1. Bhat SA, Yousuf A, Mushtaq Z, Kumar V, Qurashi A. Fragile X premutation rCGG repeats impair synaptic growth and synaptic transmission at Drosophila larval neuromuscular junction. Human molecular genetics. 2021; 30(18): 1677-92.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disease that develops in some premutation (PM) carriers of the FMR1 gene with alleles bearing 55-200 CGG repeats. The discovery of a broad spectrum of clinical and cell-developmental abnormalities among PM carriers with or without FXTAS and in model systems suggests that neurodegeneration seen in FXTAS could be the inevitable end-result of pathophysiological processes set during early development. Hence, it is imperative to trace early PM-induced pathological abnormalities. Previous studies have shown that transgenic Drosophila carrying PM-length CGG repeats are sufficient to cause neurodegeneration. Here, we used the same transgenic model to understand the effect of CGG repeats on the structure and function of the developing nervous system. We show that presynaptic expression of CGG repeats restricts synaptic growth, reduces the number of synaptic boutons, leads to aberrant presynaptic varicosities, and impairs synaptic transmission at the larval neuromuscular junctions. The postsynaptic analysis shows that both glutamate receptors and subsynaptic reticulum proteins were normal. However, a high percentage of boutons show a reduced density of Bruchpilot protein, a key component of presynaptic active zones required for vesicle release. The electrophysiological analysis shows a significant reduction in quantal content, a measure of total synaptic vesicles released per excitation potential. Together, these findings suggest that synapse perturbation caused by riboCGG (rCGG) repeats mediates presynaptically during larval neuromuscular junction development. We also suggest that the stress-activated c-Jun N-terminal kinase protein Basket and CIDE-N protein Drep-2 positively mediate Bruchpilot active zone defects caused by rCGG repeats.

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2. Fan L, Shire S, Couture M, Zwaigenbaum L, Thompson-Hodgetts S. The influence of disclosure of an autism diagnosis on peer engagement and interactions for a child with autism in summer camps: a case study. Disability and rehabilitation. 2021: 1-12.

PURPOSE: Little research has evaluated how disclosure of an autism diagnosis influences peer engagement and understanding of children with autism in community recreation programs. This study describes outcomes of disclosing an autism diagnosis for a child with autism participating in mainstream, community summer camps. METHODS: This case study includes a 9-year-old boy diagnosed with autism who participated in two camps, one in which he disclosed and one in which he did not disclose. Quantitative data on peer engagement states and reciprocal interactions were coded through structured behavioral observation of video recorded on the first, second, and last day of each program. Qualitative interviews about perceived outcomes of disclosure were completed with the child with autism, camp leaders, and peers in the disclosure camp. RESULTS: Peer engagement and reciprocal interactions improved following the disclosure protocol and continued to improve on the final day of the camp, which was not observed in the non-disclosure camp. A key qualitative theme revealed that changed behavioral attribution was the main contributor to improved inclusion following disclosure. CONCLUSIONS: This study provides preliminary data to support that disclosure may be a simple intervention to improve peer engagement and understanding of children with autism in community programs.IMPLICATIONS FOR REHABILITATIONChildren with Autism Spectrum Disorder are at high risk of experiencing social exclusion, especially in community programs.A disclosure protocol (disclosure + explanation for behaviors) could be a simple intervention to facilitate peer acceptance and inclusion of children with autism, however this intervention has not been evaluated in a real life context.This study provides preliminary evidence to support the use of a simple disclosure protocol for families who want to disclose, within short-term community programs.

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3. Halbur M, Kodak T, McKee M, Carroll R, Preas E, Reidy J, Cordeiro MC. Tolerance of face coverings for children with autism spectrum disorder. Journal of applied behavior analysis. 2021; 54(2): 600-17.

Healthcare professionals and government officials have advised the use of personal protective equipment, such as face masks and face shields, to assist with limiting the spread of the SARS-CoV-2 (COVID-19). Due to the prevalence of challenging behavior associated with other medical routines, the present study evaluated a treatment package composed of graduated exposure, prompts, reinforcement, and escape extinction on tolerance of wearing a face covering for up to 5 min for 12 children with ASD in a systematic replication of Cox et al. (2017) and Sivaraman et al. (2020). We also extended previous research by measuring generalization of face covering type (i.e., face shield) and the efficacy of a treatment extension for tolerating a face covering for up to 15 min during the participants’ trial-based instruction and play periods.

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4. Movaghar A, Page D, Scholze D, Hong J, DaWalt LS, Kuusisto F, Stewart R, Brilliant M, Mailick M. Artificial intelligence-assisted phenotype discovery of fragile X syndrome in a population-based sample. Genetics in medicine : official journal of the American College of Medical Genetics. 2021; 23(7): 1273-80.

