1. Bacchelli E, Viggiano M, Ceroni F, Visconti P, Posar A, Scaduto M, Sandoni L, Baravelli I, Cameli C, Rochat M, Maresca A, Vaisfeld A, Gentilini D, Calzari L, Carelli V, Zody M, Maestrini E. Whole genome analysis of rare deleterious variants adds further evidence to BRSK2 and other risk genes in Autism Spectrum Disorder. Research square. 2023.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We have performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2 . Moreover, the identification of 9 severe de novo pdSNVs in genes not previously implicated in ASD ( RASAL2, RAP1A, IRX5, SLC9A1, AGPAT3, MGAT3, RAB8B, MGAT5B, YME1L1 ), highlighted novel candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3 , NEGR1 , TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, but this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in new ASD/NDD candidates. In conclusion, our study strengthens the role of BRSK2 and other neurodevelopmental genes in ASD risk, highlights novel candidates and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.

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2. Baker JK, Fenning RM, Preston AE, Chan N, McGregor HA, Neece CL. Parental Distress and Parenting Behavior in Families of Preschool Children with and Without ASD: Spillover and Buffering. Journal of autism and developmental disorders. 2023.

Parents of children with autism spectrum disorder (ASD) report increased distress relative to parents of children with neurotypical development. Parent well-being is generally considered a key determinant of parenting behavior, thus increased distress may spill over into less optimal parenting in families of children with ASD. However, evidence is mixed regarding the degree to which parenting is actually compromised in this population, suggesting the possibility of buffering, wherein the parenting of children with ASD may be robust against spillover from increased parental distress. The current study tested competing spillover and buffering models with regard to relations among child ASD status, parental distress, and parenting behavior. Parents of preschoolers with (n = 73) and without (n = 55) ASD completed self-report measures of parenting stress, depressive symptoms, and emotion dysregulation, as well as of positive and negative parenting behaviors. Families of preschoolers with ASD reported higher distress and negative parenting, and lower positive parenting than did their counterparts. Findings supported the spillover model for negative parenting such that increased parental distress accounted for status-group differences in negative parenting. In contrast, potential buffering was observed for positive parenting in that an inverse association between distress and parenting was observed for parents of children with neurotypical development only. Findings highlight the potential benefit of intervention to reduce parental distress in families of children with ASD, but also suggest some existing ability of these families to buffer certain parenting behaviors from deleterious effects of parent distress.

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3. Bearer C, Abman SH, Agostoni C, Ballard P, Bliss J, de Boode WP, Canpolat FE, Chalak L, Cilio MR, Dammann O, Davis J, El-Metwally D, Ferriero D, Ford S, Fuentes-Afflick E, Gano D, Giussani D, Gonzalez F, Gunn A, Hogeveen M, Huang AY, Kaplan J, Klebanoff M, Lachman P, Mak R, Malhotra A, Miller S, Mitchell WB, Molloy E, Mulkey SB, Roland D, Sampath V, Sant’Anna G, Schaff P, Singer LT, Stroustrup A, Tingay D, Tiribelli C, Toldi G, Tryggestad J, Valente EM, Wilson-Costello D, Zupancic J. Asperger’s syndrome – about time to rename it?. Pediatric research. 2023.

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4. Bustos FJ, Pandian S, Haensgen H, Zhao JP, Strouf H, Heidenreich M, Swiech L, Deverman BE, Gradinaru V, Zhang F, Constantine-Paton M. Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer. BMC biology. 2023; 21(1): 232.

BACKGROUND: Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies. RESULTS: Using the ASD and anxiety mouse model Flailer, which contains a partial genomic duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700 bp genomic region in vitro and in vivo. Importantly, DN-CRISPRs have not been used to remove genomic regions using sgRNA with an offset greater than 300 bp. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene editing. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescue some of the mutant behaviors, while intracerebroventricular delivery, completely recovers the Flailer animal phenotype associated to anxiety and ASD. CONCLUSIONS: Our results demonstrate the potential of DN-CRISPR to efficiently remove larger genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases.

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5. El-Ansary A, Al-Ayadhi L. Effects of Walnut and Pumpkin on Selective Neurophenotypes of Autism Spectrum Disorders: A Case Study. Nutrients. 2023; 15(21).

