1. Costa CIS, da Silva Campos G, da Silva Montenegro EM, Wang JYT, Scliar M, Monfardini F, Zachi EC, Lourenço NCV, Chan AJS, Pereira SL, Engchuan W, Thiruvahindrapuram B, Zarrei M, Scherer SW, Passos-Bueno MR. Three generation families: Analysis of de novo variants in autism. European journal of human genetics : EJHG. 2023.

De novo variants (DNVs) analysis has proven to be a powerful approach to gene discovery in Autism Spectrum Disorder (ASD), which has not yet been shown in a Brazilian ASD cohort. The relevance of inherited rare variants has also been suggested, particularly in oligogenic models. We hypothesized that three-generation analyses of DNVs could provide new insights into the relevance of de novo and inherited variants across generations. To accomplish this goal, we performed whole-exome sequencing of 33 septet families composed of probands, parents, and grandparents (n = 231 individuals) and compared DNV rates (DNVr) between generations and those from two control cohorts. The DNVr in the probands (DNVr = 1.16) was marginally higher than in parents (DNVr = 0.60; p = 0.054), and in controls (DNVr = 0.68; p = 0.035, congenital heart disorder and DNVr = 0.70; p = 0.047, unaffected ASD siblings from Simons Simplex Collection). Moreover, most of the DNVs were found to have paternal origin in both generations (84.6%). Finally, we observed that 40% (6/15) of the DNVs in parents transmitted for probands are in ASD or ASD candidate genes, representing recently emerged risk variants to ASD in their families and suggest ZNF536, MSL2 and HDAC9 as ASD candidate genes. We did not observe an enrichment of risk variants nor sex bias of transmitted variants in the three generations, that can be due to sample size. These results further reinforce the relevance of de novo variants in ASD.

Lien vers le texte intégral (Open Access ou abonnement)

2. Dias CM, Issac B, Sun L, Lukowicz A, Talukdar M, Akula SK, Miller MB, Walsh K, Rockowitz S, Walsh CA. Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2023; 120(23): e2300052120.

Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type-specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type-specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition.

Lien vers le texte intégral (Open Access ou abonnement)

3. Ghafouri-Fard S, Pourtavakoli A, Hussen BM, Taheri M, Ayatollahi SA. A Review on the Role of Genetic Mutations in the Autism Spectrum Disorder. Molecular neurobiology. 2023.

Autism spectrum disorder (ASD) is among the most widespread neurodevelopmental diseases, with an approximate prevalence rate of 1 in 59. From a genetic point of view, this disorder is highly heterogeneous. This disorder is associated with both inheritable and de novo mutations in several genes. In addition to genetic loci that are identified through early karyotype analyses, recent advent of high throughput sequencing methods has facilitated identification of several genetic loci that confer risk of ASD. The current review provides an overview of different types of identified mutations including missense and nonsense mutations and copy number variations in various genes in individuals affected with ASD.

Lien vers le texte intégral (Open Access ou abonnement)