PURPOSE: Fragile X syndrome (FXS), the most prevalent inherited cause of intellectual disability, remains underdiagnosed in the general population. Clinical studies have shown that individuals with FXS have a complex health profile leading to unique clinical needs. However, the full impact of this X-linked disorder on the health of affected individuals is unclear and the prevalence of co-occurring conditions is unknown. METHODS: We mined the longitudinal electronic health records from more than one million individuals to investigate the health characteristics of patients who have been clinically diagnosed with FXS. Additionally, using machine-learning approaches, we created predictive models to identify individuals with FXS in the general population. RESULTS: Our discovery-oriented approach identified the associations of FXS with a wide range of medical conditions including circulatory, endocrine, digestive, and genitourinary, in addition to mental and neurological disorders. We successfully created predictive models to identify cases five years prior to clinical diagnosis of FXS without relying on any genetic or familial data. CONCLUSION: Although FXS is often thought of primarily as a neurological disorder, it is in fact a multisystem syndrome involving many co-occurring conditions, some primary and some secondary, and they are associated with a considerable burden on patients and their families.

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5. Ohi K, Ochi R, Noda Y, Wada M, Sugiyama S, Nishi A, Shioiri T, Mimura M, Nakajima S. Polygenic risk scores for major psychiatric and neurodevelopmental disorders contribute to sleep disturbance in childhood: Adolescent Brain Cognitive Development (ABCD) Study. Translational psychiatry. 2021; 11(1): 187.

Sleep disturbance is a common symptom of psychiatric and neurodevelopmental disorders and, especially in childhood, can be a precursor to various mental disorders. However, the genetic etiology of mental illness that contributes to sleep disturbance during childhood is poorly understood. We investigated whether the polygenic features of psychiatric and neurodevelopmental disorders are associated with sleep disturbance during childhood. We conducted polygenic risk score (PRS) analyses by utilizing large-scale genome-wide association studies (GWASs) (n = 46,350-500,199) of five major psychiatric and neurodevelopmental disorders (autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and bipolar disorder) and, additionally, anxiety disorders as base datasets. We used the data of 9- to 10-year-olds from the Adolescent Brain Cognitive Development study (n = 9683) as a target dataset. Sleep disturbance was assessed based on the Sleep Disturbance Scale for Children (SDSC) scores. The effects of PRSs for these psychiatric and neurodevelopmental disorders on the total scores and six subscale scores of the SDSC were investigated. Of the PRSs for the five psychiatric and neurodevelopmental disorders, the PRSs for ADHD and MDD positively correlated with sleep disturbance in children (ADHD: R(2) = 0.0033, p = 6.19 × 10(-5), MDD: R(2) = 0.0042, p = 5.69 × 10(-6)). Regarding the six subscale scores of the SDSC, the PRSs for ADHD positively correlated with both disorders of initiating and maintaining sleep (R(2) = 0.0028, p = 2.31 × 10(-4)) and excessive somnolence (R(2) = 0.0023, p = 8.44 × 10(-4)). Furthermore, the PRSs for MDD primarily positively correlated with disorders of initiating and maintaining sleep (R(2) = 0.0048, p = 1.26 × 10(-6)), followed by excessive somnolence (R(2) = 0.0023, p = 7.74 × 10(-4)) and sleep hyperhidrosis (R(2) = 0.0014, p = 9.55 × 10(-3)). Despite high genetic overlap between MDD and anxiety disorders, PRSs for anxiety disorders correlated with different types of sleep disturbances such as disorders of arousal or nightmares (R(2) = 0.0013, p = 0.011). These findings suggest that greater genetic susceptibility to specific psychiatric and neurodevelopmental disorders, as represented by ADHD, MDD, and anxiety disorders, may contribute to greater sleep problems among children.

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6. Saha S, Chatterjee M, Sinha S, Mukhopadhyay K. A pioneering study indicate role of GABRQ rs3810651 in ASD severity of Indo-Caucasoid female probands. Scientific reports. 2021; 11(1): 7010.

Alteration in gamma aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is speculated to be a potential risk factor for Autism Spectrum Disorder (ASD) due to an altered expression in the brain. Sensory, social, and emotional deficits of subjects with ASD were reported to be caused by an imbalance between excitatory and inhibitory neurotransmission as well as GABAergic dysfunction caused by inadequate receptor function. We for the first time studied association between ASD and a missense coding variant rs3810651 (I478F) in the GABRQ gene, encoding for one of the subunits of GABA(A) receptors. Stratified analysis on families with ASD probands (N = 251) and ethnically matched control subjects (N = 250) revealed marginally higher frequency of « A » allele and « AA » genotype in female ASD probands as compared to gender matched controls. Female probands demonstrated higher severity for Verbal communication (χ(2) = 5.75, P = 0.01), Activity level (χ(2) = 7.26, P  = 0.007), as well as Level and consistency of intellectual response (χ(2) = 7.83 P = 0.005) in presence of « A/AA » warranting further in-depth investigation on the role of rs3810651 in ASD.