Special diets or nutritional supplements are regularly given to treat children with autism spectrum disorder (ASD). The increased consumption of particular foods has been demonstrated in numerous trials to lessen autism-related symptoms and comorbidities. A case study on a boy with moderate autism who significantly improved after three years of following a healthy diet consisting of pumpkin and walnuts was examined in this review in connection to a few different neurophenotypes of ASD. We are able to suggest that a diet high in pumpkin and walnuts was useful in improving the clinical presentation of the ASD case evaluated by reducing oxidative stress, neuroinflammation, glutamate excitotoxicity, mitochondrial dysfunction, and altered gut microbiota, all of which are etiological variables. Using illustrated figures, a full description of the ways by which a diet high in pumpkin and nuts could assist the included case is offered.

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6. Goodrich AJ, Kleeman MJ, Tancredi DJ, Ludeña YJ, Bennett DH, Hertz-Picciotto I, Schmidt RJ. Ultrafine particulate matter exposure during second year of life, but not before, associated with increased risk of autism spectrum disorder in BKMR mixtures model of multiple air pollutants. Environmental research. 2023: 117624.

Prenatal and early postnatal air pollution exposures have been shown to be associated with autism spectrum disorder (ASD) risk but results regarding specific air pollutants and exposure timing are mixed and no study has investigated the effects of combined exposure to multiple air pollutants using a mixtures approach. We aimed to evaluate prenatal and early life multipollutant mixtures for the drivers of associations of air pollution with ASD. This study examined 484 typically developing (TD) and 660 ASD children from the CHARGE case-control study. Daily air concentrations for NO(2), O(3), ultrafine (PM(0.1)), fine (PM(0.1-2.5)), and coarse (PM(2.5-10)) particles were predicted from chemical transport models with statistical bias adjustment based on ground-based monitors. Daily averages were calculated for each exposure period (pre-pregnancy, each trimester of pregnancy, first and second year of life) between 2000 and 2016. Air pollution variables were natural log-transformed and then standardized. Individual and joint effects of pollutant exposure with ASD, and potential interactions, were evaluated for each period using hierarchical Bayesian Kernel Machine Regression (BKMR) models, with three groups: PM size fractions (PM(0.1), PM(0.1-2.5), PM(2.5-10)), NO(2), and O(3). In BKMR models, the PM group was associated with ASD in year 2 (group posterior inclusion probability (gPIP) = 0.75), and marginally associated in year 1 (gPIP = 0.497). PM(2.5-10) appeared to drive the association (conditional PIP (cPIP) = 0.64) in year 1, while PM(0.1) appeared to drive the association in year 2 (cPIP = 0.76), with both showing a moderately strong increased risk. Pre-pregnancy O(3) showed a slight J-shaped risk of ASD (gPIP = 0.55). No associations were observed for exposures during pregnancy. Pre-pregnancy O(3) and year 2 p.m.(0.1) exposures appear to be associated with an increased risk of ASD. Future research should examine ultrafine particulate matter in relation to ASD.

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7. Harker SA, Al-Hassan L, Huentelman MJ, Braden BB, Lewis CR. APOE ε4-Allele in Middle-Aged and Older Autistic Adults: Associations with Verbal Learning and Memory. International journal of molecular sciences. 2023; 24(21).

Autism spectrum disorder (ASD) is a neurodevelopmental disability and recent evidence suggests that autistic adults are more likely to develop Alzheimer’s disease (Alz) and other dementias compared to neurotypical (NT) adults. The ε4-allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alz and negatively impacts cognition in middle-aged and older (MA+) adults. This study aimed to determine the impact of the APOE ε4-allele on verbal learning and memory in MA+ autistic adults (ages 40-71 years) compared to matched NT adults. Using the Auditory Verbal Learning Test (AVLT), we found that ε4 carriers performed worse on short-term memory and verbal learning across diagnosis groups, but there was no interaction with diagnosis. In exploratory analyses within sex and diagnosis groups, only autistic men carrying APOE ε4 showed worse verbal learning (p = 0.02), compared to autistic men who were not carriers. Finally, the APOE ε4-allele did not significantly affect long-term memory in this sample. These findings replicate previous work indicating that the APOE ε4-allele negatively impacts short-term memory and verbal learning in MA+ adults and presents new preliminary findings that MA+ autistic men may be vulnerable to the effects of APOE ε4 on verbal learning. Future work with a larger sample is needed to determine if autistic women may also be vulnerable.

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8. Hirata R, Yoshimura S, Kobayashi K, Aki M, Shibata M, Ueno T, Miyagi T, Oishi N, Murai T, Fujiwara H. Differences between subclinical attention-deficit/hyperactivity and autistic traits in default mode, salience, and frontoparietal network connectivities in young adult Japanese. Scientific reports. 2023; 13(1): 19724.

