1. Adnan M, Motiwala F, Trivedi C, Chaudhari G, Mansuri Z, Jain S. Human Umbilical Cord Blood Infusions in the Management of Autism Spectrum Disorder. The primary care companion for CNS disorders. 2022; 24(3).

Objective: To provide an overview of the role of umbilical cord blood (UCB) in managing autism spectrum disorder (ASD) symptoms in children aged 4-8 years. Data Sources: A systematic literature search was conducted using the terms (autism OR autism spectrum disorder AND umbilical cord blood infusion UCB OR umbilical cord blood). The review was limited to articles published in the English language from 1945 to September 2020. The database search included PubMed, Scopus, and EMBASE. Study Selection: The initial search revealed 165 hits of potential relevance. Data Extraction: The articles were analyzed to obtain clinical information relevant to meeting the review objectives. Data Synthesis: After title, abstract, and full article review, 3 UCB studies were selected for analysis. Results: The systematic review showed mixed results. In the first study, improvements were seen in the socialization and communication domains and adaptive behavior with UCB infusion. The Pervasive Developmental Disorder Behavior Inventory composite T score and Expressive One-Word Picture Vocabulary Test (EOWPVT) score also improved. Symptomatic improvement was seen in half of the patients. The second study showed no improvement in the EOWPVT, Receptive One-Word Picture Vocabulary Test, Clinical Global Impressions scale, or Vineland Adaptive Behavior Scales (VABS), second edition. The third study showed nonsignificant improvement in the VABS, third edition socialization scale scores; however, major improvement in the communication domain was seen for those with nonverbal IQ ≥ 70. No serious adverse events were reported in any of the studies. Conclusion: Few studies have evaluated the role of UCB infusion in addressing symptoms of ASD. Due to the limited number of studies, more research is warranted.

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2. Bolbocean C, Rhidenour KB, McCormack M, Suter B, Holder JL. COVID-19 Induced Environments, Health-Related Quality of Life Outcomes and Problematic Behaviors: Evidence from Children with Syndromic Autism Spectrum Disorders. Journal of autism and developmental disorders. 2022.

Between July 2020 and January 2021, 230 principal caregivers completed a questionnaire to measure proxy-assessed health-related quality of life outcomes (HRQoL), behavioral outcomes in children with syndromic autism spectrum disorders and COVID-19 induced changes to lifestyle and environments. HRQoL and behavioral outcomes reported earlier during the pandemic were generally worse compared to those reported later. COVID-19 induced reduction to a caregiver’s mental health appointments, and hours spent watching TV were associated with decreases in HRQoL and increased the likelihood of problematic behaviors. Increasing time outdoors and time away from digital devices were positively associated with HRQoL and behaviors and might protect children from COVID-19 induced restrictions.

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3. Cahart MS, Amad A, Draper SB, Lowry RG, Marino L, Carey C, Ginestet CE, Smith MS, Williams SCR. The effect of learning to drum on behavior and brain function in autistic adolescents. Proceedings of the National Academy of Sciences of the United States of America. 2022; 119(23): e2106244119.

SignificanceThere is an acknowledged need for improved service provision in the context of autism spectrum disorders. Previous studies have demonstrated the positive role drum training can play in improving behavioral outcomes for children and adolescents with emotional and behavioral difficulties. However, to date, none of these studies has explored how these behavioral changes translate at the neural level. Our study provides strong evidence that drumming not only reduces hyperactivity and inattention in autistic adolescents but also strengthens functional connectivity in brain regions responsible for inhibitory control and action outcome monitoring.

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4. Cogram P, Deacon RMJ, Klamer D, Rebowe N, Sprouse J, Reyes ST, Missling CU, Kaufmann WE. Brain cell signaling abnormalities are detected in blood in a murine model of Fragile X syndrome and corrected by Sigma-1 receptor agonist Blarcamesine. American journal of medical genetics Part A. 2022.

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5. Desjardins L, Young M, Hancock K, Lai MC, Bartels U, Vorstman J, Barrera M. Pediatric Brain Tumor Survivors’ Understanding of Friendships: A Qualitative Analysis of ADOS-2 Interview Responses. Journal of pediatric psychology. 2022; 47(6): 662-73.

BACKGROUND: Pediatric brain tumor survivors (PBTS) are at risk of experiencing social competence challenges, but only a limited number of studies have used a qualitative approach to understand their social relationships. We examined PBTS responses to social interview questions within the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2), which includes questions related to their understanding of their own relationships, as well as the construct of friendship more generally. METHODS: Twenty-four PBTS (ages 9-17 years; M = 14.2 years from diagnosis; 50% male; 42% received radiation treatment) completed the ADOS-2. ADOS-2 social interview responses were recorded and transcribed verbatim. Themes were derived using an inductive thematic analysis approach. RESULTS: PBTS reported that they considered trust, acceptance, respect, emotional support, and spending time together to be important aspects of friendships in general. When describing their own social relationships, some PBTS noted a lack of intimacy or closeness, spending time with their friends almost exclusively at school, with structured activities outside of school being an additional basis for friendship. Challenges to their social relationships included loneliness and reliance on family for social support, experiences of teasing and bullying, social skills deficits, and lack of insight into social situations. CONCLUSION: Although PBTS were able to acknowledge many important qualities of friendships in general (e.g., trust, emotional support), these were not necessarily reported in their own friendships. PBTS also appeared to have difficulty identifying whether someone was their friend. These findings offer potential opportunities for supporting PBTS in achieving friendships consistent with their conception of this important relationship.

