1. Abbeduto L, Sahin M. Developing and evaluating treatments for the challenges of autism and related neurodevelopmental disabilities. Journal of neurodevelopmental disorders. 2021; 13(1): 56.

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2. Bradshaw J, McCracken C, Pileggi M, Brane N, Delehanty A, Day T, Federico A, Klaiman C, Saulnier C, Klin A, Wetherby A. Early social communication development in infants with autism spectrum disorder. Child development. 2021; 92(6): 2224-34.

Social-communication differences are a robust and defining feature of autism spectrum disorder (ASD) but identifying early points of divergence in infancy has been a challenge. The current study examines social communication in 9- to 12-month-old infants who develop ASD (N = 30; 23% female; 70% white) compared to typically developing (TD) infants (N = 94, 38% female; 88% white). Results demonstrate that infants later diagnosed with ASD were already exhibiting fewer social-communication skills using eye gaze, facial expression, gestures, and sounds at 9 months (effect size: 0.42-0.89). Moreover, three unique patterns of change across distinct social-communication skills were observed within the ASD group. This study documents that observable social-communication differences for infants with ASD are unfolding by 9 months, pointing to a critical window for targeted intervention.

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3. Carter M, Casey S, O’Keeffe GW, Gibson L, Murray DM. Mid-gestation cytokine profiles in mothers of children affected by autism spectrum disorder: a case-control study. Scientific reports. 2021; 11(1): 22315.

Autism Spectrum disorder is one of the commonest and most important neurodevelopmental conditions affecting children today. With an increasing prevalence and an unclear aetiology, it is imperative we find early markers of autism, which may facilitate early identification and intervention. Alterations of gestational cytokine profiles have been reported in mothers of autistic children. Increasing evidence suggests that the intrauterine environment is an important determinant of autism risk. This study aims to examine the mid-gestational serum cytokine profiles of the mothers of autistic children from a well-characterised birth cohort. A nested sub-cohort within a large mother-child birth cohort were identified based on a confirmed multi-disciplinary diagnosis of autism before the age 10 years and neuro-typical matched controls in a 2:1 ratio. IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-17A, GMCSF and TNFα were measured in archived maternal 20-week serum using MesoScale Diagnostics multiplex technology and validation of our IL-17A measurements was performed using an ultrasensitive assay. From a cohort of 2137 children, 25 had confirmed autism before 10 years and stored maternal serum from mid-gestation. We examined the sera of these 25 cases and 50 matched controls. The sex ratio was 4:1 males to females in each group, and the mean age at diagnosis was 5.09 years (SD 2.13). We found that concentrations of IL-4 were significantly altered between groups. The other analytes did not differ significantly using either multiplex or ultra-sensitive assays. In our well-characterised prospective cohort of autistic children, we confirmed mid-gestational alterations in maternal IL-4 concentrations in autism affected pregnancies versus matched controls. These findings add to promising evidence from animal models and retrospective screening programmes and adds to the knowledge in this field.

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4. Cashin A, Pracilio A, Buckley T, Morphet J, Kersten M, Trollor JN, Griffin K, Bryce J, Wilson NJ. A cross-practice context exploration of nursing preparedness and comfort to care for people with intellectual disability and autism. Journal of clinical nursing. 2021.

AIMS AND OBJECTIVES: To compare the self-perceived preparedness, knowledge, comfort and confidence of Australian Registered Nurses when caring for people with ID and/or ASD across contexts of practice: primary care and community, intensive care, acute hospital, emergency department, paediatrics and ID/ASD. BACKGROUND: There is limited research comparing nursing preparedness and competency when caring for people with intellectual disability (ID) and/or autism (ASD) across nursing contexts of practice. A greater understanding of the differed educational preparedness, confidence and comfort across contexts of practice can aid the development of tailored educational programmes to improve nursing capacity to care for this cohort. DESIGN: Cross-sectional descriptive study. METHODS: A descriptive survey tool of registered nurses (n = 69.3). Comparative inferential analysis was undertaken between the independent categorical variable of six nursing contexts of practice across several dependent variables including age, years since registration, educational content and exposure, knowledge, comfort and confidence. This cross-sectional study was undertaken according to the STROBE Statement checklist of items. RESULTS: Occupying an ID/ASD nursing role was significantly associated with higher reported levels of educational preparedness, professional development and postgraduate education relevant to caring for people with ID and/or ASD. Levels of self-reported knowledge of care issues, confidence and comfort when undertaking healthcare tasks was significantly associated with the context of practice, with nurses working in ID/ASD settings reporting the highest levels across all variables. CONCLUSION: The findings of the study highlight an association between greater educational exposure to content relevant to working with people with ID/ASD and subsequently working in that field. RELEVANCE TO CLINICAL PRACTICE: This study has highlighted that professional development programmes aiming to improve nursing capacity to care for people with ID and/or ASD, should be informed by and address differing gaps in confidence, comfort and educational preparedness across nursing contexts of practice.

