1. Abolghasemi A, Carullo MP, Aguilera EC, Laroui A, Plantefeve R, Rojas D, Benachenhou S, Ramírez MV, Proteau-Lemieux M, Lepage JF, Corbin F, Plourde M, Farez M, Cogram P, Çaku A. Alteration of Fatty Acid Profile in Fragile X Syndrome. Int J Mol Sci;2022 (Sep 16);23(18)

Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder.

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2. Abomelha FM, AlDhalaan H, Ghaziuddin M, Al-Tassan NA, Al-Mubarak BR. Autism and ADHD in the Era of Big Data; An Overview of Digital Resources for Patient, Genetic and Clinical Trials Information. Genes (Basel);2022 (Aug 28);13(9)

Even in the era of information « prosperity » in the form of databases and registries that compile a wealth of data, information about ASD and ADHD remains scattered and disconnected. These data systems are powerful tools that can inform decision-making and policy creation, as well as advancing and disseminating knowledge. Here, we review three types of data systems (patient registries, clinical trial registries and genetic databases) that are concerned with ASD or ADHD and discuss their features, advantages and limitations. We noticed the lack of ethnic diversity in the data, as the majority of their content is curated from European and (to a lesser extent) Asian populations. Acutely aware of this knowledge gap, we introduce here the framework of the Neurodevelopmental Disorders Database (NDDB). This registry was designed to serve as a model for the national repository for collecting data from Saudi Arabia on neurodevelopmental disorders, particularly ASD and ADHD, across diverse domains.

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3. Alenezi S, Alyahya AS, AlKhalifah SM, Bakhsh HR, Alismail EH, Aldhalaan H, Alwazna T, Alzrayer N, AlSuwailem SS, Alnemary F, AlAnsari AMS, Alqulaq EI, Alyamani A, Amer YS, Albawardi IM, Albalawi WM, Alhassan MA, Algazlan MS, Alramady M, Ad-Dab’bagh Y. Saudi Expert Consensus-Based Autism Spectrum Disorder Statement: From Screening to Management. Children (Basel);2022 (Aug 23);9(9)

BACKGROUND: There is a large gap between the needs of individuals diagnosed with autism spectrum disorder (ASD) and the currently available services in Saudi Arabia. Services are often difficult to access, inconsistent in quality, incomplete, unsatisfactory, and costly. As such, there is a national need for expert consensus on the appropriate standards for the assessment and management of children on the autism spectrum. METHODOLOGY: A guideline development group (GDC) was formed by professionals representing all related specialties and institutions involved in the management of individuals on the autism spectrum in Saudi Arabia. They met on a regular basis over 21 months. The guideline development process consisted of five steps starting from reviewing existing guidelines and ending with discussing and writing this manuscript. A formal voting process was utilized and recommendations were discussed until a consensus was reached. RESULTS: There was consensus on the following: A specialized diagnostic assessment needs to be carried out by an experienced multidisciplinary team for children referred to assess for ASD. They should be assessed for medical etiology, their behavioral history carefully reviewed, and symptoms directly observed. Longitudinal assessments are encouraged to reflect the effects of symptoms on the individual’s ability to function while with their family, among peers, and in school settings. An additional formal assessment of language, cognitive, and adaptive abilities as well as sensory status is essential to complete the diagnostic process. Interventions should be individualized, developmentally appropriate, and intensive, with performance data relevant to intervention goals to evaluate and adjust interventions. Target symptoms must be identified to address and develop monitoring systems to track change. CONCLUSION: ASD is a complex condition with widely varying clinical manifestations, thus requiring evaluation and intervention by a range of professionals working in coordination. Behavioral and environmental interventions are the key to optimal outcomes, in conjunction with medications when indicated for specific symptoms. Parental involvement in interventions is vital to sustaining therapeutic gains.

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4. Borrmann D, Danzer A, Sadowski G. Anomalous Water-Sorption Kinetics in ASDs. Pharmaceutics;2022 (Sep 7);14(9)

Anomalous water-sorption kinetics in amorphous solid dispersions (ASDs) are caused by the slow swelling of the polymer. In this work, we used a diffusion-relaxation model with the Williams-Landel-Ferry (WLF) equation and the Arrhenius equation to predict the anomalous water-sorption kinetics in ASDs of poly(vinyl-pyrrolidone)-co-vinyl-acetate (PVPVA) and indomethacin (IND) at 25 °C. These predictions were based on the viscosities of pure PVPVA and pure IND, as well as on the water-sorption kinetics in pure PVPVA. The diffusion-relaxation model was able to predict the different types of anomalous behavior leading to a qualitative and quantitative agreement with the experimental data. Predictions and experiments indicated more pronounced anomalous two-stage water-sorption behavior in the ASDs than in pure PVPVA. This was caused by a higher viscosity of glassy ASD-water mixtures compared to glassy PVPVA-water mixtures at the same distance from their glass transition temperature. These results suggest that this ASD swells more slowly than the polymer it is composed of. The modeling approach applied in this work can be used in the future for predicting diffusion-controlled release behavior or swelling-controlled release behavior of ASDs.

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5. Bouzroud W, Tazzite A, Berrada S, Gazzaz B, Dehbi H. R306X Mutation in the MECP2 Gene Causes an Atypical Rett Syndrome in a Moroccan Patient: A Case Report. Clin Pathol;2022 (Jan-Dec);15:2632010X221124269.

Rett syndrome (RTT) is a rare X-linked syndrome that predominantly affects girls. It is characterized by a severe and progressive neurodevelopmental disorder with neurological regression and autism spectrum features. The Rett syndrome is associated with a broad phenotypic spectrum. It ranges from a classical Rett syndrome defined by well-established criteria to atypical cases with symptoms similar to other syndromes, such as Angelman syndrome. The first case of a Moroccan female child carrying a R306X mutation in the MECP2 (Methyl-CpG-Binding Protein 2) gene, with an unusual manifestation of Rett syndrome, is presented here. She showed autistic regression, behavioral stagnation, epilepsy, unmotivated laughter, and craniofacial dysmorphia. Whole exome sequencing revealed a nonsense mutation (R306X), resulting in a truncated, nonfunctional MECP2 protein. The overlapping phenotypic spectrums between Rett and Angelman syndromes have been described, and an interaction between the MECP2 gene and the UBE3A (Ubiquitin Protein Ligase E3A) gene pathways is possible but has not yet been proven. An extensive genetic analysis is highly recommended in atypical cases to ensure an accurate diagnosis and to improve patient management and genetic counseling.

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6. Chakraborty S, Parayil R, Mishra S, Nongthomba U, Clement JP. Epilepsy Characteristics in Neurodevelopmental Disorders: Research from Patient Cohorts and Animal Models Focusing on Autism Spectrum Disorder. Int J Mol Sci;2022 (Sep 16);23(18)

Epilepsy, a heterogeneous group of brain-related diseases, has continued to significantly burden society and families. Epilepsy comorbid with neurodevelopmental disorders (NDDs) is believed to occur due to multifaceted pathophysiological mechanisms involving disruptions in the excitation and inhibition (E/I) balance impeding widespread functional neuronal circuitry. Although the field has received much attention from the scientific community recently, the research has not yet translated into actionable therapeutics to completely cure epilepsy, particularly those comorbid with NDDs. In this review, we sought to elucidate the basic causes underlying epilepsy as well as those contributing to the association of epilepsy with NDDs. Comprehensive emphasis is put on some key neurodevelopmental genes implicated in epilepsy, such as MeCP2, SYNGAP1, FMR1, SHANK1-3 and TSC1, along with a few others, and the main electrophysiological and behavioral deficits are highlighted. For these genes, the progress made in developing appropriate and valid rodent models to accelerate basic research is also detailed. Further, we discuss the recent development in the therapeutic management of epilepsy and provide a briefing on the challenges and caveats in identifying and testing species-specific epilepsy models.

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7. Cicinelli G, Nobile E, Brighenti S, Bari S, Tonella E, Aresi A, Attanasio M, Mazza M, Valenti M, Keller R. Wechsler Intelligence Scale for Adults – Fourth Edition profiles of adults with autism spectrum disorder. Epidemiol Psychiatr Sci;2022 (Sep 23);31:e67.