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are associated with attentional impairments, with both commonalities and differences in the nature of their attention deficits. This study aimed to investigate the neural correlates of ADHD and ASD traits in healthy individuals, focusing on the functional connectivity (FC) of attention-related large-scale brain networks (LSBNs). The participants were 61 healthy individuals (30 men; age, 21.9 ± 1.9 years). The Adult ADHD Self-Report Scale (ASRS) and Autism Spectrum Quotient (AQ) were administered as indicators of ADHD and ASD traits, respectively. Performance in the continuous performance test (CPT) was used as a behavioural measure of sustained attentional function. Functional magnetic resonance imaging scans were performed during the resting state (Rest) and auditory oddball task (Odd). Considering the critical role in attention processing, we focused our analyses on the default mode (DMN), frontoparietal (FPN), and salience (SN) networks. Region of interest (ROI)-to-ROI analyses (false discovery rate < 0.05) were performed to determine relationships between psychological measures with within-network FC (DMN, FPN, and SN) as well as with between-network FC (DMN-FPN, DMN-SN, and FPN-SN). ASRS scores, but not AQ scores, were correlated with less frequent commission errors and shorter reaction times in the CPT. During Odd, significant positive correlations with ASRS were demonstrated in multiple FCs within DMN, while significant positive correlations with AQ were demonstrated in multiple FCs within FPN. AQs were negatively correlated with FPN-SN FCs. During Rest, AQs were negatively and positively correlated with one FC within the SN and multiple FCs between the DMN and SN, respectively. These findings of the ROI-to-ROI analysis were only partially replicated in a split-half replication analysis, a replication analysis with open-access data sets, and a replication analysis with a structure-based atlas. The better CPT performance by individuals with subclinical ADHD traits suggests positive effects of these traits on sustained attention. Differential associations between LSBN FCs and ASD/ADHD traits corroborate the notion of differences in sustained and selective attention between clinical ADHD and ASD.

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9. Li C, Fleck JS, Martins-Costa C, Burkard TR, Themann J, Stuempflen M, Peer AM, Vertesy Á, Littleboy JB, Esk C, Elling U, Kasprian G, Corsini NS, Treutlein B, Knoblich JA. Author Correction: Single-cell brain organoid screening identifies developmental defects in autism. Nature. 2023.

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10. Li X, Peng Y, Lu Y, Zhang Y. The effect of recasting by mothers with different conversational styles on the communication behavior of autistic children: Lag sequential analysis. Autism research : official journal of the International Society for Autism Research. 2023.

Recasting is the adult rephrasing of a child’s immediately preceding utterance. It has been shown to have outstanding effects on promoting language development in autistic children. This study used lag sequential analysis to explore the impact of mothers’ conversational styles on the communicative behavior of autistic children when using recasting. This study recruited 30 Chinese autistic children (aged 3-6 years) and their mothers. The utterances of the children and their mothers during 30-min interactions were transcribed, coded, and analyzed. The mothers’ conversational styles were determined by the percentages of child-dominant, mother-dominant, and equality styles. The results indicated that mothers’ conversational styles were predominantly child-dominant, differing from the expected mother-dominant style that is typical in Eastern cultures and traditions. However, some mothers still demonstrated a significant proportion of mother-dominant style in their conversation, while some exhibited a considerable amount of equality style. Moreover, mothers with a mainly child-dominant style and minimal use of mother-dominant and equality styles used recasting after the child’s response, triggering the child to initiate new topics. Mothers with a child-dominant style combined with prominent mother-dominant features implemented untargeted self-recasting, the children did not respond significantly. Mothers with a child-dominant style combined with prominent equality features used recasting after the children responded, initiated, or expanded the conversation, which often facilitated the child’s expansion of the conversation. These findings provide suggestions for designing parent-mediated early language interventions for autistic children.

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11. Moskowitz L, Will E, Black C, Roberts J. The Effect of Anxiety and Autism Symptom Severity on Restricted and Repetitive Behaviors Over Time in Children with Fragile X Syndrome. Research square. 2023.