4. Moerkerke M, Daniels N, Van der Donck S, Tibermont L, Tang T, Debbaut E, Bamps A, Prinsen J, Steyaert J, Alaerts K, Boets B. Can repeated intranasal oxytocin administration affect reduced neural sensitivity towards expressive faces in autism? A randomized controlled trial. Journal of child psychology and psychiatry, and allied disciplines. 2023.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication and interaction. Crucial for efficient social interaction is the ability to quickly and accurately extract information from a person’s face. Frequency-tagging electroencephalography (EEG) is a novel tool to quantify face-processing sensitivity in a robust and implicit manner. In terms of intervention approaches, intranasal administration of oxytocin (OT) is increasingly considered as a potential pharmacological approach for improving socio-communicative difficulties in ASD, through enhancing social salience and/or reducing (social) stress and anxiety. METHODS: In this randomized, double-blind, placebo-controlled, mechanistic pharmaco-neuroimaging clinical trial, we implemented frequency-tagging EEG to conduct an exploratory investigation into the impact of repeated OT administration (4 weeks, 12 IU, twice daily) on neural sensitivity towards happy and fearful facial expressions in children with ASD (8-12 years old; OT: n = 29; placebo: n = 32). Neural effects were assessed at baseline, post-nasal spray (24 hr after the last nasal spray) and at a follow-up session, 4 weeks after the OT administration period. At baseline, neural assessments of children with ASD were compared with those of an age- and gender-matched cohort of neurotypical (NT) children (n = 39). RESULTS: Children with ASD demonstrated reduced neural sensitivity towards expressive faces, as compared to NT children. Upon nasal spray administration, children with ASD displayed a significant increase in neural sensitivity at the post- and follow-up sessions, but only in the placebo group, likely reflecting an implicit learning effect. Strikingly, in the OT group, neural sensitivity remained unaffected from the baseline to the post-session, likely reflecting a dampening of an otherwise typically occurring implicit learning effect. CONCLUSIONS: First, we validated the robustness of the frequency-tagging EEG approach to assess reduced neural sensitivity towards expressive faces in children with ASD. Furthermore, in contrast to social salience effects observed after single-dose administrations, repeated OT administration dampened typically occurring learning effects in neural sensitivity. In line with OT’s social anxiolytic account, these observations possibly reflect a predominant (social) stress regulatory effect towards emotionally evocative faces after repeated OT administration.

Lien vers le texte intégral (Open Access ou abonnement)

5. Nekar DM, Kang HY, Lee JW, Oh SY, Yu JH. Effects of Cooperative, Competitive, and Solitary Exergames on Cognition and Anxiety Levels in Children with Developmental Disabilities. Games for health journal. 2023.

Objective: Exergames are playing an important role in person-centered therapy, health care services, and in the rehabilitation field. This study aimed to compare the effects of cooperative, competitive, and solitary exergames on cognition and anxiety levels in children with developmental disabilities (DD). Materials and Methods: This study was a randomized controlled trial pretest-posttest including 36 children with DD who were allocated to the cooperative exergame group (CGG), competitive exergame group (CmGG), and solitary exergame group (SGG). The exergame program was performed two times a week for 8 weeks and the outcome measurements were conducted before and after the program. A paired sample t-test and one-way analysis of variance (ANOVA) were used to analyze the changes within and between the groups. Results: The result indicated a significant improvement in memory, attention, and visual perception in all groups; the CGG and CmGG showed a high increase in attention compared with the SGG. However, only the CGG presented a significant improvement in the language subscale. In terms of anxiety, only the CGG presented substantial improvements in all anxiety subscales. The CmGG showed improvement in social phobia and the SGG in physical injury fears, social phobia, and general anxiety fears. Conclusion: The findings suggest that cooperative and competitive exergames may be used to effectively improve cognitive functions; cooperative exergames can be applied as the most effective method to reduce anxiety compared with the other game types for children with DD.

Lien vers le texte intégral (Open Access ou abonnement)

6. Nimbley E, Gillespie-Smith K, Duffy F, Maloney E, Ballantyne C, Sharpe H. « It’s not about wanting to be thin or look small, it’s about the way it feels »: an IPA analysis of social and sensory differences in autistic and non-autistic individuals with anorexia and their parents. Journal of eating disorders. 2023; 11(1): 89.

BACKGROUND: Despite increasing evidence to support an overlap between autism and anorexia nervosa (AN), underlying mechanisms remain poorly understood. Social and sensory factors have emerged as promising targets in both autism and AN, however there remains scope to compare these differences across autistic and non-autistic experiences of AN. Drawing on dyadic multi-perspectives, this study explored experiences of social and sensory differences in autistic and non-autistic adults and their parents and/or carers. METHODS: Using interpretative phenomenological analysis (IPA), dyadic interviews were conducted with 14 dyads, with seven autistic dyads and seven non-autistic dyads. Data analysis was subjected to a triangulation of interpretations: (1) the participants themselves; (2) a neurotypical researcher; (3) and an Autistic researcher with lived/living experience of AN. RESULTS: IPA identified three themes in each group, with similarities and differences between autistic and non-autistic dyads. Similar themes were identified regarding the importance of social connectedness and socio-emotional difficulties, as well a common lack of trust in the social and sensory self and body. Autism-specific themes centred on feelings of social ‘defectiveness’, disparities between sensing and expressing certain cues, and lifelong, multi-sensory processing differences. Non-autistic themes reflected social comparisons and inadequacy, and sensitivities to the learning of ideals and behaviour through early experiences. CONCLUSIONS: While similarities were observed across both groups, there appeared to be notable differences in the perceived role and influence of social and sensory differences. These findings may have important implications on the delivery and modification of eating disorder interventions. Specifically, they suggest that while treatment targets may look similar, subtle differences in underlying mechanisms and approaches may be required for Autistic individuals with AN across sensory, emotion and communication-based interventions.