AIM: In this study, we have compared 229 Wechsler Adults Intelligence Scale – Fourth Edition (WAIS-IV) cognitive profiles of different severity adults with autism spectrum disorder to verify the impact of several variables including sex, age, level of education and autism severity level in an Italian sample. Moreover, we wanted to find out the optimal cut points for the major intelligence quotients in order to discriminate autism severity levels. METHODS: Participants were recruited from two National Health System Center in two different Italian regions and were assessed with gold-standard instruments as a part of their clinical evaluation. According to DSM-5, cognitive domains were also measured with multi-componential tests. We used the Italian adaptation of WAIS-IV. We checked our hypotheses using linear regression models and receiver operating characteristics (ROC) curves. RESULTS: Our results showed that age and level of education have a strong impact on Verbal Comprehension (VCI) and Working Memory Indexes (WMI). Gender differences are relevant when considering the VCI and Processing Speed index (PSI) in which women obtained the best performance. These differences are still relevant when considering cut points of ROC because 69 resulted to be the optimal cut point for women, 65 for men. CONCLUSIONS: Few conclusions can be assumed only examining Full Scale Intelligence Quotient (FSIQ) scores as it includes many different information about broader cognitive abilities. Looking deeper at main indexes and their subtests findings are consistent with previous research on the disorder (moderate correlations of FSIQ, Perceptual Reasoning index, WMI and PSI with the participants’ age), while other results are unforeseen (no effect of sex found on FSIQ score) or novel (significant effect of education on VCI and WMI). Using an algorithm predicting optimal cut point for discriminating through autism severity levels can help clinicians to better label and quantify the required help a person may need, a test cannot replace diagnostic and clinical evaluation by experienced clinicians.

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8. Como DH, Floríndez-Cox LI, Stein Duker LI, Polido JC, Jones BP, Lawlor M, Cermak SA. Oral Care Knowledge, Attitudes, and Practices of Black/African American Caregivers of Autistic Children and Non-Autistic Children. Children (Basel);2022 (Sep 19);9(9)

Oral health is a vital component of overall health. Children from underserved, minoritized populations (i.e., Black/African Americans, autistic children) are at even greater risk for experiencing oral health disparities. This study aims to illuminate the oral health knowledge, attitudes, and practices of Black/African American caregivers of autistic and non-autistic children. Black/African American caregivers of children (4-to-14 years) on the autism spectrum (n = 65) or not on the autism spectrum (n = 60), participated in a survey, with input from literature reviews, interviews, previous research, and reviews by experts. Caregivers demonstrated basic knowledge of oral health with significantly lower scores for caregivers of autistic children. Caregivers care about oral health and would like to increase their knowledge. Significant differences in oral care practices were found between the autistic and non-autistic groups. Caregivers reported they can access dental services with relative ease, including finding their child a dentist, scheduling a dental appointment, and accessing transportation (personal or public) to attend the visit. Black/African American caregivers of autistic children and children without autism seem to have foundational knowledge about oral health and basic practices; however, they are interested in learning more. Therefore, tailored oral health education programs may help mitigate oral health disparities for Black/African American families.

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9. Cucinotta F, Vetri L, Ruta L, Turriziani L, Benedetto L, Ingrassia M, Maggio R, Germanò E, Alquino A, Siracusano R, Roccella M, Gagliano A. Impact of Three Kinds of Early Interventions on Developmental Profile in Toddlers with Autism Spectrum Disorder. J Clin Med;2022 (Sep 15);11(18)

Autism spectrum disorder is a neurodevelopmental disorder with a rising prevalence disorder. This high-cost/high-burden condition needs evidence-based behavioral treatments that are able to reduce the impact of symptoms on children’s functioning. This retrospective chart review study compared the impact of different types of early interventions on toddlers diagnosed with an autism spectrum disorder developmental profile. Analyses were conducted on 90 subjects (mean = 27.76 months, range 18-44 months; M:F = 4.29:1), of which 36 children underwent the usual treatment, 13 children underwent an intervention based on early intensive behavioral intervention (EIBI) and 41 children received the Early Start Denver Model, for one year, with the same weekly frequency of about 6 h a week. A significant decrease in the severity of autism symptoms was observed for all children when looking at the Ados-2 severity score (average difference = 3.05, SD = 0.71, p = < 0.001) and the Ados-2 social subscale (average difference = 2.87, SD = 0.59, p < 0.001). Otherwise, for most of the Griffiths subscales, we found a significant improvement only for those children who underwent the Early Start Denver Model intervention (General Quotient average difference = 14.47, SD = 3.22, corrected p < 0.001). Analyzing the influence of age on the investigated scores, we found a significant association with the Eye-hand Coordination Quotient (p = 0.003), Performance Quotient (p = 0.042) and General Quotient (p = 0.006). In all these domains, a mild negative correlation with age was observed, as measured by the Pearson’s correlation coefficient (r = -0.32, p = 0.002; r = -0.21, p = 0.044; r = -0.25, p = 0.019, respectively), suggesting less severe developmental skills at the start of treatment for older children. Our results are consistent with the literature that underlines the importance of early intervention, since prompt diagnosis can reduce the severity of autism symptoms; nevertheless, in toddlers, our study demonstrated that an intervention model based on naturalistic developmental behavioral principles such as the Early Start Denver Model is more effective on children’s developmental profile. Further studies are required to assess the extent of effectiveness of different early intervention models in community settings.

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10. Dahl V, Helmbrecht H, Rios Sigler A, Hildahl K, Sullivan H, Janakiraman S, Jasti S, Nance E. Characterization of a mGluR5 Knockout Rat Model with Hallmarks of Fragile X Syndrome. Life (Basel);2022 (Aug 25);12(9)

The number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and the most common monogenetic inheritable form of ASDs is Fragile X Syndrome (FXS). Previous studies indicate that FXS is linked to glutamate signaling regulation by the G-protein-coupled metabotropic glutamate receptor 5 (mGluR5), which has been shown to have a regulatory role in neuroinflammation. We characterized the effect of knocking out mGluR5 in an organism known to have complex cognitive functions-the rat. The heterozygous phenotype is the most clinically relevant; therefore, we performed analysis in heterozygous pups. We showed developmental abnormalities in heterozygous mGluR5 knockout rats, as well as a significant increase in chemokine (C-X-C motif) ligand 1 (CXCL) expression, a hallmark indicator of early onset inflammation. We quantified an increase in microglial density in the knockout pups and quantified morphological phenotypes representative of greater reactivity in the male vs. female and postnatal day 28 heterozygous pups compared to postnatal day 14 heterozygous pups. In response to injury, reactive microglia release matrix metalloproteases, contribute to extracellular matrix (ECM) breakdown, and are responsible for eradicating cellular and molecular debris. In our study, the changes in microglial density and reactivity correlated with abnormalities in the mRNA expression levels of ECM proteins and with the density of perineuronal nets. We saw atypical neuropsychiatric behavior in open field and elevated plus tests in heterozygous pups compared to wild-type litter and age-matched controls. These results demonstrate the pathological potential of the mGluR5 knockout in rats and further support the presence of neuroinflammatory roots in ASDs.

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11. Edwards DJ. Going beyond the DSM in predicting, diagnosing, and treating autism spectrum disorder with covarying alexithymia and OCD: A structural equation model and process-based predictive coding account. Front Psychol;2022;13:993381.

BACKGROUND: There is much overlap among the symptomology of autistic spectrum disorders (ASDs), obsessive compulsive disorders (OCDs), and alexithymia, which all typically involve impaired social interactions, repetitive impulsive behaviors, problems with communication, and mental health. AIM: This study aimed to identify direct and indirect associations among alexithymia, OCD, cardiac interoception, psychological inflexibility, and self-as-context, with the DV ASD and depression, while controlling for vagal related aging. METHODOLOGY: The data involved electrocardiogram (ECG) heart rate variability (HRV) and questionnaire data. In total, 1,089 participant’s data of ECG recordings of healthy resting state HRV were recorded and grouped into age categories. In addition to this, another 224 participants completed an online survey that included the following questionnaires: Yale-Brown Obsessive Compulsive Scale (Y-BOCS); Toronto Alexithymia Scale 20 (TAS-20); Acceptance and Action Questionnaire (AAQII); Depression, Anxiety, and Stress Scale 21 (DAS21); Multi-dimensional Assessment of Interoceptive Awareness Scale (MAIA); and the Self-as-Context Scale (SAC). RESULTS: Heart rate variability was shown to decrease with age when controlling for BMI and gender. In the two SEMs produced, it was found that OCD and alexithymia were causally associated with autism and depression indirectly through psychological inflexibility, SAC, and ISen interoception. CONCLUSION: The results are discussed in relation to the limitations of the DSM with its categorical focus of protocols for syndromes and provide support for more flexible ideographic approaches in diagnosing and treating mental health and autism within the Extended Evolutionary Meta-Model (EEMM). Graph theory approaches are discussed in their capacity to depict the processes of change potentially even at the level of the relational frame.