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6. Fortunato A, Giovanardi G, Innocenzi E, Mirabella M, Caviglia G, Lingiardi V, Speranza AM. Is It Autism? A Critical Commentary on the Co-Occurrence of Gender Dysphoria and Autism Spectrum Disorder. Journal of homosexuality. 2022; 69(7): 1204-21.

An increasing amount of literature revealed a link between GD and ASD. Both GD and ASD are complex and heterogeneous conditions characterized by a large variety of presentations. Studies have reported that individuals with GD tend to have higher prevalence rates of autistic traits in comparison to the general population. The purpose of this commentary is to provide, through the description of a clinical case, our reading and a possible interpretation of the correlation of these two conditions in light of the several methodological limitations found in literature. We hypothesize that the traits often classified as autistic could be more accurately related to the distress and discomfort evoked by GD. The autistic traits of individuals with GD as forms of psychological defenses and coping mechanisms aimed at dealing with socio-relational and identity problems are discussed.

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7. Gandía-Abellán H, Nieto C, García-Rubio C. Mindfulness for adults with autism spectrum disorder and intellectual disability: A pilot study. Journal of intellectual disabilities : JOID. 2022: 17446295221107283.

The present study aims to examine the effects of the MindfulTEA program, an Mindfulness-based Interventions (MBIs) specifically designed for adults with Autism Spectrum Disorder (ASD) and Intellectual Disability, to reduce behavioural problems. MBIs are effective in improving well-being in people with high-functioning ASD, but little is known about the impact of the MBIs on people with ASD and intellectual disability associated. Fourteen adults (age 18 to 44) with ASD and intellectual disability participated in the program. Results showed a significant decrease in self-injurious and aggressive/destructive behaviours after the MBI. Stereotyped behaviour did not show significant change. Results suggest that the MindfulTEA program could effectively reduce some types of behaviour problems in people with ASD and intellectual disability. MBIs could be a useful alternative to traditional behaviour management interventions for reducing behaviour problems in this population.

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8. Goldman KJ, DeLeon IG. Increasing selection of and engagement in physical activity in children with autism spectrum disorder. Journal of applied behavior analysis. 2022.

Children with autism spectrum disorder (ASD) engage in reduced levels of physical activity relative to neurotypical children. Researchers conducted 2 studies to 1) evaluate the influence of the number of physical activity options and effort on choice and 2) develop a token-based intervention to increase physical activity engagement and evaluate whether the opportunity to access the intervention supported responding similar to physical or sedentary activity alone. Four children with ASD participated. Additional physical activity options alone did not increase physical activity selection, but increased effort reduced selection of sedentary activity. Tokens increased physical activity for 2 participants. A combination of physical and sedentary activities maintained as much as or more responding than either activity in isolation for all participants. Limitations and potential areas of future research on choice and physical activity are discussed.

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9. Haine-Schlagel R, Corsello C, Caplan B, Gould H, Brookman-Frazee L. Setting Families Up for Success: A Pilot Study of a Toolkit to Enhance the Autism Spectrum Disorder Diagnostic Evaluation Process. Journal of autism and developmental disorders. 2022.

Families of children with autism spectrum disorder (ASD) face challenges engaging in services following diagnosis. This study: (1) developed and implemented a toolkit to tailor ASD evaluation feedback to families’ needs, and (2) evaluated caregiver and provider perceptions of the toolkit. Focus groups with providers (N = 11) informed toolkit development. Seven providers participated in pilot training and implementation. Provider and caregiver toolkit perceptions were assessed using interviews, surveys, and a fidelity checklist. Toolkit strategies reflect focus group themes. Provider and caregiver ratings suggest the initial feasibility, acceptability, and utility of the toolkit. This toolkit may be feasible to implement in community settings and may increase caregiver satisfaction, though further refinements are needed to support service connection.

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10. Hart LC, Msall ME. Defining A High-Quality Transition for Youth With Intellectual and Developmental Disabilities. Pediatrics. 2022.

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11. Harvey PC, Willis EPE, Brown DJ, Byrne AL, Baldwin APA, Heard D, Augutis W. Navigating the care of families with a child or children with autistic spectrum disorder. Journal of intellectual disabilities : JOID. 2022: 17446295221106001.

The aim of this project was to better understand nurse navigators work with children and families who are living with severe autism spectrum disorder to achieve improved health and wellbeing outcomes. Nurse navigators were introduced into the public health sector in Queensland in 2016, with 400 navigators currently working across 16 health services in diverse geographic and demographic settings. Narrative inquiry was used to explore one nurse navigator’s journey working with children and families living with severe Autism. The challenges of rigid health systems to adapt to the requirements of children with special needs, particularly in relation to care in the emergency department and where interventional procedures are necessary were apparent. Nurse navigators can effectively co-ordinate the care of an extremely vulnerable patient cohort and provide essential advocacy in a health system that is rigid and lacking the flexibility to deal with individual needs.

