample of adults with a confirmed ASD diagnosis and a matched sample of typically-developed adults were tested (N = 48). Participants were required to indicate the appearance of a target invisible to their interaction partner nonverbally through gaze and pointing gestures. Special eye-tracking software allowed automated extraction of temporal delays between nonverbal signals and their intrapersonal variability with millisecond temporal resolution as indices for IaPS. Likelihood ratio tests of multilevel models showed enlarged delays between nonverbal signals in ASD. Larger delays were associated with greater intrapersonal variability in delays. The results provide a quantitative constraint on nonverbal temporality in typically-developed adults and suggest weaker temporal coherence between nonverbal signals in adults with ASD. The results provide a potential diagnostic marker and inspire predictive coding theories about the role of IaPS in interpersonal synchronization processes.

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5. Brugnaro BH, Vieira FN, Fernandes G, de Camargo OK, Fumincelli L, de Campos AC, Pavão SL, Rocha N. Exploration of the Feasibility of Remote Assessment of Functioning in Children and Adolescents with Developmental Disabilities: Parents’ Perspectives and Related Contextual Factors. International journal of environmental research and public health. 2022; 19(22).

The COVID-19 pandemic interrupted face-to-face health services, leveraging telehealth strategies. The aim of this cross-sectional study was to investigate, from a parent’s perspective, the feasibility of a remote assessment of functioning in children with developmental disabilities during the pandemic and related contextual factors, based on how parents carry out the assessment. Parents of children with developmental disabilities (mean age = 7.56 ± 3.68) responded to a remote assessment via electronic forms and telephone interview. We analyzed parents’ perspectives about the feasibility of the assessment. We also tested the association between feasibility score and sociodemographics/pandemic experience. Regression analysis tested if children’s functioning characteristics predicted feasibility. A total of 57 mothers completed the remote assessment, and more than 95% did not report difficulties in accessing/responding to electronic forms. They scored remote assessment as easy and feasible, and reported no difficulties with telephone interview. Greater feasibility rates were related to lower maternal age (rho Spearman = -0.290; p = 0.029). The model shows that children’s characteristics predicted 20.4% of feasibility (p < 0.005). Remote assessment showed to be feasible. Younger mothers might consider easier-to-use technologies, beyond considering remote assessment more viable. These results can guide the next steps in research and remote clinical practice.

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6. Casten LG, Thomas TR, Doobay AF, Foley-Nicpon M, Kramer S, Nickl-Jockschat T, Abel T, Assouline S, Michaelson JJ. The combination of autism and exceptional cognitive ability is associated with suicidal ideation. Neurobiology of learning and memory. 2022: 107698.

Autism with co-occurring exceptional cognitive ability is often accompanied by severe internalizing symptoms and feelings of inadequacy. Whether cognitive ability also translates into greater risk for suicidal ideation is unclear. To investigate this urgent question, we examined two samples of high-ability autistic individuals for factors that were predictive of suicidal ideation. In the first sample (N=1,074 individuals seen at a clinic specializing in gifted/talented youth), we observed a striking excess of parent-reported suicidal ideation in autistic individuals with IQ ≥ 120 (Odds Ratio=5.9, p=0.0007). In a separate sample of SPARK participants, we confirmed higher rates of suicidal thoughts compared to non-autistic children from the ABCD cohort (combined N=16,049, Odds Ratio=6.8, p<2.2e-16), and further that autistic children with suicidal thoughts had significantly higher cognitive ability (p<2.2e-16) than those without. Elevated polygenic scores (PGS) for cognitive performance were associated with increased suicidal thoughts (N=1,983, Z=2.16,p=0.03), with PGS for educational attainment trending in the same direction (Z=1.4,p=0.17). Notably, similar results were found in parents of these autistic youth, where higher PGS for educational attainment was associated with increasing thoughts of suicide (N=736, Z=2.28,p=0.02). Taken together, these results suggest that on a phenotypic and genetic level, increasing cognitive ability is an unexpected risk factor for suicidal ideation in individuals diagnosed with, or at risk for autism.

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7. Cipriani C, Tartaglione AM, Giudice M, D’Avorio E, Petrone V, Toschi N, Chiarotti F, Miele MT, Calamandrei G, Garaci E, Matteucci C, Sinibaldi-Vallebona P, Ricceri L, Balestrieri E. Differential Expression of Endogenous Retroviruses and Inflammatory Mediators in Female and Male Offspring in a Mouse Model of Maternal Immune Activation. International journal of molecular sciences. 2022; 23(22).