Background: Restricted and repetitive behaviors (RRBs) are highly prevalent and reduce function in individuals with fragile X syndrome (FXS). As transdiagnostic features of intellectual disability, elevated rates of RRBs in FXS could represent various underlying known co-occurring conditions in FXS such as anxiety or autism spectrum disorder (ASD), yet this distinction has not been investigated. Further, delineating whether RRBs are more indicative of anxiety or ASD in FXS may clarify phenotypic profiles within FXS and improve differential assessment. Methods: We longitudinally examined the potentially independent or multiplicative effect of ASD and anxiety symptom severity on RRBs in 60 children with FXS. Anxiety was measured using the Child Behavior Checklist (CBCL), ASD severity was measured using the Childhood Autism Rating Scale (CARS), and RRBs were measured using The Repetitive Behavior Scale – Revised (RBS-R). We estimated a series of moderated regression models with anxiety and ASD symptoms at the initial assessment (Time 1) as predictors of RRBs at the outcome assessment two years later (Time 2), along with an anxiety-by-ASD interaction term to determine the potential multiplicative effect of these co-occurring conditions on RRBs. Results : Results identified a significant interaction between ASD and anxiety symptom severity at the initial assessment that predicted elevated sensory-motor RRBs two years later. Increased sensory-motor RRBs were predicted by elevated ASD symptoms only when anxiety symptom severity was low. Likewise, increased sensory-motor RRBs were predicted by elevated anxiety symptoms only when ASD symptom severity was low. Interestingly, this relationship was isolated to Sensory-Motor RRBs, with evidence that it could also apply to total RRBs. Conclusions: Findings suggest that ASD and anxiety exert independent and differential effects on Sensory-Motor RRBs when at high severity levels and a multiplicative effect when at moderate levels.

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12. Palatucci JS, Chakravarty S, Kratchman AL, Harris J, Pizzi LT, Coffield CN, Ibitamuno G, Spitalnik DM. Commentary: Determining Economic Factors That Matter to People With Intellectual and Developmental Disabilities and Their Caregivers: A Process Framework. Medical care. 2023; 61(12 Suppl 2): S104-s8.

BACKGROUND: The 2020-2029 strategic plan for the Patient-Centered Outcomes Research Trust Fund calls for addressing data infrastructure gaps that are critical for studying issues around intellectual and developmental disabilities (I/DD). Specifically, the plan calls for data collection on economic factors that affect person-centered approaches to health care decision-making. Among people with I/DD and their caregivers, such economic factors may include financial costs of care, decreased opportunities for leisure and recreation, income losses associated with caregiving, and foregone opportunities for skill acquisition or other human capital investments. OBJECTIVE: This commentary supports responsiveness to the Patient-Centered OutcomesResearch Trust Fund (PCORTF) calls by conceptualizing and operationalizing a framework for identifying preferences on economic factors that are relevant to people with I/DD and their caregivers. MAIN ARGUMENTS: The framework outlined in this commentary addresses barriers to data collection that hinder measure development in the study of I/DD. This work is significant and timely given the continued movement to integrate and maintain people with I/DD within communities and recent methodological advances for eliciting preferences among people with I/DD. RELEVANCE TO THE SPECIAL ISSUE: Readers will be introduced to a framework for building data capacity in the study of economic outcomes among a population that is a high research priority for federal funding agencies. This commentary aims to be useful to researchers in planning, developing, and initiating projects in this area.

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13. Paparella A, L’Abbate A, Palmisano D, Chirico G, Porubsky D, Catacchio CR, Ventura M, Eichler EE, Maggiolini FAM, Antonacci F. Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus. International journal of molecular sciences. 2023; 24(21).

The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader-Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications. Comparative analysis of human and nonhuman primate duplication structures suggests a human-specific gain of directly oriented duplications in the regions flanking the GOLGA cores and HERC segmental duplications, representing potential genomic drivers for the human-specific expansions. The increasing complexity of segmental duplication organization over the course of evolution underlies its association with human susceptibility to recurrent disease-associated rearrangements.

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14. Petanjek Z, Banovac I, Sedmak D, Hladnik A. Dendritic Spines: Synaptogenesis and Synaptic Pruning for the Developmental Organization of Brain Circuits. Advances in neurobiology. 2023; 34: 143-221.

Synaptic overproduction and elimination is a regular developmental event in the mammalian brain. In the cerebral cortex, synaptic overproduction is almost exclusively correlated with glutamatergic synapses located on dendritic spines. Therefore, analysis of changes in spine density on different parts of the dendritic tree in identified classes of principal neurons could provide insight into developmental reorganization of specific microcircuits.The activity-dependent stabilization and selective elimination of the initially overproduced synapses is a major mechanism for generating diversity of neural connections beyond their genetic determination. The largest number of overproduced synapses was found in the monkey and human cerebral cortex. The highest (exceeding adult values by two- to threefold) and most protracted overproduction (up to third decade of life) was described for associative layer IIIC pyramidal neurons in the human dorsolateral prefrontal cortex.Therefore, the highest proportion and extraordinarily extended phase of synaptic spine overproduction is a hallmark of neural circuitry in human higher-order associative areas. This indicates that microcircuits processing the most complex human cognitive functions have the highest level of developmental plasticity. This finding is the backbone for understanding the effect of environmental impact on the development of the most complex, human-specific cognitive and emotional capacities, and on the late onset of human-specific neuropsychiatric disorders, such as autism and schizophrenia.