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12. Hwang JY, Monday HR, Yan J, Gompers A, Buxbaum AR, Sawicka KJ, Singer RH, Castillo PE, Zukin RS. CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X. Cell reports. 2022; 39(10): 110853.

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca(2+)-permeable to GluA2-containing, Ca(2+)-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance-a common theme in FXS and other autism spectrum disorders.

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13. Kirby AV, Diener ML, Dean EE, Darlington AN, Myers A, Henderson J. Autistic Adolescents’ and Their Parents’ Visions for the Future: How Aligned are They?. Autism in adulthood : challenges and management. 2022; 4(1): 32-41.

INTRODUCTION: The expectations individuals hold about the future can influence the decisions they make toward achieving their goals. Existing research suggests parents of autistic adolescents hold expectations about the future that are significantly related to the postsecondary outcomes they achieve. However, less research exists about the adolescents’ own expectations and the extent to which autistic adolescents and their parents agree about the future. METHODS: We used a scoring procedure to « quantitize » semi-structured interview data about what 46 adolescent-parent dyads envisioned for the future of the autistic adolescent across three areas of adulthood (postsecondary education, employment, and living situation). Adolescents ranged in age from 13-19 years (85.1% male) and were able to participate in a verbal interview. We scored the dyads’ interviews on the extent to which they agreed or disagreed about the postsecondary future of the adolescent, as well as whose expectations were higher (when they differed). RESULTS: Proportions of agreement and disagreement did not significantly differ, demonstrating moderate agreement. Notably, fewer than half (37.0-47.8%) of adolescents and their parents partly or strongly agreed about their visions for the future in each of the three areas. Only 17.4% of dyads partly or strongly agreed across all three areas, and 23.9% did not agree in any area. When adolescents’ and parents’ views differed, adolescents were significantly more likely to have a higher expectation across all three areas (ps < 0.01). CONCLUSIONS: Future research is needed to examine differences in autistic adolescents' and parents' visions of the future, and to explore interventions to support families to work toward shared goals for the future. This study contributes to a growing body of literature emphasizing the importance of including the perspectives of autistic adolescents in research and for them to have an active and substantial role in their own transition planning.

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14. Kushima I, Nakatochi M, Aleksic B, Okada T, Kimura H, Kato H, Morikawa M, Inada T, Ishizuka K, Torii Y, Nakamura Y, Tanaka S, Imaeda M, Takahashi N, Yamamoto M, Iwamoto K, Nawa Y, Ogawa N, Iritani S, Hayashi Y, Lo T, Otgonbayar G, Furuta S, Iwata N, Ikeda M, Saito T, Ninomiya K, Okochi T, Hashimoto R, Yamamori H, Yasuda Y, Fujimoto M, Miura K, Itokawa M, Arai M, Miyashita M, Toriumi K, Ohi K, Shioiri T, Kitaichi K, Someya T, Watanabe Y, Egawa J, Takahashi T, Suzuki M, Sasaki T, Tochigi M, Nishimura F, Yamasue H, Kuwabara H, Wakuda T, Kato TA, Kanba S, Horikawa H, Usami M, Kodaira M, Watanabe K, Yoshikawa T, Toyota T, Yokoyama S, Munesue T, Kimura R, Funabiki Y, Kosaka H, Jung M, Kasai K, Ikegame T, Jinde S, Numata S, Kinoshita M, Kato T, Kakiuchi C, Yamakawa K, Suzuki T, Hashimoto N, Ishikawa S, Yamagata B, Nio S, Murai T, Son S, Kunii Y, Yabe H, Inagaki M, Goto YI, Okumura Y, Ito T, Arioka Y, Mori D, Ozaki N. Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder. Biological psychiatry. 2022.

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

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15. Lane AE, Simpson K, Masi A, Grove R, Moni MA, Montgomery A, Roberts J, Silove N, Whalen O, Whitehouse AJO, Eapen V. Patterns of sensory modulation by age and sex in young people on the autism spectrum. Autism research : official journal of the International Society for Autism Research. 2022.

Sensory modulation symptoms form a diagnostic criterion for autism spectrum disorder and are associated with significant daily functional limitations. Utilizing caregiver report on Short Sensory Profile-2 (SSP-2) for 919 autistic children (3-14.11 years), we examined the expression of sensory modulation symptoms by age and sex and investigated the existence of specific sensory modulation subtypes. Sensory modulation symptoms appeared to peak in frequency during middle childhood, particularly in sensory sensitivity and avoidance. Symptoms associated with sensory hypo-reactivity and seeking tended not differ between age cohorts. Males and females demonstrated similar overall sensory modulation profiles, however, females showed elevated symptoms relating to sensory sensitivity. Model-based cluster analysis revealed five interpretable sensory modulation subtypes which related to symptom severity (low, mid-range, high). Subtypes demonstrating mid-range symptom severity differed in focus on sensory hyper-reactivity or seeking symptoms. The findings of this study report for the first time that age-related differences in sensory modulation symptoms may be associated with sensory hyper-reactivity only. The subtyping results also suggest that sensory modulation symptom severity is a reliable means of classifying variance within autistic children, however, consideration of differences in the behavioral strategies employed by individuals to manage sensory modulation symptoms may inform tailored supportive strategies.