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12. Escolano-Pérez E, Acero-Ferrero M. Evaluating in the Real-World Educational Intervention to Improve Interference Control in Children with Autism Spectrum Disorder. Children (Basel);2022 (Aug 26);9(9)

Children with autism spectrum disorder (ASD) present deficiencies in interference control processes. The main aim of this pilot study was to analyze the efficacy of an educational intervention designed to optimize the interference control of eight ASD children, attending to their ASD severity level. A mixed-methods approach grounded in systematic observation and nomothetic/follow-up/multidimensional observational designs was used. An observation instrument was developed to code data, which were grouped according to the ASD severity level (Group 1, requires support; Group 2, requires substantial support) and were analyzed using a lag sequential analysis. The results show that, although both groups progressed during the intervention and could have continued to improve, each group evolved differently. Group 1 performed relatively well from the onset and increased and developed their interference control strategies throughout the intervention, while Group 2, despite also acquiring new interference control strategies, took more time to show improvements. One month after the intervention ended, both groups were unable to consolidate the strategies learned. A mixed-methods approach allowed for real interference control deficits in ASD children to be captured in a natural context. To conclude, it would be necessary to lengthen this intervention and adapt it to the needs of each group.

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13. Gómez-Rodríguez MJ, Morales-Conejo M, Arteche-López A, Sánchez-Calvín MT, Quesada-Espinosa JF, Gómez-Manjón I, Palma-Milla C, Lezana-Rosales JM, Pérez de la Fuente R, Martin-Ramos ML, Fernández-Guijarro M, Moreno-García M, Alvarez-Mora MI. Fragile X Syndrome Caused by Maternal Somatic Mosaicism of FMR1 Gene: Case Report and Literature Review. Genes (Basel);2022 (Sep 8);13(9)

Fragile X syndrome (FXS) is caused by an abnormal expansion of the number of trinucleotide CGG repeats located in the 5′ UTR in the first exon of the FMR1 gene. Size and methylation mosaicisms are commonly observed in FXS patients. Both types of mosaicisms might be associated with less severe phenotypes depending on the number of cells expressing FMRP. Although this dynamic mutation is the main underlying cause of FXS, other mechanisms, including point mutations or deletions, can lead to FXS. Several reports have demonstrated that de novo deletions including the entire or a portion of the FMR1 gene end up with the absence of FMRP and, thus, can lead to the typical clinical features of FXS. However, very little is known about the clinical manifestations associated with FMR1 gene deletions in mosaicism. Here, we report an FXS case caused by an entire hemizygous deletion of the FMR1 gene caused by maternal mosaicism. This manuscript reports this case and a literature review of the clinical manifestations presented by carriers of FMR1 gene deletions in mosaicism.

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14. Guidetti C, Salvini E, Viri M, Deidda F, Amoruso A, Visciglia A, Drago L, Calgaro M, Vitulo N, Pane M, Caucino AC. Randomized Double-Blind Crossover Study for Evaluating a Probiotic Mixture on Gastrointestinal and Behavioral Symptoms of Autistic Children. J Clin Med;2022 (Sep 6);11(18)

Autism spectrum disorders (ASDs) represent a diagnostic challenge with a still partially uncertain etiology, in which genetic and environmental factors have now been assessed. Among the hypotheses underlying the involvement of biological and environmental factors, the gut-brain axis is of particular interest in autism spectrum disorders. Several studies have highlighted the related incidence of particular gastrointestinal symptoms (GISs) in children suffering from ASDs. Probiotics have shown success in treating several gastrointestinal dysbiotic disorders; therefore, it is plausible to investigate whether they can alleviate behavioral symptoms as well. On these bases, a randomized double-blind crossover study with a placebo was conducted, evaluating the effects of a mixture of probiotics in a group of 61 subjects aged between 24 months and 16 years old with a diagnosis of ASD. Behavioral evaluation was performed through the administration of a questionnaire including a Parenting Stress Index (PSI) test and the Vineland Adaptive Behavior Scale (VABS). The Psycho-Educational Profile and the Autism Spectrum Rating Scale (ASRS) were also evaluated. Microbial composition analyses of fecal samples of the two groups was also performed. The study showed significant improvements in GISs, communication skills, maladaptive behaviors, and perceived parental stress level after the administration of probiotics. Microbiome alpha diversity was comparable between treatment arms and no significant differences were found, although beta diversity results were significantly different in the treatment group between T0 and T1 time points. Streptococcus thermophilus, Bifidobacterium longum, Limosilactobacillus fermentum, and Ligilactobacillus salivarius species were identified as some of the most discriminant taxa positively associated with T1 samples. This preliminary study corroborates the relationship between intestinal microbiota and ASD recently described in the literature.

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15. Guy MW, Richards JE, Roberts JE. Cortical Source Analysis of the Face Sensitive N290 ERP Component in Infants at High Risk for Autism. Brain Sci;2022 (Aug 25);12(9)

Appropriate head models for cortical source analysis were investigated and applied to source analyses examining the neural bases of the face-sensitive N290 event-related potential (ERP) component in infants at high risk for autism spectrum disorder (ASD). This included infant siblings of children with ASD (ASIBs) and infants with fragile X syndrome (FXS). First, alternative head models for use with ASIBs and FXS were investigated. Head models created from the infant’s own MRI were examined in relation to five head models based on average MRI templates. The results of the head model comparison identified group-specific (i.e., ASIB or FXS) head models created from a large collection of structural MRIs as the best substitution for the head model created from the participant’s own structural MRI. Second, the cortical source analysis was completed on N290 data collected from a previous study to investigate brain areas associated with face sensitive ERP responses. Participants’ own MRIs were used for head models when available, and the group-specific head model was used when the participants’ own MRIs were not available. The results provide evidence for unique patterns of neural activation during face processing across infants at high and low risk for ASD and across etiologically distinct high-risk groups. All infants demonstrated greater activation to faces than toys in brain areas most associated with specialized face processing. Infants with FXS displayed higher levels of activation to faces across all areas analyzed, while ASIBs show more muted levels of activation. Overall, the results of the current study demonstrate the importance of group-specific head models for accurate cortical source analysis in infants at high risk for ASD. This also allows for further research on early distinctions in brain function based on risk status.

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16. Heleven E, Bylemans T, Ma Q, Baeken C, Baetens K. Impaired sequence generation: a preliminary comparison between high functioning autistic and neurotypical adults. Front Behav Neurosci;2022;16:946482.

Earlier research demonstrated robust cerebellar involvement in sequencing, including high-level social information sequencing that requires mental state attributions, termed mentalizing. Earlier research also found cerebellar deficiencies in autism spectrum disorders (ASD) which are characterized by social difficulties. However, studies on high-level social sequencing functionality by persons with ASD are almost non-existent. In this study, we, therefore, perform a comparison between behavioral performances of high-functioning ASD and neurotypical participants on the Picture and Verbal Sequencing Tasks. In these tasks, participants are requested to put separate events (depicted in cartoon-like pictures or behavioral sentences, respectively) in their correct chronological order. To do so, some of these events require understanding of high-level social beliefs, of social routines (i.e., scripts), or nonsocial mechanical functionality. As expected, on the Picture Sequencing task, we observed longer response times for persons with ASD (in comparison with neurotypical controls) when ordering sequences requiring an understanding of social beliefs and social scripts, but not when ordering nonsocial mechanical events. This confirms our hypotheses that social sequence processing is impaired in ASD. The verbal version of this task did not reveal differences between groups. Our results are the first step toward new theoretical insights for social impairments of persons with ASD. They highlight the importance of taking into account sequence processing, and indirectly the cerebellum when investigating ASD difficulties.

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17. Keles U, Kliemann D, Byrge L, Saarimäki H, Paul LK, Kennedy DP, Adolphs R. Atypical gaze patterns in autistic adults are heterogeneous across but reliable within individuals. Mol Autism;2022 (Sep 24);13(1):39.