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15. Quesnel KM, Martin-Kenny N, Bérubé NG. A mouse model of ATRX deficiency with cognitive deficits and autistic traits. Journal of neurodevelopmental disorders. 2023; 15(1): 39.

BACKGROUND: ATRX is an ATP-dependent chromatin remodeling protein with essential roles in safeguarding genome integrity and modulating gene expression. Deficiencies in this protein cause ATR-X syndrome, a condition characterized by intellectual disability and an array of developmental abnormalities, including features of autism. Previous studies demonstrated that deleting ATRX in mouse forebrain excitatory neurons postnatally resulted in male-specific memory deficits, but no apparent autistic-like behaviours. METHODS: We generated mice with an earlier embryonic deletion of ATRX in forebrain excitatory neurons and characterized their behaviour using a series of memory and autistic-related paradigms. RESULTS: We found that mutant mice displayed a broader spectrum of impairments, including fear memory, decreased anxiety-like behaviour, hyperactivity, as well as self-injurious and repetitive grooming. Sex-specific alterations were also observed, including male-specific aggression, sensory gating impairments, and decreased social memory. CONCLUSIONS: Collectively, the findings indicate that early developmental abnormalities arising from ATRX deficiency in forebrain excitatory neurons contribute to the presentation of fear memory deficits as well as autistic-like behaviours.

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16. Romano A, Lotan M, Fabio RA. A Severity Comparison between Italian and Israeli Rett Syndrome Cohorts. Diagnostics (Basel, Switzerland). 2023; 13(21).

Rett syndrome (RTT) is a neurodevelopmental disorder marked by profound cognitive, communication, and motor impairments. Despite identified genotype/phenotype connections, the extent of clinical severity varies even among individuals sharing the same genetic mutation. Diverse sociocultural environments, such as the level of inclusivity of the scholar system, the time spent with family, and the intensity of the rehabilitative intervention provided, might influence their development diversely. This study examines the severity of RTT in people in Italy and Israel, countries with distinct contradictory approaches to caring for those with intricate disabilities, across two age groups. Data from 136 Italian and 59 Israeli girls and women with RTT were assessed and divided into two age categories: above and below 12 years. The RARS, a standardized RTT-specific clinical severity tool, was administered. Despite no differences in age and genetic characteristics, the Italian group showed better scores in the RARS motor and disease-related characteristics areas in both age groups. Moreover, the young Italian participants gathered better total RARS scores and emotional and behavioral characteristics area scores. Furthermore, the young group showed significantly less scoliosis, foot problems, and epilepsy than the older group. These findings endorse the inclusion of girls with RTT in the regular schooling system for a limited daily period, investing in high activity levels within the home and community environments, and suggest continuously providing the person with daily occasions of physical activity and socialization.

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17. Sandbank M, Bottema-Beutel K, Crowley LaPoint S, Feldman JI, Barrett DJ, Caldwell N, Dunham K, Crank J, Albarran S, Woynaroski T. Autism intervention meta-analysis of early childhood studies (Project AIM): updated systematic review and secondary analysis. BMJ (Clinical research ed). 2023; 383: e076733.