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5. Delling JP, Boeckers TM. Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications. Journal of neurodevelopmental disorders. 2021; 13(1): 55.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. MAIN TEXT: This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. CONCLUSIONS: Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

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6. Durr MR, Petryk S, Mela M, DesRoches A, Wekerle M, Newaz S. Utilization of psychotropic medications in children with FASD: a retrospective review. BMC pediatrics. 2021; 21(1): 512.

BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is a neurodevelopmental condition resulting from pre-natal alcohol exposure. In Canada, an estimated 1.4-4% of newborns are affected by FASD. FASD is often associated with behavioural comorbidities and many individuals require psychotropic medication. However, to date there are no FASD specific guidelines for prescribing medication. Recently, Mela and colleagues described four behavioural symptom clusters commonly seen in FASD with suggested pharmacologic treatment for each cluster within an algorithm. The primary objective was to compare the proposed treatment algorithm retrospectively to actual treatment in a real-world FASD pediatric practice. The secondary objective was to refine the description of symptom clusters which will be targeted with treatment. METHODS: We collected the diagnostic and medication history from all patient visits of a Regina Developmental Pediatrician who specializes in FASD diagnosis and medication treatment. Three hundred fifty-four FASD patients were identified between 2005 to 2020. The medications that would be predicted from the algorithm were compared to the real-world historical data. A positive case was defined as all algorithm-predicted medications matching the historical data; a negative case had one or more medications failing to match. RESULTS: Of the 354 patients, 36 were removed for insufficient information. Of the remaining 318 cases, 172 (54.1%) were positive compared to 146 (45.9%) negatives. In single prescription cases (n=147), the incidence of positives was 67.3%; in multi-prescriptions (n=72) it was 27.8%; and in cases where no prescription was needed (n=99), the positive incidence was 53.5%. CONCLUSIONS: The prescription algorithm is promising but requires further refinement to accommodate the range of presentations in children with FASD. With respect to unclassified symptoms, we propose the following: sleep onset difficulty as hyperarousal; gender dysphoria and obsessive compulsive disorder as cognitive inflexibility; grief as emotional regulation; and autism spectrum disorder as hyperactive/neurocognitive.

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7. Hekimoğlu M, Başak A, Yılmaz A, Yıldırım H, Aydın AL, Karadag K, Özer AF. Adjacent Segment Disease (ASD) in Incidental Segmental Fused Vertebra and Comparison With the Effect of Stabilization Systems on ASD. Cureus. 2021; 13(10): e18647.

Objective Adjacent segment disease is a controversial process after spine stabilization. The two important factors discussed are natural aging and hypermobility in incidental segmental fusion anomalies; patients have two or more fused vertebrae from birth, which are the results of spinal movement restriction due to the fusion of some spinal units. This article’s main purpose is to determine the degree of relationship of hypermobility and the aging process in the deterioration of the disks adjacent to fusion. Methods In this study, the degenerative process developed by hypermobility in the adjacent segment due to incidental segmental fusion was evaluated. The MRI images of 52 adjacent and nonadjacent disks of 45 patients in total were analyzed according to the Pfirrmann grading systems. The average Pfirrmann rating of the disks just above and below the fused segment and the distant first, second, and third non-neighboring levels were evaluated and calculated, respectively. Results The highest rate of incidental fusion is determined on the cervical area with 51.9%, followed by the thoracal area with 32.7%, and the lumbar area with 15.4%. Damage to the adjacent segment disks in cases with incidental fusion can still be seen at any age, with fusion, indicating that the hypermobility effect plays a more prominent role. The evidence of hypermobility without aging is that the segments adjacent to fusion undergo more degeneration than the distant disks. Conclusion Adjacent segment disease is under the influence of many factors. Our findings suggest that its incidence is increasing with the pathological processes initiated by hypermobility. It seems that, at least, it carries equal importance as compared to age. Fusion surgeries damage the adjacent segments under the influence of the passage of time beyond the physiological aging of the patient.

