1. Abbeduto L, Del Hoyo Soriano L, Berry-Kravis E, Sterling A, Edgin JO, Abdelnur N, Drayton A, Hoffmann A, Hamilton D, Harvey DJ, Thurman AJ. Expressive language sampling and outcome measures for treatment trials in fragile X and down syndromes: composite scores and psychometric properties. Scientific reports. 2023; 13(1): 9267.

The lack of psychometrically sound outcome measures has been a barrier to evaluating the efficacy of treatments proposed for core symptoms of intellectual disability (ID). Research on Expressive Language Sampling (ELS) procedures suggest it is a promising approach to measuring treatment efficacy. ELS entails collecting samples of a participant’s talk in interactions with an examiner that are naturalistic but sufficiently structured to ensure consistency and limit examiner effects on the language produced. In this study, we extended previous research on ELS by analyzing an existing dataset to determine whether psychometrically adequate composite scores reflecting multiple dimensions of language can be derived from ELS procedures administered to 6- to 23-year-olds with fragile X syndrome (n = 80) or Down syndrome (n = 78). Data came from ELS conversation and narration procedures administered twice in a 4-week test-retest interval. We found that several composites emerged from variables indexing syntax, vocabulary, planning processes, speech articulation, and talkativeness, although there were some differences in the composites for the two syndromes. Evidence of strong test-retest reliability and construct validity of two of three composites were obtained for each syndrome. Situations in which the composite scores would be useful in evaluating treatment efficacy are outlined.

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2. 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.

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3. Eaton C, Roarty K, Doval N, Shetty S, Goodall K, Rhodes SM. The Prevalence of Attention Deficit/Hyperactivity Disorder Symptoms in Children and Adolescents With Autism Spectrum Disorder Without Intellectual Disability: A Systematic Review. Journal of attention disorders. 2023: 10870547231177466.

OBJECTIVE: ADHD commonly co-occurs with ASD without ID in young people. It has been difficult to obtain accurate prevalence estimates of ADHD in this population, as a dual-diagnosis was not permitted until DSM-V. We systematically reviewed the literature on the prevalence of ADHD symptoms in young people with ASD without ID. METHOD: 9,050 articles were identified through six databases. Articles were reviewed against inclusion and exclusion criteria and 23 studies were included. RESULTS: ADHD symptom prevalence varied from 2.6% to 95.5%. We discuss these findings according to the ADHD assessment measure, informant, diagnostic criteria, risk of bias rating and recruitment pool. CONCLUSION: ADHD symptoms are common in young people with ASD without ID, but there is substantial variance in study reporting. Future studies should recruit participants from community sources, provide information on key sociodemographic sample characteristics and assess ADHD with standardized diagnostic criteria, using both parent/carer and teacher report.

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4. Hou W, Li X, Yang Y, Li J. Joint intention understanding in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2023.

This study examined the ability of children with autism spectrum disorder (ASD) to generate joint intention-based action prediction in a joint action task. Children were presented with a series of videos in which two actors either played with blocks based on joint intention (social condition) or played with blocks independently (nonsocial condition). In the familiarization stage, two actors demonstrated how they played with blocks three times. In the test stage, one actor left the scene, and another actor grasped a block and asked where she should place it. Children’s gaze behavior was assessed by an eye tracker. After watching videos, children were asked to answer two questions: an action prediction question and an intention understanding question. The results showed that in the implicit eye movement task, children with ASD and typically developing (TD) children exhibited location-based anticipatory gaze under both conditions. However, in terms of explicit behavioral responses, TD children showed higher accuracy in response to action prediction questions and intention understanding questions than children with ASD in the social condition, while no significant group difference was found in the nonsocial condition. These results indicate that children with ASD have difficulty understanding joint intention and that their action prediction is primarily driven by bottom-up sensory inputs.

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5. Li X, Laplante DP, Elgbeili G, King S. Preconception and prenatal maternal stress are associated with broad autism phenotype in young adults: Project Ice Storm. Journal of developmental origins of health and disease. 2023: 1-9.