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16. Li Q, Zhang L, Shan H, Yu J, Dai Y, He H, Li WG, Langley C, Sahakian BJ, Yao Y, Luo Q, Li F. The immuno-behavioural covariation associated with the treatment response to bumetanide in young children with autism spectrum disorder. Translational psychiatry. 2022; 12(1): 228.

Bumetanide, a drug being studied in autism spectrum disorder (ASD) may act to restore gamma-aminobutyric acid (GABA) function, which may be modulated by the immune system. However, the interaction between bumetanide and the immune system remains unclear. Seventy-nine children with ASD were analysed from a longitudinal sample for a 3-month treatment of bumetanide. The covariation between symptom improvements and cytokine changes was calculated and validated by sparse canonical correlation analysis. Response patterns to bumetanide were revealed by clustering analysis. Five classifiers were used to test whether including the baseline information of cytokines could improve the prediction of the response patterns using an independent test sample. An immuno-behavioural covariation was identified between symptom improvements in the Childhood Autism Rating Scale (CARS) and the cytokine changes among interferon (IFN)-γ, monokine induced by gamma interferon and IFN-α2. Using this covariation, three groups with distinct response patterns to bumetanide were detected, including the best (21.5%, n = 17; Hedge’s g of improvement in CARS = 2.16), the least (22.8%, n = 18; g = 1.02) and the medium (55.7%, n = 44; g = 1.42) responding groups. Including the cytokine levels significantly improved the prediction of the best responding group before treatment (the best area under the curve, AUC = 0.832) compared with the model without the cytokine levels (95% confidence interval of the improvement in AUC was [0.287, 0.319]). Cytokine measurements can help in identifying possible responders to bumetanide in ASD children, suggesting that immune responses may interact with the mechanism of action of bumetanide to enhance the GABA function in ASD.

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17. Martínez-Álvarez R, Torres-Diaz C. Surgery of autism: Is it possible?. Progress in brain research. 2022; 272(1): 73-84.

Autism spectrum disorder (ASD) is a developmental disability of the brain that can be associated to severe conductual alterations, such as self or heteroaggression and obsessive and compulsive behavior. Many of these patients do not improve with any pharmacological or behavioral therapy and represent a major social problem. We describe the outcome of patients with ASD, treated with radiofrequency brain lesions combined with Gamma Knife radiosurgery for therapy-resistant aggressiveness, obsessive thoughts, and compulsions. The ASD adapted YBOCS, PCQ and EAE scales assessed the therapeutic effect on symptoms. All patients had a significant reduction of their symptoms (YBOCS:34 and 22 PCQ 42 and 35, EAE 11 and 5.5, respectively), although all needed more than one treatment to maintain this improvement. The treatments resulted very safe for the patients and their neurological status has not change. We conclude that in these patients after surgery, there is a marked improvement in behavior, quality of life and relationship with the environment, with no evidence of secondary damage. Changes in connectivity might mediate the clinical improvement, although it is necessary to confirm these results with further studies.

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18. Neale M, Landers E, Sajjadi NB, Mazur-Mosiewicz A, Hartwell M. The impact of COVID-19 on autism research: A cross-sectional analysis of discontinued or suspended clinical trials. Autism research : official journal of the International Society for Autism Research. 2022.

Due to uncertainties associated with the COVID-19 public health crisis, several clinical trials had to be withdrawn or postponed. Our investigation aimed to assess the rate of discontinuation of clinical trials focusing on Autism Spectrum Disorder. Of the 197 registered trials included in our systematic review, 15 (7.6%) were discontinued, with nearly half of these explicitly citing COVID-19 as their reason for discontinuation. Pharmacological trials were six times more likely to be discontinued during the pandemic than non-pharmacological studies. The difference between the likelihood of discontinuation was statistically significant (OR: 6.13; 95% CI: 1.22-30.71). There was no evidence of association between funding source and reasons for discontinuation. Limitations, along with implications for future trials are discussed. LAY SUMMARY: We investigated the impact of the COVID-19 pandemic on the discontinuation rate of autism clinical trials. We found that drug trials were six times more likely to be discontinued during the pandemic compared to behavioral, diagnostic, and nutritional trials. The overall discontinuation rate was notably lower in autism clinical trials than in other areas of medical research. We recommend an examination of the methodology of the continued autism trials to assess their applicability in other fields.

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19. Ozbaran NB, Ozyasar SC, Dogan N, Kafali HY, Isik E, Satar A, Kose S, Atik T, Cogulu O. Evaluation of social cognition, autistic traits, and dysmorphology in comorbid specific learning disorder and attention-deficit/hyperactivity disorder. Clinical child psychology and psychiatry. 2022: 13591045221095428.