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8. Jao J, Ciernia AV. MGEnrichment: A web application for microglia gene list enrichment analysis. PLoS computational biology. 2021; 17(11): e1009160.

Gene expression analysis is becoming increasingly utilized in neuro-immunology research, and there is a growing need for non-programming scientists to be able to analyze their own genomic data. MGEnrichment is a web application developed both to disseminate to the community our curated database of microglia-relevant gene lists, and to allow non-programming scientists to easily conduct statistical enrichment analysis on their gene expression data. Users can upload their own gene IDs to assess the relevance of their expression data against gene lists from other studies. We include example datasets of differentially expressed genes (DEGs) from human postmortem brain samples from Autism Spectrum Disorder (ASD) and matched controls. We demonstrate how MGEnrichment can be used to expand the interpretations of these DEG lists in terms of regulation of microglial gene expression and provide novel insights into how ASD DEGs may be implicated specifically in microglial development, microbiome responses and relationships to other neuropsychiatric disorders. This tool will be particularly useful for those working in microglia, autism spectrum disorders, and neuro-immune activation research. MGEnrichment is available at https://ciernialab.shinyapps.io/MGEnrichmentApp/ and further online documentation and datasets can be found at https://github.com/ciernialab/MGEnrichmentApp. The app is released under the GNU GPLv3 open source license.

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9. Kurosaki T, Sakano H, Pröschel C, Wheeler J, Hewko A, Maquat LE. NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome. Genome biology. 2021; 22(1): 317.

BACKGROUND: Fragile X syndrome (FXS) is an intellectual disability attributable to loss of fragile X protein (FMRP). We previously demonstrated that FMRP binds mRNAs targeted for nonsense-mediated mRNA decay (NMD) and that FMRP loss results in hyperactivated NMD and inhibition of neuronal differentiation in human stem cells. RESULTS: We show here that NMD is hyperactivated during the development of the cerebral cortex, hippocampus, and cerebellum in the Fmr1-knockout (KO) mouse during embryonic and early postnatal periods. Our findings demonstrate that NMD regulates many neuronal mRNAs that are important for mouse brain development. CONCLUSIONS: We reveal the abnormal regulation of these mRNAs in the Fmr1-KO mouse, a model of FXS, and highlight the importance of early intervention.

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10. Liu C, Zhai H, Su S, Song S, Chen G, Jiang Y. Visuospatial Bias in Children with Autism Spectrum Disorder: Evidence from Line Bisection Tasks. Journal of autism and developmental disorders. 2021.

Previous studies have found reduced leftward bias of facial processing in individuals with Autism Spectrum Disorder (ASD). However, it is not clear whether they manifest a leftward bias in general visual processing. To shed light on this issue, the current study used the manual line bisection task to assess children 5 to 15 years of age with ASD as well as typically developing (TD) children. Results showed that children with ASD, similar to TD children, demonstrate a leftward bias in general visual processing, especially for bisecting long lines (≧ 80 mm). In both groups, participant performance in line bisection was affected by the hand used, the length of the line, the cueing symbol, and the location of the symbol. The ASD group showed a rightward bias when bisecting short lines (30 mm) with their left hands, which slightly differed from the TD group. These results indicate that while ASD individuals and TD individuals share a similar leftward bias in general visual processing, when using their left hands to bisect short lines, ASD individuals may show an atypical bias pattern.

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11. Mihandoust S, Radfar M, Soleymani M. Logotherapy to improve parent-child relationship among mothers of autistic children: a randomized clinical trial. European review for medical and pharmacological sciences. 2021; 25(21): 6642-51.

OBJECTIVE: Autism spectrum disorders are characterized by three characteristics: impairment in the quality of social relationships, severe impairment in communication, and restricted, repetitive behavioral patterns. The aim of this research is to determine the effect of logotherapy on the parent-child relationship among mothers of autistic children. PATIENTS AND METHODS: This research is a clinical trial with pre-test, post-test design, and control group. Forty mothers were selected and randomly assigned into two groups of intervention and control. The intervention group attended 10 sessions (90 min) of logotherapy, twice a week, while the control group received the routine intervention. A mother-child relationship evaluation questionnaire was used to collect data. SPSS statistical software was employed to analyze the data. RESULTS: The results showed that group logotherapy training affects the parent-child relationship in mothers of autistic children. We only examined the relatively short-term effects of logotherapy on parents’ and children’s outcomes because after the children’s school year ended, their mothers did not refer to the center. In order to achieve accurate results, we recommend examining the long-term effects of this approach in future studies. CONCLUSIONS: Logotherapy is an effective approach to improve the parent-child relationship in mothers of autistic children.