OBJECTIVE: To summarize the breadth and quality of evidence supporting commonly recommended early childhood autism interventions and their estimated effects on developmental outcomes. DESIGN: Updated systematic review and meta-analysis (autism intervention meta-analysis; Project AIM). DATA SOURCES: A search was conducted in November 2021 (updating a search done in November 2017) of the following databases and registers: Academic Search Complete, CINAHL Plus with full text, Education Source, Educational Administration Abstracts, ERIC, Medline, ProQuest Dissertations and Theses, PsycINFO, Psychology and Behavioral Sciences Collection, and SocINDEX with full text, Trials, and ClinicalTrials.gov. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Any controlled group study testing the effects of any non-pharmacological intervention on any outcome in young autistic children younger than 8 years. REVIEW METHODS: Newly identified studies were integrated into the previous dataset and were coded for participant, intervention, and outcome characteristics. Interventions were categorized by type of approach (such as behavioral, developmental, naturalistic developmental behavioral intervention, and technology based), and outcomes were categorized by domain (such as social communication, adaptive behavior, play, and language). Risks of bias were evaluated following guidance from Cochrane. Effects were estimated for all intervention and outcome types with sufficient contributing data, stratified by risk of bias, using robust variance estimation to account for intercorrelation of effects within studies and subgroups. RESULTS: The search yielded 289 reports of 252 studies, representing 13 304 participants and effects for 3291 outcomes. When contributing effects were restricted to those from randomized controlled trials, significant summary effects were estimated for behavioral interventions on social emotional or challenging behavior outcomes (Hedges’ g=0.58, 95% confidence interval 0.11 to 1.06; P=0.02), developmental interventions on social communication (0.28, 0.12 to 0.44; P=0.003); naturalistic developmental behavioral interventions on adaptive behavior (0.23, 0.02 to 0.43; P=0.03), language (0.16, 0.01 to 0.31; P=0.04), play (0.19, 0.02 to 0.36; P=0.03), social communication (0.35, 0.23 to 0.47; P<0.001), and measures of diagnostic characteristics of autism (0.38, 0.17 to 0.59; P=0.002); and technology based interventions on social communication (0.33, 0.02 to 0.64; P=0.04) and social emotional or challenging behavior outcomes (0.57, 0.04 to 1.09; P=0.04). When effects were further restricted to exclude caregiver or teacher report outcomes, significant effects were estimated only for developmental interventions on social communication (0.31, 0.13 to 0.49; P=0.003) and naturalistic developmental behavioral interventions on social communication (0.36, 0.23 to 0.49; P<0.001) and measures of diagnostic characteristics of autism (0.44, 0.20 to 0.68; P=0.002). When effects were then restricted to exclude those at high risk of detection bias, only one significant summary effect was estimated-naturalistic developmental behavioral interventions on measures of diagnostic characteristics of autism (0.30, 0.03 to 0.57; P=0.03). Adverse events were poorly monitored, but possibly common. CONCLUSION: The available evidence on interventions to support young autistic children has approximately doubled in four years. Some evidence from randomized controlled trials shows that behavioral interventions improve caregiver perception of challenging behavior and child social emotional functioning, and that technology based interventions support proximal improvements in specific social communication and social emotional skills. Evidence also shows that developmental interventions improve social communication in interactions with caregivers, and naturalistic developmental behavioral interventions improve core challenges associated with autism, particularly difficulties with social communication. However, potential benefits of these interventions cannot be weighed against the potential for adverse effects owing to inadequate monitoring and reporting.

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18. Schendel D, Ejlskov L, Overgaard M, Jinwala Z, Kim V, Parner E, Kalkbrenner AE, Acosta CL, Fallin MD, Xie S, Mortensen PB, Lee B. 3-generation family medical histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions associated with autism. medRxiv : the preprint server for health sciences. 2023.

BACKGROUND: Family histories of different mental and non-mental conditions have often been associated with autism spectrum disorder (ASD) but the restricted scope of conditions and family members that have been investigated limits etiologic understanding. We aimed to perform a comprehensive assessment of ASD associations with 3-generation family histories of 90 mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. The assessment comprised separate estimates of association with ASD overall; separate estimates by sex and intellectual disability (ID) status; as well as separate estimates of the co-occurrence of each of the 90 disorders in autistic persons. Additionally, we aimed to provide interactive catalogues of results to facilitate results visualization and further hypothesis-generation. METHODS: We conducted a population-based, registry cohort study comprised of all live births in Denmark, 1980-2012, of Denmark-born parents, and with birth registry information (1,697,231 births), and their 3-generation family member types (20 types). All cohort members were followed from birth through April 10, 2017 for an ASD diagnosis. All participants (cohort members and each family member) were followed from birth through April 10, 2017 for each of 90 diagnoses, emigration or death. Adjusted hazard ratios (aHR) were estimated for ASD overall; by sex; or accounting for ID via separate Cox regression models for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person. aHRs were also calculated for sex-specific co-occurrence of each disorder, for ASD overall and considering ID. A catalogue of all results is displayed via interactive heat maps here: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries of results are here: https://public.tableau.com/views/ASDPlots_16918786403110/e-Figure5 . RESULTS: Increased aHRs for ASD (26,840 cases; 1.6% of births) were observed for almost all individual mental disorder-family member type combinations yet for fewer non-mental disorder-family member type combinations. aHRs declined with diminishing degree of relatedness between the index person and family member for some disorders, especially mental disorders. Variation in aHR magnitude by family member sex (e.g., higher maternal than paternal aHRs) or side of the family (e.g., higher maternal versus paternal half sibling aHRs) was more evident among non-mental than mental disorders. Co-occurring ID in the family member or the index person impacted aHR variation. CONCLUSION: Our approach revealed considerable breadth and variation in magnitude of familial health history associations with ASD by type of condition, sex of the affected family member, side of the family, sex of the index person, and ID status which is indicative of diverse genetic, familial, and non-genetic ASD etiologic pathways. More careful attention to identifying sources of autism likelihood encompassed in family medical history, in addition to genetics, may accelerate understanding of factors underlying neurodiversity.