BACKGROUND: Across behavioral studies, autistic individuals show greater variability than typically developing individuals. However, it remains unknown to what extent this variability arises from heterogeneity across individuals, or from unreliability within individuals. Here, we focus on eye tracking, which provides rich dependent measures that have been used extensively in studies of autism. Autistic individuals have an atypical gaze onto both static visual images and dynamic videos that could be leveraged for diagnostic purposes if the above open question could be addressed. METHODS: We tested three competing hypotheses: (1) that gaze patterns of autistic individuals are less reliable or noisier than those of controls, (2) that atypical gaze patterns are individually reliable but heterogeneous across autistic individuals, or (3) that atypical gaze patterns are individually reliable and also homogeneous among autistic individuals. We collected desktop-based eye tracking data from two different full-length television sitcom episodes, at two independent sites (Caltech and Indiana University), in a total of over 150 adult participants (N = 48 autistic individuals with IQ in the normal range, 105 controls) and quantified gaze onto features of the videos using automated computer vision-based feature extraction. RESULTS: We found support for the second of these hypotheses. Autistic people and controls showed equivalently reliable gaze onto specific features of videos, such as faces, so much so that individuals could be identified significantly above chance using a fingerprinting approach from video epochs as short as 2 min. However, classification of participants into diagnostic groups based on their eye tracking data failed to produce clear group classifications, due to heterogeneity in the autistic group. LIMITATIONS: Three limitations are the relatively small sample size, assessment across only two videos (from the same television series), and the absence of other dependent measures (e.g., neuroimaging or genetics) that might have revealed individual-level variability that was not evident with eye tracking. Future studies should expand to larger samples across longer longitudinal epochs, an aim that is now becoming feasible with Internet- and phone-based eye tracking. CONCLUSIONS: These findings pave the way for the investigation of autism subtypes, and for elucidating the specific visual features that best discriminate gaze patterns-directions that will also combine with and inform neuroimaging and genetic studies of this complex disorder.

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18. Kyle G, Connolly A. Developing an e-learning curriculum to educate healthcare staff in the acute hospital setting about autism. Br J Nurs;2022 (Sep 22);31(17):894-900.

When attending acute hospital settings, autistic children and adults rely on health professionals and ancillary staff to interact with them appropriately to facilitate accurate diagnoses and management of health concerns. Health outcomes for autistic people are adversely affected by comorbidities as well as difficulties in accessing and navigating acute healthcare environments. These factors demonstrate a need to develop targeted education for healthcare staff working in the acute hospital setting. This article discusses the background to the project, including the results of a literature review that highlighted some of the difficulties this patient group experiences in accessing health care. It discusses the development and evaluation of an e-learning education programme for healthcare staff working in an acute hospital setting using Kern et al’s (1998) six-step approach to curriculum development. Staff reported a desire to learn more about autism and how to make patient consultations and experiences more accessible and productive. It was acknowledged that there are many undiagnosed autistic adults navigating the acute health system and it is anticipated that the e-learning programme will assist staff in identifying and meeting their needs. During research with an autism advocacy group, there was a clear recommendation for the use of the term ‘autistic person’ rather than ‘person with autism’, which is reflected in the resulting education programme and this article.

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19. László K, Vörös D, Kiss O, László BR, Ollmann T, Péczely L, Mintál K, Tóth A, Kovács A, Zagoracz O, Kertes E, Kállai V, Berta B, Karádi Z, Lénárd L. The Role of Intraamygdaloid Oxytocin and D2 Dopamine Receptors in Reinforcement in the Valproate-Induced Autism Rat Model. Biomedicines;2022 (Sep 16);10(9)

BACKGROUND: autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting around 1 out of 68 children and its incidence shows an increasing tendency. There is currently no effective treatment for ASD. In autism research, the valproate (VPA)-induced autism rodent model is widely accepted. Our previous results showed that intraamygdaloid oxytocin (OT) has anxiolytic effects on rats showing autistic signs under the VPA-induced autism model. METHODS: rats were stereotaxically implanted with guide cannulae bilaterally and received intraamygdaloid microinjections. In the present study, we investigated the possible role of intraamygdaloid OT and D2 dopamine (DA) receptors on reinforcement using VPA-treated rats in a conditioned place preference test. OT and/or an OT receptor antagonist or a D2 DA antagonist were microinjected into the central nucleus of the amygdala (CeA). RESULTS: valproate-treated rats receiving 10 ng OT spent significantly longer time in the treatment quadrant during the test session of the conditioned place preference test. Prior treatment with an OT receptor antagonist or with a D2 DA receptor antagonist blocked the positive reinforcing effects of OT. The OT receptor antagonist or D2 DA antagonist in themselves did not influence the time rats spent in the treatment quadrant. CONCLUSIONS: Our results show that OT has positive reinforcing effects under the VPA-induced autism rodent model and these effects are OT receptor-specific. Our data also suggest that the DAergic system plays a role in the positive reinforcing effects of OT because the D2 DA receptor antagonist can block these actions.

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20. Lee CE, Hagiwara M, Chiu CY, Takishima M. Caregiving and future planning perspectives of siblings of individuals with intellectual and developmental disabilities: Insights from South Korea, Japan and Taiwan. J Appl Res Intellect Disabil;2022 (Sep 24)

BACKGROUND: As individuals with intellectual and developmental disabilities age, their siblings are more likely to assume caregiving responsibilities. However, little is known about experiences of East Asian siblings with respect to their caregiving and future-planning within their own country, as well as other East Asian countries. METHODS: Using a national survey, this study explored experiences of 576 siblings across South Korea, Japan and Taiwan. RESULTS: A common factor across the three countries was that siblings were less engaged in advocacy and future-planning activities and felt less competent to play the role of caregiving. Korean siblings reported more negative views about disability, while Japanese siblings reported less engagement in future-planning and Taiwanese siblings reported greater involvement in caregiving. CONCLUSION: Based on ‘universalism without uniformity’, it is recommended to develop culturally sensitive sibling-targeted intervention based on each country’s context.

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21. Lee IH, Koelliker E, Kong SW. Quantitative trait locus analysis for endophenotypes reveals genetic substrates of core symptom domains and neurocognitive function in autism spectrum disorder. Transl Psychiatry;2022 (Sep 24);12(1):407.

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders and is largely attributable to genetic risk factors. Phenotypic and genetic heterogeneity of ASD have been well-recognized; however, genetic substrates for endophenotypes that constitute phenotypic heterogeneity are not yet known. In the present study, we compiled data from the Autism Genetic Resource Exchange, which contains the demographic and detailed phenotype information of 11,961 individuals. Notably, the whole-genome sequencing data available from MSSNG and iHART for 3833 individuals in this dataset was used to perform an endophenotype-wide association study. Using a linear mixed model, genome-wide association analyses were performed for 29 endophenotype scores and 0.58 million common variants with variant allele frequency ≥ 5%. We discovered significant associations between 9 genetic variants and 6 endophenotype scores comprising neurocognitive development and severity scores for core symptoms of ASD at a significance threshold of p < 5 × 10(-7). Of note, the Stereotyped Behaviors and Restricted Interests total score in Autism Diagnostic Observation Schedule Module 3 was significantly associated with multiple variants in the VPS13B gene, a causal gene for Cohen syndrome and a candidate gene for syndromic ASD. Our findings yielded loci with small effect sizes due to the moderate sample size and, thus, require validation in another cohort. Nonetheless, our endophenotype-wide association analysis extends previous candidate gene discovery in the context of genotype and endophenotype association. As a result, these candidate genes may be responsible for specific traits that constitute core symptoms and neurocognitive function of ASD rather than the disorder itself.

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22. Lewis S, DePass A, Hagerman RJ, Lozano R. Case Reports of Aortic Aneurism in Fragile X Syndrome. Genes (Basel);2022 (Aug 30);13(9)

Fragile X syndrome (FXS) is an inherited genetic condition that is the leading known cause of inherited intellectual developmental disability. Phenotypically, individuals with FXS also present with distinct physical features including, elongated face, prominent ears, pectus excavatum, macroorchidism, and joint laxity, which suggests connective tissue dysplasia. In addition to mitral valve prolapse, aortic dilatation has been identified within individuals with FXS. Abnormal elastin fiber networks have been found in the skin, valves, and aorta in individual cases. Aortic dilatation has been described in other connective tissue disorders, particularly Marfan syndrome. However, while aortic aneurysms are characteristic of Marfan syndrome, no similar cases have been reported in FXS patients to date. This case report details the presentation of two patients with FXS and aortic aneurysm. Our two cases highlight the risks of aortic pathology in FXS, and the need for monitoring in asymptomatic patients with significant aortic dilatation.