Research on areas such as social cognition, autistic traits, and minor physical anomalies in comorbid Specific Learning Disorder (SLD) and attention-deficit/hyperactivity disorder (ADHD) is limited. In this study, we compared these areas in children aged between 8 and 14 with comorbid SLD and ADHD and their typically developed peers. Emotion recognition and social cognition were evaluated by Faces Test, Reading the Mind in the Eyes Test, Comprehension Test, and Difficulties in Emotion Regulation Scale. Autism Spectrum Screening Questionnaire and Social Responsiveness Scale were used for screening of autism spectrum disorder in children. Furthermore, autistic traits in parents were measured by Autism-Spectrum Quotient. The MPAs of all the subjects were determined by pediatric geneticists. We detected that children with comorbid SLD and ADHD performed worse than controls in all social cognition tests and maternal AQ score had a strong correlation with the Faces Test, DERS, and SRS scores. Also, the total ASSQ score in the comorbid SLD and ADHD group was significantly higher than controls. Finally, MPAs were significantly more frequent in the comorbid SLD and ADHD group. Impairment in social cognition and evaluation of autistic traits and dysmorphology in children with comorbid SLD and ADHD may provide useful information on neurodevelopmental disorders.

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20. Patel SP, Winston M, Guilfoyle J, Nicol T, Martin GE, Nayar K, Kraus N, Losh M. Neural Processing of Speech Sounds in ASD and First-Degree Relatives. Journal of autism and developmental disorders. 2022.

Efficient neural encoding of sound plays a critical role in speech and language, and when impaired, may have reverberating effects on communication skills. This study investigated disruptions to neural processing of temporal and spectral properties of speech in individuals with ASD and their parents and found evidence of inefficient temporal encoding of speech sounds in both groups. The ASD group further demonstrated less robust neural representation of spectral properties of speech sounds. Associations between neural processing of speech sounds and language-related abilities were evident in both groups. Parent-child associations were also detected in neural pitch processing. Together, results suggest that atypical neural processing of speech sounds is a heritable ingredient contributing to the ASD language phenotype.

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21. Santos JX, Rasga C, Marques AR, Martiniano H, Asif M, Vilela J, Oliveira G, Sousa L, Nunes A, Vicente AM. A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics. Frontiers in neuroscience. 2022; 16: 862315.

Heritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.

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22. Smith M, Arthur B, Cikowski J, Holt C, Gonzalez S, Fisher NM, Vermudez SAD, Lindsley CW, Niswender CM, Gogliotti RG. Clinical and Preclinical Evidence for M(1) Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2022.

Rett syndrome (RTT) is a neurodevelopmental disorder that is characterized by developmental regression, loss of communicative ability, stereotyped hand wringing, cognitive impairment, and central apneas, among many other symptoms. RTT is caused by loss-of-function mutations in a methyl-reader known as methyl-CpG-binding protein 2 (MeCP2), a protein that links epigenetic changes on DNA to larger chromatin structure. Historically, target identification for RTT has relied heavily on Mecp2 knockout mice; however, we recently adopted the alternative approach of performing transcriptional profiling in autopsy samples from RTT patients. Through this mechanism, we identified muscarinic acetylcholine receptors (mAChRs) as potential therapeutic targets. Here, we characterized a cohort of 40 temporal cortex samples from individuals with RTT and quantified significantly decreased levels of the M(1), M(2), M(3), and M(5) mAChRs subtypes relative to neurotypical controls. Of these four subtypes, M(1) expression demonstrated a linear relationship with MeCP2 expression, such that M(1) levels were only diminished in contexts where MeCP2 was also significantly decreased. Further, we show that M(1) potentiation with the positive allosteric modulator (PAM) VU0453595 (VU595) rescued social preference, spatial memory, and associative memory deficits, as well as decreased apneas in Mecp2(+/-) mice. VU595’s efficacy on apneas in Mecp2(+/-) mice was mediated by the facilitation of the transition from inspiration to expiration. Molecular analysis correlated rescue with normalized global gene expression patterns in the brainstem and hippocampus, as well as increased Gsk3β inhibition and NMDA receptor trafficking. Together, these data suggest that M(1) PAMs could represent a new class of RTT therapeutics.

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23. Stancliffe RJ, Pettingell SL, Bershadsky J, Houseworth J, Tichá R. Community participation and staying home if you want: US adults with intellectual and developmental disabilities. Journal of applied research in intellectual disabilities : JARID. 2022.

BACKGROUND: Requiring adults with intellectual and developmental disabilities to go on community outings with co-residents and staff is contrary to community-living policy’s focus on person centredness and choice of activities/companions. METHOD: We analysed 2018-19 National Core Indicators data from 36 US states concerning 7968 adults living in staffed, non-family, multi-client settings. The focus outcome was being able to stay home if you want when others in your home go out. RESULTS: The 42.0% of participants who could stay home were more likely to go out with friends, family or alone, and less likely to go out with staff. Those who could stay home participated in a similar variety of community activities and went out more often to shop or for errands. CONCLUSIONS: Individuals who could stay home likely had more choice about where, when and with whom they went out. Strategies for greater person-centredness are proposed.

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24. Tajik-Parvinchi D, Rosenbaum P, Hidecker MJC, Duku E, Zwaigenbaum L, Roncadin C, Georgiades S, Gentles S, Fang H, Di Rezze B. Construct Validity of the Autism Classification System of Functioning: Social Communication (ACSF:SC) Across Childhood and Adolescence. Journal of autism and developmental disorders. 2022.