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12. Penev Y, Dunlap K, Husic A, Hou C, Washington P, Leblanc E, Kline A, Kent J, Ng-Thow-Hing A, Liu B, Harjadi C, Tsou M, Desai M, Wall DP. A Mobile Game Platform for Improving Social Communication in Children with Autism: A Feasibility Study. Applied clinical informatics. 2021; 12(5): 1030-40.

BACKGROUND: Many children with autism cannot receive timely in-person diagnosis and therapy, especially in situations where access is limited by geography, socioeconomics, or global health concerns such as the current COVD-19 pandemic. Mobile solutions that work outside of traditional clinical environments can safeguard against gaps in access to quality care. OBJECTIVE: The aim of the study is to examine the engagement level and therapeutic feasibility of a mobile game platform for children with autism. METHODS: We designed a mobile application, GuessWhat, which, in its current form, delivers game-based therapy to children aged 3 to 12 in home settings through a smartphone. The phone, held by a caregiver on their forehead, displays one of a range of appropriate and therapeutically relevant prompts (e.g., a surprised face) that the child must recognize and mimic sufficiently to allow the caregiver to guess what is being imitated and proceed to the next prompt. Each game runs for 90 seconds to create a robust social exchange between the child and the caregiver. RESULTS: We examined the therapeutic feasibility of GuessWhat in 72 children (75% male, average age 8 years 2 months) with autism who were asked to play the game for three 90-second sessions per day, 3 days per week, for a total of 4 weeks. The group showed significant improvements in Social Responsiveness Score-2 (SRS-2) total (3.97, p <0.001) and Vineland Adaptive Behavior Scales-II (VABS-II) socialization standard (5.27, p = 0.002) scores. CONCLUSION: The results support that the GuessWhat mobile game is a viable approach for efficacious treatment of autism and further support the possibility that the game can be used in natural settings to increase access to treatment when barriers to care exist.

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13. van Andel DM, van Stel HF, Scheepers FE, Oostrom KJ, Haverman L, Bruining H. The sensory-reactivity PROM set: identification of a parent reported outcome measure set for autism spectrum disorder. Journal of patient-reported outcomes. 2021; 5(1): 123.

BACKGROUND: Most children with autism spectrum disorder (ASD) suffer from aberrant responses to sensory stimuli that significantly impact the quality of life. To develop sensory interventions, individually tailored outcome measures are crucially needed for the domain of sensory reactivity problems. Here, we describe the identification of relevant sensory themes according to caregivers of children with ASD according to the guidelines for developing a (parent proxy) patient-reported outcome measure set. Subsequently, we identify parallels between these themes and a well-validated and supported PROMIS® portal to facilitate implementation. Interviews with clinicians and focus groups and interviews with parents of children with ASD were used in the initial phase for concept elicitation. Codes and themes were generated by qualitative thematic data analysis on the transcripts and cognitive interviews with different parents were used for revisions. The resulting themes were compared to existing generic PROMIS-item banks and other existing questionnaires. RESULTS: A total of 11 parent-reported outcomes were identified that could be either classified as directly or indirectly related to sensory reactivity. Directly related themes comprised of: (1) sensory stimulation tolerance and (2) sensitivity to sensory stimuli. Indirectly related themes were: (3) irritable behavior (4) anxiety problems (5) mood problems (6) sleep problems (7) fatigue (8) physical complaints (9) daily functioning and participation (10) routines, structure and dealing with change and (11) problems in social interaction and communication. Seven out of 11 themes could be measured with generic PROMIS item banks. The four remaining outcomes (sensory stimulation tolerance; irritable behaviour; routines, structure and dealing with change; and sensitivity to sensory stimuli) were found suitable to be inventoried by existing PROMs. CONCLUSION: The majority of parent-reported problems seemed related to indirect consequences of sensory reactivity, which are suitable to be measured with generic item banks. In sum, we identified a sensory-reactivity PROM (parent-proxy) set consisting of PROMIS® item banks and additional domains that together form a comprehensive and readily available outcome set for sensory reactivity problems in children with ASD.

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