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23. Li F, Xu M, Wu D, Tang Y, Zhang L, Liu X, Zhou L, Jiang L. From child social impairment to parenting stress in mothers of children with ASD: The role of parental self-efficacy and social support. Front Psychiatry;2022;13:1005748.

OBJECTIVES: Children with autism spectrum disorder (ASD) can exhibit persistent deficits in social communication, causing their mothers to experience elevated parenting stress during the childrearing process. Some internal and external psychosocial resources may mediate or moderate the mother-child relationship, though the underlying mechanisms remain unclear. This study aimed to explore the predictors of parenting stress in mothers of children with ASD and elucidate the mechanisms underlying the relationship between child social impairment and parenting stress. METHODS: A cross-sectional study was conducted between October 2020 and March 2022 in Shanghai, China. Mothers of children with ASD completed a survey investigating child social impairment, parenting stress, parental self-efficacy, and social support. RESULTS: A total of 185 mothers of children with ASD were included in the final analysis. 70.27 percent of mothers experienced a clinically significant level of parenting stress. Child social impairment (r = 0.46, P < 0.001), parental self-efficacy (r = -0.58, P < 0.001), and social support (r = -0.35, P < 0.001) were significantly correlated with parenting stress. Parental self-efficacy completely mediated the relationship between child social impairment and parenting stress (B = 0.51, P < 0.001), after controlling for socioeconomic status (SES) correlated with parenting stress. There was no significant moderating effect of social support between child social impairment and parenting stress (B = 0.01, P = 0.09). CONCLUSION: Future early intervention programs that focused on child's social communication skills and empowered mothers with related strategies through group-based parent training programs may help reduce parenting stress.

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24. Lim M, Carollo A, Dimitriou D, Esposito G. Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022. Genes (Basel);2022 (Sep 14);13(9)

Genetic research in Autism Spectrum Disorder (ASD) has progressed tremendously in recent decades. Dozens of genetic loci and hundreds of alterations in the genetic sequence, expression, epigenetic transformation, and interactions with other physiological and environmental systems have been found to increase the likelihood of developing ASD. There is therefore a need to represent this wide-ranging yet voluminous body of literature in a systematic manner so that this information can be synthesised and understood at a macro level. Therefore, this study made use of scientometric methods, particularly document co-citation analysis (DCA), to systematically review literature on ASD genetic research from 2018 to 2022. A total of 14,818 articles were extracted from Scopus and analyzed with CiteSpace. An optimized DCA analysis revealed that recent literature on ASD genetic research can be broadly organised into 12 major clusters representing various sub-topics. These clusters are briefly described in the manuscript and potential applications of this study are discussed.

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25. Liu H, Ding L, Qu G, Guo X, Liang M, Ma S, Sun Y. Particulate matter exposure during pregnancy and infancy and risks of autism spectrum disorder in children: A systematic review and meta-analysis. Sci Total Environ;2022 (Sep 20):158830.

PURPOSE: This meta-analysis aimed to clarify the relationship between particulate matter (PM) and autism spectrum disorder (ASD) in detail. METHODS: A systematic literature search was performed using eight databases before April 9, 2022. The estimated effects were combined separately according to the PM type. Subgroup analyses were conducted in terms of the study design type, study location, exposure window, birth year, and sex. RESULTS: PM(2.5) was associated with an increased risk of ASD, while PM(10) was not. PMc, PM(1), and diesel particulate matter (DPM) were also associated with an increased risk of ASD. Specifically, a 10 μg/m(3) increase in PM(2.5) was associated with a 1.337-fold increased risk of ASD in children, and a 10 μg/m(3) increase in PMc and PM(1) may increase the risk of ASD by 1.062 and 3.643 times, respectively. PM(2.5) exposure may increase the risk of ASD in boys. Exposure to PMc might increase the risk of ASD in children born after the year 2000. The combined results of different PM differed between studies with continuous and non-continuous data for different study design type, study location, and birth year. The sensitive window for PM(2.5) exposure to increase the risk of ASD may be from the first, second, and third trimesters to the first year of the postnatal period. Exposure to PMc during pregnancy was significantly associated with ASD. CONCLUSION: Exposure to PM(2.5) may increase the risk of ASD in boys. Exposure to PM(2.5) during the first, second, and third trimesters and postnatally increased the risk of ASD.

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26. López-Nieto L, Compañ-Gabucio LM, Torres-Collado L, Garcia-de la Hera M. Scoping Review on Play-Based Interventions in Autism Spectrum Disorder. Children (Basel);2022 (Sep 5);9(9)

Play as a therapeutic strategy can help to improve daily functioning in children and adolescents with autism spectrum disorder (ASD). Play-based intervention can thus be an optimal option for treatment of this population. Our aim was to describe play-based interventions used in children and adolescents with ASD. We conducted a scoping review. A peer-reviewed literature search was conducted on PubMed, Scopus, EMBASE, Web of Science and PsycINFO databases. We included experimental studies which analyzed play-based interventions in children and adolescents with ASD, which were published in English/Spanish with full text available. We used three tables elaborated a priori to perform data extraction by two authors. Fifteen studies were included, mostly conducted in Australia and published during the past 10 years. Play-based intervention was categorized into three groups: new technologies, symbolic play or official techniques. Interventions lasted approximately 11 weeks, contained one weekly session of 30-60 min and were delivered by parents and teachers. Play-based interventions using new technologies were the most used. Intervention duration and number of sessions varied between articles. Further studies are needed to create play-based intervention protocols which can be implemented in clinical practice with children and adolescents with ASD, thus promoting evidence-based interventions in this field.

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27. Lozano R, Thompson T, Dixon-Weber J, Erickson CA, Berry-Kravis E, Williams S, Smith E, Frazier JA, Rosselot H, Farmer C, Hessl D. Observable Symptoms of Anxiety in Individuals with Fragile X Syndrome: Parent and Caregiver Perspectives. Genes (Basel);2022 (Sep 16);13(9)

Caregiver reports, clinical observations, and diagnostic assessments indicate that most individuals with fragile X syndrome experience high levels of chronic anxiety. However, anxiety is a challenging endpoint for outcome measurement in FXS because most individuals cannot reliably report internal emotional or body states. A comprehensive survey of the presence, frequency, and duration of anxiety-related symptoms and questions to elicit open-ended responses was completed by caregivers of 456 individuals with FXS, ages 2-81 years (87 female, 369 male) and 24 female and 2 male FXS self-advocates ages 15-66 years. Caregivers reported classic behavioral indicators of anxiety, such as avoidance, irritability, motor agitation, and physiological symptoms, as well as behavioral features in FXS such as repetitive behavior, aggression, and self-injury. Self-advocate accounts largely paralleled caregiver data. Factor analyses yielded four factors: (1) increased irritability, aggression, and self-injury; (2) increased physical movement, nervous activity, and restlessness; (3) physical and physiological features of anxiety; and (4) internalizing and gastrointestinal symptoms. Caregivers are capable of observing and reporting behaviors that are valid indicators of anxious states that are usually reported in self-report standardized assessments. These results support the development of an anxiety measure for FXS that minimizes problems with rater inference.

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28. Maertens M, Silver H, Dixon Weber J, Rosselot H, Lozano R. Parent and Caregiver Perspectives towards Cannabidiol as a Treatment for Fragile X Syndrome. Genes (Basel);2022 (Sep 6);13(9)

Cannabidiol (CBD) is a non-intoxicating chemical in cannabis plants that is being investigated as a candidate for treatment in Fragile X Syndrome (FXS), a leading known cause of inherited intellectual developmental disability. Studies have shown that CBD can reduce symptoms such as anxiety, social avoidance, hyperactivity, aggression, and sleep problems. This is a qualitative study that utilized a voluntary-anonymous survey that consisted of questions regarding demographics, medical information, the form, type, brand, dose, and frequency of CBD use, the rationale for use, the perception of effects, side effects, and costs. The full survey contained a total of 34 questions, including multiple-choice, Likert-scale, and optional free-response questions. This research revealed that there are a wide range of types, brands, and doses of CBD being administered to individuals with FXS by their parents and caregivers. There were many reasons why CBD was chosen, the most common ones being that respondents had heard positive things about CBD from members of the community, the perception that CBD had fewer side effects than other medications, and because respondents felt that CBD was a more natural substance. Most of the parents and caregivers who responded agreed that CBD improved some of the symptoms of FXS and made a positive difference overall. CBD has the therapeutic potential to help relieve some FXS symptoms. Future research is necessary to understand the benefits of CBD in FXS.