Lien vers le texte intégral (Open Access ou abonnement)

7. Sandhu A, Rawat K, Gautam V, Sharma A, Kumar A, Saha L. Phosphodiesterase inhibitor, Ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder. Brain research. 2023: 148443.

BACKGROUND: Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats. METHODS: Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum. KEY FINDINGS: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage. CONCLUSIONS: Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

Lien vers le texte intégral (Open Access ou abonnement)

8. Seggie AJR. Using Verbal De-escalation to Manage Children With Autism in the Emergency Department. Pediatric emergency care. 2023.

Lien vers le texte intégral (Open Access ou abonnement)

9. Shawler LA, Zhelezoglo KN, Miguel CF, Brand D. Procedural parameters in equivalence-based instruction with individuals diagnosed with autism: A call for systematic research. Journal of applied behavior analysis. 2023.

Equivalence-based instruction (EBI) is an efficient and efficacious methodology to establish equivalence classes that has been used to teach various academic skills to neurotypical adults. Although previous reviews confirmed the utility of EBI with participants with developmental disabilities, it is unclear whether certain procedural parameters are associated with positive equivalence outcomes. We extended previous reviews by categorizing studies that used EBI with individuals diagnosed with autism spectrum disorder and assessed whether any procedural parameters were associated with better equivalence responding. Due to the wide variability of procedural parameters in EBI research, the best procedural permutations to form equivalence classes with individuals diagnosed with autism spectrum disorder are still unknown. Thus, this paper serves as a call to action for applied researchers. Specifically, we encourage and invite researchers to systematically investigate the necessary variables or combination of variables that may lead to successful equivalence class formation.

Lien vers le texte intégral (Open Access ou abonnement)

10. Xu M, Wang L, Wang Y, Deng J, Wang X, Wang F, Pan S, Zhao Y, Liao A, Wang X, Chen D, Shen J, Yang F, Li Y, Wang S. Melatonin ameliorates sleep-wake disturbances and autism-like behaviors in the Ctnnd2 knock out mouse model of autism spectrum disorders. Genes, brain, and behavior. 2023: e12852.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by atypical patterns of social interaction and communication, as well as restrictive and repetitive behaviors. In addition, patients with ASD often presents with sleep disturbances. Delta (δ) catenin protein 2 (CTNND2) encodes δ-catenin protein, a neuron-specific catenin implicated in many complex neuropsychiatric diseases. Our previous study demonstrated that the deletion of Ctnnd2 in mice led to autism-like behaviors. However, to our knowledge, no study has investigated the effects of Ctnnd2 deletion on sleep in mice. In this study, we investigated whether the knockout (KO) of exon 2 of the Ctnnd2 gene could induce sleep-wake disorders in mice and identified the effects of oral melatonin (MT) supplementation on Ctnnd2 KO mice. Our results demonstrated that the Ctnnd2 KO mice exhibited ASD-like behaviors and sleep-wake disorders that were partially attenuated by MT supplementation. Overall, our current study is the first to identify that knockdown of Ctnnd2 gene could induce sleep-wake disorders in mice and suggests that treatment of sleep-wake disturbances by MT may benefit to autism-like behaviors causing by Ctnnd2 gene deletion.

Lien vers le texte intégral (Open Access ou abonnement)