This study examined the construct validity of the Autism Classification System of Functioning: Social Communication (ACSF). Participants included 145 parents of children with autism (2-19 years). The degree of convergent and discriminant validity between parent reported ACSF and subscales from Social Responsiveness Scale 2nd edition and Behavior Assessment System for Children, 3rd Edition were examined against a priori hypotheses. We examined construct validity in the entire sample as well as in specific age cohorts. Our findings suggest that ACSF can provide a valid classification system of social communication ability in children with autism 2-19 years of age, and its two subscales may be used to examine different aspects of social communication ability.

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25. Teles ESAL, Glaser T, Griesi-Oliveira K, Corrêa-Velloso J, Wang JYT, da Silva Campos G, Ulrich H, Balan A, Zarrei M, Higginbotham EJ, Scherer SW, Passos-Bueno MR, Sertié AL. Rare CACNA1H and RELN variants interact through mTORC1 pathway in oligogenic autism spectrum disorder. Translational psychiatry. 2022; 12(1): 234.

Oligogenic inheritance of autism spectrum disorder (ASD) has been supported by several studies. However, little is known about how the risk variants interact and converge on causative neurobiological pathways. We identified in an ASD proband deleterious compound heterozygous missense variants in the Reelin (RELN) gene, and a de novo splicing variant in the Cav3.2 calcium channel (CACNA1H) gene. Here, by using iPSC-derived neural progenitor cells (NPCs) and a heterologous expression system, we show that the variant in Cav3.2 leads to increased calcium influx into cells, which overactivates mTORC1 pathway and, consequently, further exacerbates the impairment of Reelin signaling. Also, we show that Cav3.2/mTORC1 overactivation induces proliferation of NPCs and that both mutant Cav3.2 and Reelin cause abnormal migration of these cells. Finally, analysis of the sequencing data from two ASD cohorts-a Brazilian cohort of 861 samples, 291 with ASD; the MSSNG cohort of 11,181 samples, 5,102 with ASD-revealed that the co-occurrence of risk variants in both alleles of Reelin pathway genes and in one allele of calcium channel genes confer significant liability for ASD. Our results support the notion that genes with co-occurring deleterious variants tend to have interconnected pathways underlying oligogenic forms of ASD.

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26. Wang J, Xiong M, Fan Y, Liu C, Wang Q, Yang D, Yuan Y, Huang Y, Wang S, Zhang Y, Niu S, Yue J, Su H, Zhang C, Chen H, Zheng L, Huang K. Mecp2 protects kidney from ischemia-reperfusion injury through transcriptional repressing IL-6/STAT3 signaling. Theranostics. 2022; 12(8): 3896-910.

Rationale: Ischemia-reperfusion (IR) induced acute kidney injury (AKI) causes serious clinical problems associated with high morbidity and mortality. Mecp2 is a methyl-CpG binding protein, its mutation or deletion causes a neurodevelopment disease called Rett syndrome. Notably, some Rett syndrome patients present urological dysfunctions. It remains unclear whether and how Mecp2 affects AKI. Methods: Renal tubular cell specific Mecp2 deletion mice challenged with IR injury were used to investigate the effects of Mecp2 on renal tubular damage, function, cell death, fibrosis and inflammation. Cultured renal epithelial cell lines were transfected with wildtype or different domain-deletion mutants of Mecp2 to study the effects of Mecp2 on Il-6/STAT3 signaling. Results: Our results indicated rapidly upregulated Mecp2 upon acute in vivo and in vitro renal injury. Notably, increased tubular MeCP2 staining was also found in the renal sections of AKI patients. Furthermore, ablation of Mecp2 aggravated renal injury, and promoted renal cell death, inflammation, and fibrosis. Mechanistically, through its transcriptional repression domain, Mecp2 bound to the promoter of proinflammatory cytokine Il-6 to negatively regulate its expression, thus inhibiting STAT3 activation. Conclusions: A novel protective role of Mecp2 against AKI via repressing the Il-6/STAT3 axis was suggested.

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27. Wang T, Zhao T, Liu L, Teng H, Fan T, Li Y, Wang Y, Li J, Xia K, Sun Z. Integrative analysis prioritised oxytocin-related biomarkers associated with the aetiology of autism spectrum disorder. EBioMedicine. 2022; 81: 104091.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. The common variants of specific oxytocin-related genes (OTRGs), particularly OXTR, are associated with the aetiology of ASD. The contribution of rare genetic variations in OTRGs to ASD aetiology remains unclear. METHODS: We catalogued publicly available de novo mutations (DNMs) [from 6,511 patients with ASD and 3,391 controls], rare inherited variants (RIVs) [from 1,786 patients with ASD and 1,786 controls], and both de novo copy number variations (dnCNVs) and inherited CNVs (ihCNVs) [from 15,581 patients with ASD and 6,017 controls] in 963 curated OTRGs to explore their contribution to ASD pathology, respectively. Finally, a combined model was designed to prioritise the contribution of each gene to ASD aetiology by integrating DNMs and CNVs. FINDINGS: The rare genetic variations of OTRGs were significantly associated with ASD aetiology, in the order of dnCNVs > ihCNVs > DNMs. Furthermore, 172 OTRGs and their connected 286 ASD core genes were prioritised to positively contribute to ASD aetiology, including top-ranked MAPK3. Probands carrying rare disruptive variations in these genes were estimated to account for 10∼11% of all ASD probands. INTERPRETATION: Our findings suggest that rare disruptive variations in 172 OTRGs and their connected 286 ASD core genes are associated with ASD aetiology and may be potential biomarkers predicting the effects of oxytocin treatment. FUNDING: Guangdong Key Project, National Natural Science Foundation of China, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province.