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29. McCarthy J, Chaplin E, Hayes S, Søndenaa E, Chester V, Morrissey C, Allely CS, Forrester A. Defendants with intellectual disability and autism spectrum conditions: the perspective of clinicians working across three jurisdictions. Psychiatr Psychol Law;2022;29(5):698-717.

The treatment of vulnerable defendants by criminal justice systems or correctional systems varies within and between countries. The purpose of this paper is to examine three legal jurisdictions – New South Wales in Australia; Norway; England and Wales – to understand the extent of variation in practice within the court systems for defendants with intellectual disabilities (ID) and/or autism spectrum conditions (ASC). Two of the jurisdictions had a process for screening in place, either in police custody or at court, but this was not universally implemented across each jurisdiction. All three jurisdictions had a process for supporting vulnerable defendants through the legal system. Across the three jurisdictions, there was variation in disposal options from a mandatory care setting to hospital treatment to a custodial sentence for serious offences. This variation requires further international exploration to ensure the rights of defendants with ID or ASC are understood and safeguarded.

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30. Nees F, Banaschewski T, Bokde ALW, Desrivières S, Grigis A, Garavan H, Gowland P, Grimmer Y, Heinz A, Brühl R, Isensee C, Becker A, Martinot JL, Paillère Martinot ML, Artiges E, Papadopoulos Orfanos D, Lemaître H, Stringaris A, van Noort B, Paus T, Penttilä J, Millenet S, Fröhner JH, Smolka MN, Walter H, Whelan R, Schumann G, Poustka L, On Behalf Of The Imagen C. Global and Regional Structural Differences and Prediction of Autistic Traits during Adolescence. Brain Sci;2022 (Sep 2);12(9)

Autistic traits are commonly viewed as dimensional in nature, and as continuously distributed in the general population. In this respect, the identification of predictive values of markers such as subtle autism-related alterations in brain morphology for parameter values of autistic traits could increase our understanding of this dimensional occasion. However, currently, very little is known about how these traits correspond to alterations in brain morphology in typically developing individuals, particularly during a time period where changes due to brain development processes do not provide a bias. Therefore, in the present study, we analyzed brain volume, cortical thickness (CT) and surface area (SA) in a cohort of 14-15-year-old adolescents (N = 285, female: N = 162) and tested their predictive value for autistic traits, assessed with the social responsiveness scale (SRS) two years later at the age of 16-17 years, using a regression-based approach. We found that autistic traits were significantly predicted by volumetric changes in the amygdala (r = 0.181), cerebellum (r = 0.128) and hippocampus (r = -0.181, r = -0.203), both in boys and girls. Moreover, the CT of the superior frontal region was negatively correlated (r = -0.144) with SRS scores. Furthermore, we observed a significant association between the SRS total score and smaller left putamen volume, specifically in boys (r = -0.217), but not in girls. Our findings suggest that neural correlates of autistic traits also seem to lie on a continuum in the general population, are determined by limbic-striatal neuroanatomical brain areas, and are partly dependent on sex. As we imaged adolescents from a large population-based cohort within a small age range, these data may help to increase the understanding of autistic-like occasions in otherwise typically developing individuals.

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31. Nekar DM, Kang H, Alao H, Yu J. Feasibility of Using Multiplayer Game-Based Dual-Task Training with Augmented Reality and Personal Health Record on Social Skills and Cognitive Function in Children with Autism. Children (Basel);2022 (Sep 15);9(9)

The purpose of this preliminary study was to evaluate the feasibility of multiplayer game contents with dual-task exercises using augmented reality (AR) and a personal health record (PHR) system for social skills and cognitive function in children with autism. The present study used a single group pretest-posttest study design with fourteen children diagnosed with autism and aged 6-16 years. The intervention consisted of various game contents designed specifically with cognitive and motor tasks, performed for 30 min per session, twice a week, for three weeks. Outcome measures were conducted before and after the intervention and included social skills and cognitive function. A satisfactory survey was conducted post-intervention to assess the usability of the performed games. As result, statistically significant improvements were observed in all subscales of the social skills and cognitive function expected in two subscales of each measured outcome. Parents and children appreciated the overall game program, and no risk of injury and dizziness were mentioned. This preliminary study found that multiplayer game-based dual-task training using AR and PHR was feasible and has a promising efficacy for children with autism. However, there is the need to conduct a randomized control study with a large sample size.

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32. Nguyen J, Zhang B, Hanson E, Mylonas D, Maski K. Neurobehavioral Associations with NREM and REM Sleep Architecture in Children with Autism Spectrum Disorder. Children (Basel);2022 (Aug 30);9(9)

OBJECTIVE: Insomnia and daytime behavioral problems are common issues in pediatric autism spectrum disorder (ASD), yet specific underlying relationships with NonRapid Eye Movement sleep (NREM) and Rapid Eye Movement (REM) sleep architecture are understudied. We hypothesize that REM sleep alterations (REM%, REM EEG power) are associated with more internalizing behaviors and NREM sleep deficits (N3%; slow wave activity (SWA) 0.5-3 Hz EEG power) are associated with increased externalizing behaviors in children with ASD vs. typical developing controls (TD). METHODS: In an age- and gender-matched pediatric cohort of n = 23 ASD and n = 20 TD participants, we collected macro/micro sleep architecture with overnight home polysomnogram and daytime behavior scores with Child Behavior Checklist (CBCL) scores. RESULTS: Controlling for non-verbal IQ and medication use, ASD and TD children have similar REM and NREM sleep architecture. Only ASD children show positive relationships between REM%, REM theta power and REM beta power with internalizing scores. Only TD participants showed an inverse relationship between NREM SWA and externalizing scores. CONCLUSION: REM sleep measures reflect concerning internalizing behaviours in ASD and could serve as a biomarker for mood disorders in this population. While improving deep sleep may help externalizing behaviours in TD, we do not find evidence of this relationship in ASD.

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33. Orchard ER, Dakin SC, van Boxtel JJA. Internal noise measures in coarse and fine motion direction discrimination tasks and the correlation with autism traits. J Vis;2022 (Sep 2);22(10):19.

Motion perception is essential for visual guidance of behavior and is known to be limited by both internal additive noise (i.e., a constant level of random fluctuations in neural activity independent of the stimulus) and motion pooling (global integration of local motion signals across space). People with autism spectrum disorder (ASD) display abnormalities in motion processing, which have been linked to both elevated noise and abnormal pooling. However, to date, the impact of a third limit-induced internal noise (internal noise that scales up with increases in external stimulus noise)-has not been investigated in motion perception of any group. Here, we describe an extension on the double-pass paradigm to quantify additive noise and induced noise in a motion paradigm. We also introduce a new way to experimentally estimate motion pooling. We measured the impact of induced noise on direction discrimination, which we ascribe to fluctuations in decision-related variables. Our results are suggestive of higher internal noise in individuals with high ASD traits only on coarse but not fine motion direction discrimination tasks. However, we report no significant correlations between autism traits and additive noise, induced noise, or motion pooling in either task. We conclude that, under some conditions, the internal noise may be higher in individuals with pronounced ASD traits and that the assessment of induced internal noise is a useful way of exploring decision-related limits on motion perception, irrespective of ASD traits.

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34. Rabia A, Harripaul R, Mikhailov A, Mahmood S, Maqbool S, Vincent JB, Ayub M. Biallelic Loss of Function Mutation in Sodium Channel Gene SCN10A in an Autism Spectrum Disorder Trio from Pakistan. Genes (Basel);2022 (Sep 11);13(9)

The genetic dissection of autism spectrum disorders (ASD) has uncovered the contribution of de novo mutations in many single genes as well as de novo copy number variants. More recent work also suggests a strong contribution from recessively inherited variants, particularly in populations in which consanguineous marriages are common. What is also becoming more apparent is the degree of pleiotropy, whereby mutations in the same gene may have quite different phenotypic and clinical consequences. We performed whole exome sequencing in a group of 115 trios from countries with a high level of consanguineous marriages. In this paper we report genetic and clinical findings on a proband with ASD, who inherited a biallelic truncating pathogenic/likely pathogenic variant in the gene encoding voltage-gated sodium channel X alpha subunit, SCN10A (NM_006514.2:c.937G>T:(p.Gly313*)). The biallelic pathogenic/likely pathogenic variant in this study have different clinical features than heterozygous mutations in the same gene. The study of consanguineous families for autism spectrum disorder is highly valuable.