Maternal infections during pregnancy and the consequent maternal immune activation (MIA) are the major risk factors for autism spectrum disorder (ASD). Epidemiological evidence is corroborated by the preclinical models in which MIA leads to ASD-like behavioral abnormalities and altered neuroinflammatory profiles, with an increase in pro-inflammatory cytokines and microglial markers. In addition to neuroinflammatory response, an abnormal expression of endogenous retroviruses (ERVs) has been identified in neurodevelopmental disorders and have been found to correlate with disease severity. Our aim was to evaluate the transcriptional profile of several ERV families, ERV-related genes, and inflammatory mediators (by RT real-time PCR) in mouse offspring of both sexes, prenatally exposed to polyinosinic:polycytidylic acid (Poly I:C), a synthetic double-stranded RNA molecule targeting TLR-3 that mimics viral maternal infection during pregnancy. We found that prenatal exposure to Poly I:C deregulated the expression of some ERVs and ERV-related genes both in the prefrontal cortex (PFC) and hippocampus, while no changes were detected in the blood. Interestingly, sex-related differences in the expression levels of some ERVs, ERV-related genes, and inflammatory mediators that were higher in females than in males emerged only in PFC. Our findings support the tissue specificity of ERV and ERV-related transcriptional profiles in MIA mice.

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8. Dai H, Kitami Y, Goto YI, Itoh M. 5-HT(1A) Receptor Agonist Treatment Partially Ameliorates Rett Syndrome Phenotypes in mecp2-Null Mice by Rescuing Impairment of Neuron Transmission and the CREB/BDNF Signaling Pathway. International journal of molecular sciences. 2022; 23(22).

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene that encodes methyl CpG-binding protein 2 (MECP2) and is characterized by the loss of acquired motor and language skills, stereotypic movements, respiratory abnormalities and autistic features. There has been no effective treatment for this disorder until now. In this study, we used a Mecp2-null (KO) mouse model of RTT to investigate whether repeated intraperitoneal treatment with the 5-HT(1A) receptor agonist tandospirone could improve the RTT phenotype. The results showed that administration of tandospirone significantly extended the lifespan of Mecp2-KO mice and obviously ameliorated RTT phenotypes, including general condition, hindlimb clasping, gait, tremor and breathing in Mecp2-KO mice. Tandospirone treatment significantly improved the impairment in GABAergic, glutaminergic, dopaminergic and serotoninergic neurotransmission in the brainstem of Mecp2-KO mice. Decreased dopaminergic neurotransmission in the cerebellum of Mecp2-KO mice was also significantly increased by tandospirone treatment. Moreover, RNA-sequencing analysis found that tandospirone modulates the RTT phenotype, partially through the CREB1/BDNF signaling pathway in Mecp2-KO mice. These findings provide a new option for clinical treatment.

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9. Dardani C, Schalbroeck R, Madley-Dowd P, Jones HJ, Strelchuk D, Hammerton G, Croft J, Sullivan SA, Zammit S, Selten JP, Rai D. Childhood Trauma As a Mediator of the Association Between Autistic Traits and Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children Cohort. Schizophrenia bulletin. 2022.

BACKGROUND: Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. STUDY DESIGN: We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. STUDY RESULTS: Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01-1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97-2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. CONCLUSIONS: Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

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10. Dell’Osso L, Nardi B, Benedetti F, Cremone IM, Casagrande D, Massimetti G, Carmassi C, Carpita B. Orthorexia and autism spectrum in University workers: relationship with gender, body mass index and dietary habits. Eating and weight disorders : EWD. 2022.

OBJECTIVE: To date, few studies have investigated the relationship between autistic traits and emerging phenotypes of restrictive disorders, such as Orthorexia nervosa (ON). The aim of the present work was to investigate the relationship between ON symptoms and autistic traits in a population of University employees, focusing on the impact of gender, weight and type of diet. METHODS: All academic and technical/administrative workers of University of Pisa were invited by mail to fulfil through an anonymous online form the Adult Autism Sub-threshold Spectrum (AdAS Spectrum) and the ORTO-R. RESULTS: A total of 285 subjects filled out the questionnaires. Participants with significant autistic traits were included into the Broad autism phenotype (BAP) group, while others into the No BAP group. Subjects in the BAP group reported significantly higher ORTO-R scores than others, while no difference was reported for gender, work position, type of diet, age and BMI. Females showed significantly higher ORTO-R scores and lower BMI than males. Older subjects showed a higher BMI. No significant differences in ORTO-R scores were reported depending on type of diet and work position. A decision tree model, with ORTO-R score as dependent variable, revealed in the first step significantly higher ORTO-R scores in the BAP group than in the No BAP group, and in the second step significantly higher ORTO-R scores among females only in the No BAP group. CONCLUSION: Our results further confirm the association between ON and autism spectrum, which seems to overcome the impact of gender in this population. LEVEL OF EVIDENCE: Level V, descriptive study.