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28. Wigham S, Ingham B, Le Couteur A, Wilson C, Ensum I, Parr JR. Consensus statements on optimal adult post-autism diagnosis support and services: Delphi process following a UK survey of autistic adults, relatives and clinicians. Autism : the international journal of research and practice. 2022: 13623613221097502.

Research has identified types of support helpful to autistic people, for example, physical and mental health interventions, psycho-education, peer support, developing positive identities and affiliation with social groups. However, accessing suitable post-autism diagnosis support and services is extremely difficult. We asked autistic adults, relatives and clinicians about their experiences of receiving and delivering post-autism diagnosis support/services. In Stage 1, 343 autistic adults and 45 relatives completed a survey. They answered questions about their experiences of UK autism post-diagnosis support/services for adults within 12 months after receiving a diagnosis. Thirty-five clinicians completed a similar survey. Just over half of adults and relatives said there was a follow-up appointment or discussion about support after diagnosis. Fewer than 40% received any support/services in 12 months after diagnosis. We used information from the surveys to create 11 statements describing characteristics of appropriate adult post-autism diagnosis support/services. In Stage 2, we asked clinicians for their views on the statements – they agreed with all of them. For example, those adults are offered an additional follow-up meeting after diagnosis and have access to mental and physical health services. We shared results with autistic adults, relatives and clinicians at two events. Some autistic adults, relatives and clinicians were positive about post-autism diagnosis support/services. However, they described many areas for improvement. The study findings can be used to define, develop and improve the types of adult post-diagnosis support services.

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29. Wu S, Jiang C, Li J, Zhang G, Shen Y, Wang J. A novel missense variant in the CASK gene causes intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia. BMC medical genomics. 2022; 15(1): 127.

BACKGROUND: Variants in the CASK gene result in a wide range of observed phenotypes in humans, such as FG Syndrome 4 and intellectual disabilities. Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder that affects females and is characterized by severely impaired intellectual development and variable degrees of pontocerebellar hypoplasia. Variants in CASK are the main genetic cause of MICPCH. Variants in CASK can explain most patients with MICPCH, but there are still some patients whose disease aetiology cannot be explained. CASE PRESENTATION: An 11-month-old female diagnosed with MICPCH exhibited general developmental delays, microcephaly, and cerebellar hypoplasia. Whole-exome sequencing (WES) was used to find a novel heterozygous missense variant (NM_003688.3: c.638T>G) of CASK in this patient. Strikingly, this variant reduced the expression of CASK at the protein level but not at the mRNA level. By using protein structure prediction analysis, this study found that the amino acid change caused by the variant resulted in further changes in the stability of the protein structure, and these changes caused the downregulation of protein expression and loss of protein function. CONCLUSION: In this study, we first reported a novel heterozygous pathogenic variant and a causative mechanism of MICPCH. The amino acid change cause by this variant led to changes in the protein structure and a decrease in its stability, which caused a loss of protein function. This study could be helpful to the genetic diagnosis of this disease.

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30. Yates TM, Lain A, Campbell J, FitzPatrick DR, Simpson TI. Creation and evaluation of full-text literature-derived, feature-weighted disease models of genetically determined developmental disorders. Database : the journal of biological databases and curation. 2022; 2022.

There are >2500 different genetically determined developmental disorders (DD), which, as a group, show very high levels of both locus and allelic heterogeneity. This has led to the wide-spread use of evidence-based filtering of genome-wide sequence data as a diagnostic tool in DD. Determining whether the association of a filtered variant at a specific locus is a plausible explanation of the phenotype in the proband is crucial and commonly requires extensive manual literature review by both clinical scientists and clinicians. Access to a database of weighted clinical features extracted from rigorously curated literature would increase the efficiency of this process and facilitate the development of robust phenotypic similarity metrics. However, given the large and rapidly increasing volume of published information, conventional biocuration approaches are becoming impractical. Here, we present a scalable, automated method for the extraction of categorical phenotypic descriptors from the full-text literature. Papers identified through literature review were downloaded and parsed using the Cadmus custom retrieval package. Human Phenotype Ontology terms were extracted using MetaMap, with 76-84% precision and 65-73% recall. Mean terms per paper increased from 9 in title + abstract, to 68 using full text. We demonstrate that these literature-derived disease models plausibly reflect true disease expressivity more accurately than widely used manually curated models, through comparison with prospectively gathered data from the Deciphering Developmental Disorders study. The area under the curve for receiver operating characteristic (ROC) curves increased by 5-10% through the use of literature-derived models. This work shows that scalable automated literature curation increases performance and adds weight to the need for this strategy to be integrated into informatic variant analysis pipelines. Database URL: https://doi.org/10.1093/database/baac038.