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35. Reetzke R, Singh V, Hong JS, Holingue CB, Kalb LG, Ludwig NN, Menon D, Pfeiffer DL, Landa RJ. Profiles and correlates of language and social communication differences among young autistic children. Front Psychol;2022;13:936392.

Delays in early language development are characteristic of young autistic children, and one of the most recognizable first concerns that motivate parents to seek a diagnostic evaluation for their child. Although early language abilities are one of the strongest predictors of long-term outcomes, there is still much to be understood about the role of language impairment in the heterogeneous phenotypic presentation of autism. Using a person-centered, Latent Profile Analysis, we first aimed to identify distinct patterns of language and social communication ability in a clinic-based sample of 498 autistic children, ranging in age from 18 to 60 months (M = 33 mo, SD = 12 mo). Next, a multinomial logistic regression analysis was implemented to examine sociodemographic and child-based developmental differences among the identified language and social communication profiles. Three clinically meaningful profiles were identified from parent-rated and clinician-administered measures: Profile 1 (48% of the sample) « Relatively Low Language and Social Communication Abilities, » Profile 2 (34% of the sample) « Relatively Elevated Language and Social Communication Abilities, » and Profile 3 (18% of the sample) « Informant Discrepant Language and Relatively Elevated Social Communication Abilities. » Overall, young autistic children from the lowest-resource households exhibited the lowest language and social communication abilities, and the lowest non-verbal problem-solving and fine-motor skills, along with more features of attention-deficit/hyperactivity disorder and atypical auditory processing. These findings highlight the need for effective community-based implementation strategies for young autistic children from low-resource households and underrepresented communities to improve access to individualized quality care.

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36. Ringold SM, McGuire RW, Jayashankar A, Kilroy E, Butera CD, Harrison L, Cermak SA, Aziz-Zadeh L. Sensory Modulation in Children with Developmental Coordination Disorder Compared to Autism Spectrum Disorder and Typically Developing Children. Brain Sci;2022 (Aug 31);12(9)

Developmental Coordination Disorder (DCD) is one of the least studied and understood developmental disorders. One area that has been minimally investigated in DCD is potential issues with sensory modulation. Further, in other neurodevelopmental disorders (e.g., autism spectrum disorder (ASD)) sensory modulation is related to many other challenges (e.g., social issues, repetitive behaviors, anxiety); however, such potential relationships in children with DCD have been largely unexplored. The purpose of this study is to explore sensory modulation differences in DCD and to understand the relationships between sensory modulation and social emotional measures, behavior, and motor skills in DCD in comparison to ASD and typically developing (TD) peers. Participants (aged 8-17) and their caregivers (DCD, N = 26; ASD, N = 57; and TD, N = 53) completed behavioral and clinical measures. The results indicated that 31% of the DCD group showed sensory modulation difficulties, with the DCD group falling between the ASD and TD groups. In the DCD group, sensory modulation was significantly associated with anxiety, empathic concern, repetitive behaviors, and motor skills. Data are compared to patterns seen in ASD and TD groups and implications for interventions are discussed.

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37. Rong P, Zhao S, Fu Q, Chen M, Yang L, Song Y, Zhang X, Ma R. Case report: One child with an autism spectrum disorder who had chronically elevated serum levels of CK and CK-MB. Front Psychiatry;2022;13:995237.

Some patients with autism spectrum disorder (ASD) exhibit elevated serum creatine kinase levels, which are believed to be associated with mitochondrial dysfunction. Although a few articles have reported this situation in the past and the increase mostly ranges from 100 to 300 U/L, there is a paucity of previous study focusing on the serum creatine kinase MB isoenzyme. This article discusses a 5-year-old girl with ASD, whose serum creatine kinase and creatine kinase MB isoenzyme have been rising for nearly 2 years, fluctuating at 584-993 and 111-625 U/L respectively. Except for behavioral and language symptoms associated with ASD, the child appears normal in other aspects. The child’s laboratory tests showed no abnormality, except that the serum levels of lactic acid was slightly higher than normal (1.89 mmol/L, normal 1.33-1.78 mmol/L). The child was prescribed with a traditional Chinese medicine during the process and the serum creatine kinase MB isoenzyme level decreased dramatically to 111 U/L after the treatment. This study firstly recorded the serum creatine kinase levels and the MB isoenzyme in patients with autism spectrum disorder for nearly 2 years, indicating that patients with ASD may experience long-term increases in serum creatine kinase and creatine kinase MB isoenzyme, and that the traditional Chinese medicine decoction Xinfukang can temporarily reduce the serum creatine kinase MB isoenzyme level in patients. Nevertheless, the effect is not sustained. Therefore, it is of great importance to conduct long-term longitudinal studies so as to elucidate the potential mechanism responsible for long-term elevation of serum creatine kinase level.

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38. Rosen NE, Schiltz HK, Lord C. Sibling Influences on Trajectories of Maladaptive Behaviors in Autism. J Clin Med;2022 (Sep 12);11(18)

Siblings play an important role in the behavioral trajectories of individuals with autism spectrum disorder (ASD). While having siblings has been associated with positive outcomes in ASD, including stronger adaptive functioning, social and non-verbal communication, and theory of mind, little is known about the impact of siblings on more negative outcomes, such as maladaptive behaviors. To address this gap, the present longitudinal study tested sibling predictors of trajectories of maladaptive behaviors (e.g., teacher- and parent-reported hyperactivity, irritability, and social withdrawal) from childhood through early adulthood among individuals with ASD and non-spectrum delays. Multilevel models revealed that, while the mere presence of a sibling did not impact maladaptive behavior trajectories apart from teacher-reported hyperactivity, the diagnostic profile of the sibling (e.g., emotional/behavioral disorder, ASD, medical condition) emerged as an important predictor. Specifically, although findings varied across teacher and parent reports, more hyperactivity and irritability across time was identified when the sibling had diagnoses of an emotional/behavioral disorder, ASD, and/or a medical condition. Overall, this study provides novel insight into the broader family-level factors that influence the presentation of maladaptive behaviors across time and across contexts.

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39. Shuleski K, Zalles L, Lozano R. Exploring Parents’ Concerns Regarding Long-Term Support and Living Arrangements for Their Children with Fragile X Syndrome. Genes (Basel);2022 (Sep 15);13(9)

Given limited data regarding future planning specific to Fragile X Syndrome (FXS) individuals and the growing population of individuals within this community, this study sought to explore the concerns and challenges caregivers of individuals affected by FXS encounter when considering long-term support plans. This involved identifying the reasons individuals with FXS continue to reside with family and the reservations caregivers have regarding future supports and living arrangements. We administered an anonymous online survey consisting of 34 questions assessing eligibility, living arrangements/supports, and future concerns. We found that most individuals with FXS were affected with moderate Intellectual and Developmental Disabilities (IDD) and co-occurring behavioral conditions but had overall good health. The majority of individuals with FXS currently resided with family due to parental desire, their own desire, and the inability to live independently. For one-third of caregivers, the plan for future living arrangements is to continue residing with family members long-term. A large proportion of caregivers had not considered alternative arrangements or were unsure. More than 70% of caregivers of individuals with FXS are concerned about multiple aspects of the individual’s future. Caregivers of younger individuals are the most concerned, but also believe they have time before they need to plan or are unable to currently assess the future need for support.

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40. Silver H, Rosselot H, Shaffer R, Lozano R. The Impact of the COVID-19 Pandemic on School-Aged Children with Fragile X Syndrome. Genes (Basel);2022 (Sep 17);13(9)

The pandemic caused by the spread of the coronavirus disease (COVID-19), beginning in early 2020, had an impact beyond anything experienced in recent history. People with Fragile X Syndrome (FXS), the leading known heritable cause of ASD and intellectual disability, were uniquely vulnerable to pandemic-related changes. This study surveyed parent perspectives of the impact on 33 school-aged children with FXS across daily living skills, education, therapies, behaviors, health visits, and mask wearing. Academic performance was perceived to have decreased in most of the children (58%). Students in online school had the most reports of decline and those in person had the most reported improvement. Parents were significantly more satisfied with services that remained in person compared to those delivered online or in hybrid settings. Additionally, depression (75%), sleep problems (80%), attention problems (73%), and social skills (61%) were reported to have worsened the most. Parents reported that in addition to continuing with a structured schedule, the most helpful strategies were increasing face-to-face social interactions and outdoor activities. Future research should explore strategies to help online interventions and education to be more successful with individuals with FXS, given this may become a resource for families not geographically able to access in-person resources.