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19. Sheikhshoaee S, Taheri F, Esmaeilpour K, Firouzeh N, Fard SRN. Aggravation of cognitive impairments in the valproic acid-induced animal model of autism in BALB/c mice infected with Toxoplasma gondii. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2023.

PURPOSE: Toxoplasmosis is a disease caused by infection with a type of coccidial protozoan parasite called Toxoplasma gondii. The relationship between toxoplasmosis and cognitive disorders in neurodegenerative diseases has been proven. There is also evidence that children born to Toxoplasma-infected mothers are more likely to develop autism. METHODS: In the present study, Toxoplasma-infected pregnant BALB/c mice were given valproic acid to induce autism in their male offspring, and their social behaviors, learning, and memory were examined. Chronic toxoplasmosis was established in BALB/c mice by intraperitoneal injection of cyst form of T. gondii. To induce autism, 600 mg/kg of valproic acid was injected intraperitoneally into mice on the 12.5th day of pregnancy. The behavioral experiments, such as social interaction, novel object recognition, and passive avoidance tasks, were performed on male offspring at 50 days. RESULTS: Toxoplasma and valproic acid during the embryonic period caused social communication deficits and disrupted recognition memory and avoidance memory in offspring. Our findings showed that administering valproic acid to Toxoplasma-infected mothers exacerbates cognitive disorders in their offspring.

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20. Smith LM, Yurkovic-Harding J, Carver LJ. Multimodal pathways to joint attention in infants with a familial history of autism. Developmental cognitive neuroscience. 2023; 64: 101325.

Joint attention (JA) is an early-developing behavior that allows caregivers and infants to share focus on an object. Deficits in JA, as measured through face-following pathways, are a defining feature of autism spectrum disorder (ASD) and are observable as early as 12 months of age in infants later diagnosed with ASD. However, recent evidence suggests that JA may be achieved through hand-following pathways by children with and without ASD. Development of JA through multimodal pathways has yet to be studied in infants with an increased likelihood of developing ASD. The current study investigated how 6-, 9- and 12-month-old infants with (FH+) and without (FH-) a family history of ASD engaged in JA. Parent-infant dyads played at home while we recorded the interaction over Zoom and later offline coded for hand movements and gaze. FH+ and FH- infants spent similar amounts of time in JA with their parents, but the cues available before JA were different. Parents of FH+ infants did more work to establish JA and used more face-following than hand-following pathways compared to parents of FH- infants, likely reflecting differences in infant motor or social behavior. These results suggest that early motor differences between FH+ and FH- infants may cascade into differences in social coordination.

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21. Ulu Aydin H, Cifci Tekinarslan I, Gulec Aslan Y. The Power Card Strategy: Strength-Based Intervention Against Bullying for Children with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2023.

The pattern of behaviors and abilities that reflect the core characteristics of students with autism spectrum disorder (ASD) and an environment that lacks the ability to understand individuals with ASD can make these students targets of bullying. Bullying is a serious problem for students with ASD, and practices against it are important in terms of improving students’ coping strategies and overall well-being. In this study, we used a multiple probe model with an interprobe phase across participants to evaluate the effectiveness of the power card strategy to teach three students with ASD to respond to bullying. At baseline, the students gave few appropriate responses based on coping strategies for bullying after listening to stories about bullying. During the application of the power cards, the students read scenarios and power cards created for their favorite heroes or special interests, which included coping strategies for three different bullying situations (exclusion, being pushed, and being tickled). Then, they watched animations prepared for these bullying situations and were asked to answer questions about strategies to deal with bullying. The findings showed that all three students learned targeted strategies for coping with bullying in the context of the sessions using power cards. The students were able to generalize to different bullying situations (teasing, damaging one’s belongings, being ignored) while retaining their strategies for coping with bullying in the context of the sessions held after the teaching was completed. The social validity findings of the power card strategy showed that one out of three students exhibited coping strategies for bullying in the school environment. The findings of the present study are discussed in the context of bullying and ASD, limitations, and recommendations.

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22. Winocur-Arias O, Amitai BC, Winocur E, Shmuly T, Grinstein Koren O, Reiter S. The prevalence of bruxism and oral parafunction activities among Israeli juveniles with autism spectrum disorder: A preliminary study during the COVID-19 pandemic. Cranio : the journal of craniomandibular practice. 2023: 1-9.