Studies show associations between prenatal maternal stress (PNMS) and child autism, with little attention paid to PNMS and autism in young adulthood. The broad autism phenotype (BAP), encompassing sub-clinical levels of autism, includes aloof personality, pragmatic language impairment and rigid personality. It remains unclear whether different aspects of PNMS explain variance in different BAP domains in young adult offspring. We recruited women who were pregnant during, or within 3 months of, the 1998 Quebec ice storm crisis, and assessed three aspects of their stress (i.e., objective hardship, subjective distress and cognitive appraisal). At age 19, the young adult offspring (n = 33, 22F / 11M) completed a BAP self-report. Linear and logistic regressions were implemented to examine associations between PNMS and BAP traits. Up to 21.4% of the variance in BAP total score and in BAP three domains tended to be explained by at least one aspect of maternal stress, For example, 16.8% of the variance in aloof personality tended to be explained by maternal objective hardship; 15.1% of the variance in pragmatic language impairment tended to be explained by maternal subjective distress; 20.0% of the variance in rigid personality tended to be explained by maternal objective hardship and 14.3% by maternal cognitive appraisal. Given the small sample size, the results should be interpreted with caution. In conclusion, this small prospective study suggests that different aspects of maternal stress could have differential effects on different components of BAP traits in young adults.

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6. Mercaldo V, Vidimova B, Gastaldo D, Fernández E, Lo AC, Cencelli G, Pedini G, De Rubeis S, Longo F, Klann E, Smit AB, Grant SGN, Achsel T, Bagni C. Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome. Neuron. 2023; 111(11): 1760-75.e8.

The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.

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7. Milstein JA, Beer D, Thomson J, Cedars A, Konstantinidis K. Atrial Fibrillation Ablation in a Patient With SV ASD and PAPVR Preceding Transcatheter Septal Closure. JACC Case reports. 2023; 15: 101862.

Atrial fibrillation (AF) is common in adults with unrepaired atrial septal defects (ASDs). Sinus venosus (SV) ASDs associated with partial anomalous pulmonary venous return (PAPVR) are traditionally managed surgically. We report the first AF catheter ablation in a patient with SV ASD and PAPVR preceding transcatheter ASD repair with a covered stent. (Level of Difficulty: Advanced.).

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8. 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.

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9. Varma M, Bhandari R, Kuhad A. Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis. Metabolic brain disease. 2023.

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer’s Disease and Parkinson’s Disease, as well as various cancers by targeting ERK/MAPK, it’s efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

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10. Wang M, Xian P, Zheng W, Li Z, Chen A, Xiao H, Xu C, Wang F, Mao H, Meng H, Zhao Y, Luo C, Wang Y, Wu S. Axin2 coupled excessive Wnt-glycolysis signaling mediates social defect in autism spectrum disorders. EMBO molecular medicine. 2023; 15(6): e17101.

Social dysfunction is the core syndrome of autism spectrum disorder (ASD) and lacks effective medicine. Although numerous risk genes and relevant environmental factors have been identified, the convergent molecular mechanism underlying ASD-associated social dysfunction remains largely elusive. Here, we report aberrant activation of canonical Wnt signaling and increased glycolysis in the anterior cingulate cortex (ACC, a key brain region of social function) of two ASD mouse models (Shank3(-/-) and valproic acid-treated mice) and their corresponding human neurons. Overexpressing β-catenin in the ACC of wild-type mice induces both glycolysis and social deficits. Suppressing glycolysis in ASD mice partially rescued synaptic and social phenotype. Axin2, a key inhibitory molecule in Wnt signaling, interacts with the glycolytic enzyme enolase 1 (ENO1) in ASD neurons. Surprisingly, an Axin2 stabilizer, XAV939, effectively blocked Axin2/ENO1 interaction, switched glycolysis/oxidative phosphorylation balance, promoted synaptic maturation, and rescued social function. These data revealed excessive neuronal Wnt-glycolysis signaling as an important underlying mechanism for ASD synaptic deficiency, indicating Axin2 as a potential therapeutic target for social dysfunction.

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