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11. Dwyer P, Vukusic S, Williams ZJ, Saron CD, Rivera SM. « Neural Noise » in Auditory Responses in Young Autistic and Neurotypical Children. Journal of autism and developmental disorders. 2022.

Elevated « neural noise » has been advanced as an explanation of autism and autistic sensory experiences. However, functional neuroimaging measures of neural noise may be vulnerable to contamination by recording noise. This study explored variability of electrophysiological responses to tones of different intensities in 127 autistic and 79 typically-developing children aged 2-5 years old. A rigorous data processing pipeline, including advanced visualizations of different signal sources that were maximally independent across different time lags, was used to identify and eliminate putative recording noise. Inter-trial variability was measured using median absolute deviations (MADs) of EEG amplitudes across trials and inter-trial phase coherence (ITPC). ITPC was elevated in autism in the 50 and 60 dB intensity conditions, suggesting diminished (rather than elevated) neural noise in autism, although reduced ITPC to soft 50 dB sounds was associated with increased loudness discomfort. Autistic and non-autistic participants did not differ in MADs, and indeed, the vast majority of the statistical tests examined in this study yielded no significant effects. These results appear inconsistent with the neural noise account.

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12. Galineau L, Arlicot N, Dupont AC, Briend F, Houy-Durand E, Tauber C, Gomot M, Gissot V, Barantin L, Lefevre A, Vercouillie J, Roussel C, Roux S, Nadal L, Mavel S, Laumonnier F, Belzung C, Chalon S, Emond P, Santiago-Ribeiro MJ, Bonnet-Brilhault F. Glutamatergic synapse in autism: a complex story for a complex disorder. Molecular psychiatry. 2022.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

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13. Labusch M, Perea M, Sahuquillo-Leal R, Bofill-Moscardó I, Carrasco-Tornero Á, Cañada-Pérez A, García-Blanco A. Development of Moral Judgments in Impersonal and Personal Dilemmas in Autistic Spectrum Disorders from Childhood to Late Adolescence. Journal of autism and developmental disorders. 2022.

A potential underlying mechanism associated with the difficulties in social interactions in Autistic Spectrum Disorders (ASD) concerns the abnormal development of moral reasoning. The present study examined utilitarian and deontological judgments in impersonal and personal moral dilemmas, comparing 66 individuals with ASD and 61 typically developing (TD) individuals between 6 and 18 years. Utilitarian judgments decreased with age. This decline was much more gradual for personal dilemmas in the ASD than in the TD group. ASD individuals rated utilitarian judgments as more appropriate but felt less calm, consistent with the Empathy Imbalance hypothesis. Utilitarian judgments were associated with social interaction difficulties in ASD. These findings identify possible social therapeutic targets for more efficient coping strategies in individuals with ASD.

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14. Mohd Radzi SF, Hassan MS, Mohd Radzi MAH. Comparison of classification algorithms for predicting autistic spectrum disorder using WEKA modeler. BMC medical informatics and decision making. 2022; 22(1): 306.

BACKGROUND: In healthcare area, big data, if integrated with machine learning, enables health practitioners to predict the result of a disorder or disease more accurately. In Autistic Spectrum Disorder (ASD), it is important to screen the patients to enable them to undergo proper treatments as early as possible. However, difficulties may arise in predicting ASD occurrences accurately, mainly caused by human errors. Data mining, if embedded into health screening practice, can help to overcome the difficulties. This study attempts to evaluate the performance of six best classifiers, taken from existing works, at analysing ASD screening training dataset. RESULT: We tested Naive Bayes, Logistic Regression, KNN, J48, Random Forest, SVM, and Deep Neural Network algorithms to ASD screening dataset and compared the classifiers’ based on significant parameters; sensitivity, specificity, accuracy, receiver operating characteristic, area under the curve, and runtime, in predicting ASD occurrences. We also found that most of previous studies focused on classifying health-related dataset while ignoring the missing values which may contribute to significant impacts to the classification result which in turn may impact the life of the patients. Thus, we addressed the missing values by implementing imputation method where they are replaced with the mean of the available records found in the dataset. CONCLUSION: We found that J48 produced promising results as compared to other classifiers when tested in both circumstances, with and without missing values. Our findings also suggested that SVM does not necessarily perform well for small and simple datasets. The outcome is hoped to assist health practitioners in making accurate diagnosis of ASD occurrences in patients.