OBJECTIVE: To evaluate the prevalence of oral habits, bruxism, and Temporomandibular Disorders (TMD) injuvenileswithautisticspectrumdisorder(ASD). METHODS: Data included 165 juveniles diagnosed with ASD, allocated to younger group aged 6 21 (n=86) and older group aged 13-21 (n=79). RESULTS: Sleep bruxism was reported by 26.7% in the younger group and by 5% in the older group. Awake bruxism was reported by 22% and 17.7%, respectively. Oral habits were reported by 43% of all participants, with similar rate in both groups. TMD related p ain was low in both groups (6.3% and 7% respectively). The influence of the COVID 19 pandemic on oral parafunction was moderate in the younger group (17.4%) and mild in the older group (8.6%), influence on bruxism was mild in both groups (5.8% and 2.5%, respectively). CONCLUSION: The prevalence of bruxism and oral parafunctions was similar to the reported in the literature for the general population.

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23. Yoshinaga K, Egawa J, Watanabe Y, Kasahara H, Sugimoto A, Someya T. Usefulness of the autism spectrum quotient (AQ) in screening for autism spectrum disorder and social communication disorder. BMC psychiatry. 2023; 23(1): 831.

BACKGROUND: In the Diagnostic and Statistical Manual and Mental Disorders, Fifth Edition (DSM-5), autism spectrum disorder (ASD) and social (pragmatic) communication disorder (SCD) were described as a new category of psychiatry nosography. SCD involves impairments in social communication and social interaction but not restricted, repetitive patterns of behavior, interests, or activities. The autism spectrum quotient (AQ) was developed to screen for autism tendencies in adults with normal intelligence. However, AQ cutoff scores for screening ASD and SCD in the DSM-5 have not been established. This study examined whether the Japanese version of the AQ (AQ-J) total scores could discriminate between an ASD group, an SCD group, and a neurotypical (NT) group. METHODS: Participants were 127 ASD patients, 52 SCD patients, and 49 NT individuals. Receiver operating characteristic (ROC) analyses were used to examine AQ-J total score cutoff values to distinguish between ASD and NT groups, SCD and NT groups, and ASD and SCD groups. RESULTS: In the ROC analysis for the ASD and NT groups, the area under the curve (AUC) was 0.96, and the optimum cutoff value was 23 points (sensitivity 92.9%, specificity 85.7%). The AUC for the SCD and NT groups was 0.89, and the optimum cutoff value was 22 points (sensitivity 84.6%, specificity 85.7%). The AUC for the ASD and SCD groups was 0.75; the optimum cutoff value was 32 points (sensitivity 67.7%, specificity 71.2%). CONCLUSION: Our findings suggest the usefulness of the AQ-J in screening for ASD and SCD.

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24. Zhan XL, Pan N, Karatela S, Shi L, Wang X, Liu ZY, Jing J, Li XH, Cai L, Lin LZ. Correction: Infant feeding practices and autism spectrum disorder in US children aged 2-5 years: the national survey of children’s health (NSCH) 2016-2020. International breastfeeding journal. 2023; 18(1): 61.

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25. Zucchini C, Serpe C, De Sanctis P, Ghezzo A, Visconti P, Posar A, Facchin F, Marini M, Abruzzo PM. TLDc Domain-Containing Genes in Autism Spectrum Disorder: New Players in the Oxidative Stress Response. International journal of molecular sciences. 2023; 24(21).

Oxidative stress (OS) plays a key role in autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by deficits in social communication, restricted interests, and repetitive behaviors. Recent evidence suggests that the TLDc [Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic] domain is a highly conserved motif present in proteins that are important players in the OS response and in neuroprotection. Human proteins sharing the TLDc domain include OXR1, TLDC1, NCOA7, TBC1D24, and C20ORF118. This study was aimed at understanding whether TLDc domain-containing mRNAs together with specific microRNAs (200b-3p and 32-5p) and long noncoding RNAs (TUG1), known to target TLDc proteins, contributed to regulate the OS response in ASD. Data showed a significant increase in the levels of OXR1 and TLDC1 mRNAs in peripheral blood mononuclear cells (PBMCs) of ASD children compared to their neurotypically developing (NTD) counterparts, along with an increase in TUG1 mRNA expression levels, suggesting its possible role in the regulation of TLDc proteins. A positive correlation between the expression of some TLDc mRNAs and the Childhood Autism Rating Scale (CARS) global score as well as inflammatory gene expression was found. In conclusion, our data suggest a novel biological pathway in the OS response of ASD subjects that deserves further exploration.

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