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31. Yip CCH, Chan KKS. Longitudinal impact of public stigma and courtesy stigma on parents of children with autism spectrum disorder: The moderating role of trait mindfulness. Research in developmental disabilities. 2022; 127: 104243.

BACKGROUND: Although the public and courtesy stigma of autism spectrum disorder (ASD) are prevalent, there are very few studies examining their adverse psychological effects on parents of children with ASD or exploring plausible factors that can alleviate these adverse effects. The present study addressed these literature gaps by investigating the longitudinal linkages of public and courtesy stigma to detrimental cognitive (i.e., self-stigma content and process) and affective (i.e., perceived stress and symptoms of depression and anxiety) consequences for parents of children with ASD and testing if these linkages would be moderated by trait mindfulness. METHODS: At two time points separated by 12 months, 372 Hong Kong parents of children with ASD provided questionnaire data on public and courtesy stigma, mindfulness, self-stigma content and process, perceived stress, and symptoms of depression and anxiety. RESULTS: Hierarchical regressions showed that public and courtesy stigma interacted significantly with mindfulness at baseline in predicting self-stigma content and process, perceived stress, and symptoms of depression and anxiety at follow-up. Moreover, simple slope analyses showed that the linkages of public and courtesy stigma to the five detrimental psychological consequences were weaker in parents with high mindfulness than in those with low mindfulness. CONCLUSIONS: Our findings highlight the longitudinal linkages of public and courtesy stigma to detrimental cognitive and affective consequences for parents of children with ASD, and reveal the plausible protective effects of mindfulness against such linkages. These findings suggest the potential utility of increasing mindfulness in parents of children with ASD in coping with community stigma and improving mental health.

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32. Yue X, Zhang G, Li X, Shen Y, Wei W, Bai Y, Luo Y, Wei H, Li Z, Zhang X, Wang M. Brain Functional Alterations in Prepubertal Boys With Autism Spectrum Disorders. Frontiers in human neuroscience. 2022; 16: 891965.

OBJECTIVES: Abnormal brain function in ASD patients changes dynamically across developmental stages. However, no one has studied the brain function of prepubertal children with ASD. Prepuberty is an important stage for children’s socialization. This study aimed to investigate alterations in local spontaneous brain activity in prepubertal boys with ASD. MATERIALS AND METHODS: Measures of the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) acquired from resting-state functional magnetic resonance imaging (RS-fMRI) database, including 34 boys with ASD and 49 typically developing (TD) boys aged 7 to 10 years, were used to detect regional brain activity. Pearson correlation analyses were conducted on the relationship between abnormal ALFF and ReHo values and Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) scores. RESULTS: In the ASD group, we found decreased ALFF in the left inferior parietal lobule (IPL) and decreased ReHo in the left lingual gyrus (LG), left superior temporal gyrus (STG), left middle occipital gyrus (MOG), and right cuneus (p < 0.05, FDR correction). There were negative correlations between ReHo values in the left LG and left STG and the ADOS social affect score and a negative correlation between ReHo values in the left STG and the calibrated severity total ADOS score. CONCLUSION: Brain regions with functional abnormalities, including the left IPL, left LG, left STG, left MOG, and right cuneus may be crucial in the neuropathology of prepubertal boys with ASD. Furthermore, ReHo abnormalities in the left LG and left STG were correlated with sociality. These results will supplement the study of neural mechanisms in ASD at different developmental stages, and be helpful in exploring the neural mechanisms of prepubertal boys with ASD.

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33. Zhu Y, Mu W, Chirica MG, Berenbaum H. Testing a theory-driven factor structure of the autism-spectrum quotient. Autism research : official journal of the International Society for Autism Research. 2022.

The Autism-Spectrum Quotient (AQ) is a popular instrument used to assess the degree to which individuals exhibit features of autism spectrum conditions (ASC). The current study aimed to develop a theory-driven factor structure of the AQ that would fit as well across samples as the 12 previously proposed factor structures, all of which, except for the original Baron-Cohen model, had been developed on the basis of exploratory factor analysis (EFA) or principal component analysis. We first proposed a six-factor solution: (1) social anhedonia; (2) interest in details/patterns; (3) imagination ability; (4) desire for predictability/routine; (5) social cognition; and (6) social discourse convention. We tested the six-factor structure and made final item selections (27 items) with EFA using data from college students (n = 503). Then, we empirically tested alternative factor structure models in three other independent samples (ns = 503; 1263; 1641) using confirmatory factor analysis. Results indicated that our model fit as well, if not better, than all of the other models across samples, regardless of parameter estimation methods and software packages. Overall, the theory-driven replicable six-factor structure that we report holds the potential to be used to measure the six domains of features that we identified in the AQ. LAY SUMMARY: Questionnaire measures of autism spectrum conditions have typically been used to measure approximately four broad dimensions. Our study suggests that the Autism-Spectrum Quotient can be used to measure six more narrowly defined dimensions: social anhedonia, interest in details/patterns, imagination ability, desire for predictability/routine, social cognition, and social discourse convention. Additional work is needed to develop measures of a much wider variety of autism spectrum features.

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