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15. Moraes Í AP, Lima JA, Silva NM, Simcsik AO, Silveira AC, Menezes LDC, Araújo LV, Crocetta TB, Voos MC, Tonks J, Silva TD, Dawes H, Monteiro CBM. Effect of Longitudinal Practice in Real and Virtual Environments on Motor Performance, Physical Activity and Enjoyment in People with Autism Spectrum Disorder: A Prospective Randomized Crossover Controlled Trial. International journal of environmental research and public health. 2022; 19(22).

(1) Background: People with ASD commonly present difficulty performing motor skills and a decline in physical activity (PA) level and low enjoyment of PA. We aimed to evaluate whether longitudinal practice of an activity in virtual and real environments improves motor performance and whether this improvement is transferred to a subsequent practice when changing the environment, promoting PA and providing enjoyment; (2) Methods: People with ASD, aged between 10 and 16 years, were included and distributed randomly into two opposite sequences. The participants performed a 10 session protocol, with five sessions practicing in each environment (virtual or real). Heart rate measurement was carried out and an enjoyment scale was applied; (3) Results: 22 participants concluded the protocol. Sequence A (virtual first) presented an improvement in accuracy and precision and transferred this when changing environment; they also had a greater change in heart rate reserve. The majority of participants reported « fun » and « great fun » levels for enjoyment; (4) Conclusions: The virtual reality activity presented a higher level of difficulty, with greater gains in terms of transference to the real environment. Considering PA, our task provided very light to light activity and the majority of participants enjoyed the task.

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16. Perego S, Alari V, Pietra G, Lamperti A, Vimercati A, Camporeale N, Garzo M, Cogliati F, Milani D, Vignoli A, Peron A, Larizza L, Pizzorusso T, Russo S. Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants. International journal of molecular sciences. 2022; 23(22).

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls’ isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes.

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17. Pouretemad HR, Sadeghi S, Badv RS, Brand S. Differentiating Post-Digital Nannying Autism Syndrome from Autism Spectrum Disorders in Young Children: A Comparative Cross-Sectional Study. Journal of clinical medicine. 2022; 11(22).

Excessive exposure of young children to digital devices has increased in recent years. Much research has shown that early excessive screentime is associated with autistic-like symptoms. This study aimed to differentiate children with Post-Digital Nannying Autism Syndrome (PDNAS) from children with autism spectrum disorders (ASD) and typically developing children (TDC), both behaviorally and cognitively. This study is comparative and cross-sectional and included three groups of children. The first group consisted of 15 young children with subthreshold autism symptoms. They had not received a formal diagnosis of ASD and had been exposed to digital devices for more than half of their waking time. The second group consisted of 15 young children with ASD, and the third group consisted of 15 young TDC. A lifestyle checklist, a modified checklist for autism in toddlers (M-CHAT), a behavioral flexibility rating scale-revised (BFRS-R), the Gilliam autism rating scale (GARS-2), and a behavior rating inventory of executive functioning-preschool version (BRIEF-P) were used to compare the three groups. The results showed that executive functions and behavioral flexibility were more impaired in children with ASD than in children with PDNAS and in TDC. Also, we found that there was no significant difference in the severity of autism symptoms between the children with ASD and the children with PDNAS. Early excessive exposure to digital devices may cause autism-like symptoms in children (PDNAS). Children with PDNAS are different from children with ASD in executive functions and behavioral flexibility. Further research is needed in this area.

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18. Saroukhani S, Samms-Vaughan M, Bressler J, Lee M, Byrd-Williams C, Hessabi M, Grove ML, Shakespeare-Pellington S, Loveland KA, Rahbar MH. Additive or Interactive Associations of Food Allergies with Glutathione S-Transferase Genes in Relation to ASD and ASD Severity in Jamaican Children. Journal of autism and developmental disorders. 2022.