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7. Simpson K, Imms C, Keen D. The experience of participation: eliciting the views of children on the autism spectrum. Disability and rehabilitation. 2021: 1-9.

PURPOSE: Children on the autism spectrum are reported to participate less in leisure activities than their peers. Little is known about what participation means for this group and the child’s voice has been largely absent, partly due to methodological limitations. To address this limitation, alternative methods of eliciting children’s perspectives are needed. The aim of this study is to elicit children’s views about their participation experiences using a multi-method approach, and children’s feedback on the method. METHODS: Four children on the autism spectrum (9-13 years) used a video recording device to collect data over a 1-week period on their participation in activities. The children recorded an in-the-moment narrative to describe the activity and their in-the-moment experiences. A follow-up individualised interview was conducted, allowing children to present their unique views on their activity participation and feedback. RESULTS: The children’s differing perspectives identified participation as a transactional and dynamic process. Involvement was described as an individual and subjective experience, with participation influenced by personal, social, and physical factors. Children viewed the research experience positively. Recording while participating « in-the-moment » was challenging. CONCLUSION: The first-person perspective provided unique insights into the children’s participation experiences. This approach has the potential to inform methodological practices.IMPLICATIONS FOR REHABILITATIONChildren can describe their experience of participation and identify internal and external factors that influence their participation.Participation is a transactional and dynamic process.Video provides a useful method for children to record their « in the moment » experiences.Children’s video recordings provide a stimulus for interview discussions in both research and clinical practice.

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8. Thomas N, Blake S. Dental disease risk in children with autism: a meta-analysis. Evidence-based dentistry. 2021; 22(1): 34-5.

Introduction Pi and colleagues reviewed eight case-control studies comparing the oral health (decayed, missing and filled teeth [DMFT], Plaque Index [PI], Gingival Index [GI] and salivary pH) of children with autism (n = 475) to children without autism (n = 565).Method The search strategy involved the use of PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang and Chinese Scientific and Technological Journal (VIP) to find case-control studies which met pre-defined inclusion criteria and were published before September 2018. The quality of each study was evaluated using the Newcastle-Ottowa Scale and only high-quality studies were included. Means and standard deviations for outcomes measured by each included study were presented. Data were pooled using the random-effects model via Review Manager 5.3, and presented as mean differences and 95% confidence intervals. Consistency was measured using I2. Sensitivity analysis was performed by removing one study with a large sample to explore effects on heterogeneity.Results The authors found eight eligible case-control studies conducted in Asia (n = 7) or South America (n = 1). Six of the eight compared DMFT of children with autism to those without and three of the eight compared PI, GI and/or salivary pH. While a meta-analysis is presented for each of the oral health outcome areas, there are discrepancies in the reporting. The included studies in each of the meta-analysis do not correspond with the characteristics of the studies provided.Conclusions The authors suggest from their meta-analyses that children with autism experience a higher prevalence of dental disease than children without autism. However, as currently presented, the study lacks internal validity and findings are not reliable.

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9. Venkatachalam K, Eissa N, Awad MA, Jayaprakash P, Zhong S, Stölting F, Stark H, Sadek B. The histamine H3R and dopamine D2R/D3R antagonist ST-713 ameliorates autism-like behavioral features in BTBR T+tf/J mice by multiple actions. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021; 138: 111517.

Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with Autism spectrum disorder (ASD). Therefore, the ameliorative effects of the novel multiple-active compound ST-713 with high binding affinities at histamine H3 receptor (H3R), dopamine D2sR and D3R on ASD-like behaviors in male BTBR T+tf/J mice model were assessed. ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine; 2.5, 5, and 10 mg/kg, i.p.) ameliorated dose-dependently social deficits, and significantly alleviated the repetitive/compulsive behaviors of BTBR mice (all P < 0.05). Moreover, ST-713 modulated disturbed anxiety levels, but failed to obliterate increased hyperactivity of tested mice. Furthermore, ST-713 (5 mg/kg) attenuated the increased levels of hippocampal and cerebellar protein expressions of NF-κB p65, COX-2, and iNOS in BTBR mice (all P < 0.05). The ameliorative effects of ST-713 on social parameters were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. The obtained results demonstrate the potential of multiple-active compounds for the therapeutic management of neuropsychiatric disorders, e.g. ASD.

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