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41. Smith J, Rabba AS, Cong L, Datta P, Dresens E, Hall G, Heyworth M, Lawson W, Lee P, Lilley R, Syeda N, Ma E, Wang J, Wang R, Yeow C, Pellicano E. They were Saying that I was a ‘typical Chinese mum’: Chinese Parents’ Experiences of Parent-Teacher Partnerships for Their Autistic Children. J Autism Dev Disord;2022 (Sep 23)

Effective parent-teacher partnerships improve outcomes for autistic students. Yet, we know little about what effective partnerships look like for parents of autistic children from different backgrounds. We conducted interviews with 17 Chinese parents of autistic children attending Australian kindergartens/schools to understand their experiences. Parents appreciated the acceptance, opportunities and supports they received in Australia. They had high expectations of children; expectations not often shared by educators. Parents were respectful of teachers’ expertise and polite and undemanding in interactions. Nevertheless, parents were frustrated by inconsistent teaching quality and inadequate communication. Navigating systems was also challenging and parents faced discrimination from teachers and their community. Recommendations include fostering open home-school communication, proactively seeking parents’ expertise about children and explicitly scaffolding parents’ self-advocacy.

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42. Timperio AM, Gevi F, Cucinotta F, Ricciardello A, Turriziani L, Scattoni ML, Persico AM. Urinary Untargeted Metabolic Profile Differentiates Children with Autism from Their Unaffected Siblings. Metabolites;2022 (Aug 26);12(9)

Autism Spectrum Disorder (ASD) encompasses a clinical spectrum of neurodevelopmental conditions that display significant heterogeneity in etiology, symptomatology, and severity. We previously compared 30 young children with idiopathic ASD and 30 unrelated typically-developing controls, detecting an imbalance in several compounds belonging mainly to the metabolism of purines, tryptophan and other amino acids, as well as compounds derived from the intestinal flora, and reduced levels of vitamins B6, B12 and folic acid. The present study describes significant urinary metabolomic differences within 14 pairs, including one child with idiopathic ASD and his/her typically-developing sibling, tightly matched by sex and age to minimize confounding factors, allowing a more reliable identification of the metabolic fingerprint related to ASD. By using a highly sensitive, accurate and unbiased approach, suitable for ensuring broad metabolite detection coverage on human urine, and by applying multivariate statistical analysis, we largely replicate our previous results, demonstrating a significant perturbation of the purine and tryptophan pathways, and further highlight abnormalities in the « phenylalanine, tyrosine and tryptophan » pathway, essentially involving increased phenylalanine and decreased tyrosine levels, as well as enhanced concentrations of bacterial degradation products, including phenylpyruvic acid, phenylacetic acid and 4-ethylphenyl-sulfate. The outcome of these within-family contrasts consolidates and extends our previous results obtained from unrelated individuals, adding further evidence that these metabolic imbalances may be linked to ASD rather than to environmental differences between cases and controls. It further underscores the excess of some gut microbiota-derived compounds in ASD, which could have diagnostic value in a network model differentiating the metabolome of autistic and unaffected siblings. Finally, it points toward the existence of a « metabolic autism spectrum » distributed as an endophenotype, with unaffected siblings possibly displaying a metabolic profile intermediate between their autistic siblings and unrelated typically-developing controls.

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43. Valagussa G, Purpura G, Nale A, Pirovano R, Mazzucchelli M, Grossi E, Perin C. Sensory Profile of Children and Adolescents with Autism Spectrum Disorder and Tip-Toe Behavior: Results of an Observational Pilot Study. Children (Basel);2022 (Sep 1);9(9)

Atypical sensory processing is frequently reported in persons with autism spectrum disorders (ASD), and it is one of the described diagnostic criteria for ASD. There is also mounting literature supporting the presence of motor impairments in individuals with ASD. Among these motor signs, tip-toe behavior (TTB) is a possible clinical finding, but its etiology is not clearly understood. It is suggested that TTB in ASD could be a sign of a sensory modulation impairment, but evidence is lacking and controversial. The main aim of this pilot study is to explore sensory features in a sample (4 females; 28 males) of children and adolescents with ASD (age range: 7-18). All participants also presented Intellectual Disability. Participants were divided in two groups, matched for age and gender, on the basis of the presence or absence of TTB (16 ASD TTB group vs. 16 ASD NO-TTB group) and then evaluated by using the Short Sensory Profile. We found that both ASD groups tend to significantly present sensory-related behavioral symptoms, but ASD TTB individuals more frequently showed the specific pattern of « under responsive/seeks sensation » than ASD NO-TTB individuals. These preliminary findings support that sensory-motor features might be taken into consideration when rehabilitation for TTB in children and adolescents with ASD is necessary.

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44. Wang X, Li J, Liu D. Effects of epidural analgesia exposure during parturition on autism spectrum disorder in newborns: A systematic review and meta-analysis based on cohort study. Front Psychiatry;2022;13:974596.

BACKGROUND: Labor epidural analgesia (LEA) is one of the most effective and widely used approaches for pain relief during parturition. we conducted this meta-analysis to evaluate the association between LEA exposure during parturition and ASD in newborns. METHODS: PubMed, Cochrane Library, EMBASE and Web of Science database were searched from inception to January 2, 2022 to identify related articles. Literature screening was carried out strictly according to the inclusion and exclusion criteria, and data were extracted and imported into STATA 15.0 software for meta-analysis. RESULTS: A total of 5 studies with 1763454 participants were included. A statistically significant correlation was observed between LEA and changed ASD (RR = 1.20, 95%CI (1.17, 1.24)), and the correlation between LEA and ASD were analyzed by univariate HR (ES = 1.34, 95%CI(1.27,1.40), P < 0.05) and Multivariate HR (ES = 1.13, 95%CI (1.05,1.21), P < 0.05). LIMITATION: First, few studies were included, and most patients were from the United States. Second, the included studies were observational cohort designs, which cannot avoid selection and measurement bias. Third, the results of the included studies were heterogeneous, and a more detailed subgroup analysis was not possible. CONCLUSION: There is a correlation between LEA during parturition and the risk of ASD in newborns. The Newborn whose mother received LEA during her birth-giving might be more likely to develop ASD.

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45. Wongpaiboonwattana W, Hnoonual A, Limprasert P. Association between 19-bp Insertion/Deletion Polymorphism of Dopamine β-Hydroxylase and Autism Spectrum Disorder in Thai Patients. Medicina (Kaunas);2022 (Sep 6);58(9)

Background and Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder the cause of which is not fully known. Genetic factors are believed to play a major role in the etiology of ASD. However, genetic factors have been identified in only some cases, and other causes remain to be identified. This study aimed to identify potential associations between ASD and the 19-bp insertion/deletion polymorphism in the dopamine beta-hydroxylase (DBH) gene which plays a crucial role in the metabolism of neurotransmitters. Materials and Methods: The 19-bp insertion/deletion polymorphism upstream of the DBH gene was analyzed for associations in 177 ASD patients and 250 healthy controls. Family-based analysis was performed in family trios of each patient using the transmission disequilibrium test to investigate the potential contributions of this DBH polymorphism to ASD. Results: The frequency of the 19-bp insertion allele was significantly higher in the patient group compared to the controls (0.624 vs. 0.556, respectively; p = 0.046). The frequency of the insertion/insertion genotype was also higher in the patient group (0.378 vs. 0.288, respectively) but without statistical significance (p = 0.110). The family-based analysis showed an association between patient families and the insertion allele when only families of male participants were analyzed (73 vs. 48 events; OR 1.521; 95% CI 1.057-2.189; p = 0.023). Conclusions: This population-based analysis found an association between the 19-bp insertion allele of the DBH gene and ASD. No association at the genotype level was found. The family-based analysis found an association between the insertion allele and ASD when the analysis was performed on male participants only, suggesting a linkage between the DBH locus and ASD.

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