To investigate additive and interactive associations of food allergies with three glutathione S-transferase (GST) genes in relation to ASD and ASD severity in Jamaican children. Using data from 344 1:1 age- and sex-matched ASD cases and typically developing controls, we assessed additive and interactive associations of food allergies with polymorphisms in GST genes (GSTM1, GSTP1 and GSTT1) in relation to ASD by applying conditional logistic regression models, and in relation to ASD severity in ASD cases as measured by the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) total and domains specific comparison scores (CSs) by fitting general linear models. Although food allergies and GST genes were not associated with ASD, ASD cases allergic to non-dairy food had higher mean ADOS-2 Restricted and Repetitive Behaviors (RRB) CS (8.8 vs. 8.0, P = 0.04). In addition, allergy to dairy was associated with higher mean RRB CS only among ASD cases with GSTT1 DD genotype (9.9 vs. 7.8, P < 0.01, interaction P = 0.01), and GSTP1 Val/Val genotype under a recessive genetic model (9.8 vs. 7.8, P = 0.02, interaction P = 0.06). Our findings are consistent with the role for GST genes in ASD and food allergies, though require replication in other populations.

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19. van der Lubbe A, Swaab H, Vermeiren R, Ester WA. Stress, Eating Behavior and Adverse Health in Parents of Young Children with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022: 1-11.

Mothers of children with Autism Spectrum Disorder (ASD) often experience chronic stress and are at risk for adverse health. However, little is known about fathers, especially when their child is in early childhood. Parenting stress, eating behavior and physical health was evaluated in mothers (n = 48) and fathers (n = 43) of young children (3-7 years) with ASD by questionnaires and physical measurements. Mother’s prevalence rates of obesity (39.1%), abdominal obesity (59.6%) and metabolic syndrome (21.6%) were higher than the norm. In fathers, the prevalence rate of clinical parenting stress (33%) was higher than the norm. Parenting stress was positively related to disinhibited eating in mothers, not in fathers. It is crucial to monitor stress and health of parents of children with ASD.

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20. Wetzel AS, Darbro BW. A comprehensive list of human microdeletion and microduplication syndromes. BMC genomic data. 2022; 23(1): 82.

OBJECTIVE: The phenotypic spectrum of human microdeletion and microduplication syndromes (MMS) is heterogeneous but often involves intellectual disability, autism spectrum disorders, dysmorphic features and/or multiple congenital anomalies. While the common recurrent copy number variants (CNVs) which underlie these MMS have been well-studied, the expansion of clinical genomic testing has led to the identification of many rare non-recurrent MMS. To date, hundreds of unique MMS have been reported in the medical literature, and no single resource exists which compiles all these MMS in one location. This comprehensive list of MMS will aid further study of CNV disorders as well as serve as a resource for clinical laboratories performing diagnostic CNV testing. DATA DESCRIPTION: Here we provide a comprehensive list of MMS which have been reported in the medical literature to date. This list is sorted by genomic location, and for each MMS, we provide a list of publications for referral, as well as the consensus coordinates, representative region, shortest regions of overlap (SRO), and/or subregions where applicable.

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21. Wu S, Pan C, Yao L, Wu X. The Impact of the Urban Built Environment on the Play Behavior of Children with ASD. International journal of environmental research and public health. 2022; 19(22).

Anxiety caused by the lack of social skills is the biggest problem faced by children with ASD. Playing can improve children’s social skills and relieve anxiety. This study aimed to explore the influence of urban built environments on ASD children’s play behavior. The participants in this study were 57 parents of children with ASD. An anonymous questionnaire was used to collect and analyze data. At the same time, retrospective semi-structured interviews with 31 parents of ASD children were performed to validate the data analysis results. The results showed that lower residential building density, higher residential greening and higher destination accessibility have positive effects on ASD children’s play behavior. Excellent transportation facilities and high NDVI vegetation coverage have positive effects on the play behavior of children with ASD. More recreational facilities and recreational playability have positive impacts on the play behavior of children with ASD. The population density and number of children in the destination, as well as public facilities, influence the play behavior of children with ASD. The research results can promote the integration of this group into urban life and further promote social equity. At the same time, with the social needs of autistic children as an intermediary, it is expected to further explore new directions for sustainable urban development. Finally, combined with the research results, parents of ASD children are given proposals for how to increase the likelihood of children’s play behavior by choosing appropriate urban built environments.

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