1. Abedini SS, Akhavantabasi S, Liang Y, Heng J, Alizadehsani R, Dehzangi I, Bauer DC, Alinejad-Rokny H. A Critical Review of the Impact of Candidate Copy Number Variants on Autism Spectrum Disorder. Mutat Res Rev Mutat Res. 2024: 108509.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder (NDD) influenced by genetic, epigenetic, and environmental factors. Recent advancements in genomic analysis have shed light on numerous genes associated with ASD, highlighting the significant role of both common and rare genetic mutations, as well as copy number variations (CNVs), single nucleotide polymorphisms (SNPs) and unique de novo variants. These genetic variations disrupt neurodevelopmental pathways, contributing to the disorder’s complexity. Notably, CNVs are present in 10%-20% of individuals with autism, with 3%-7% detectable through cytogenetic methods. While the role of submicroscopic CNVs in ASD has been recently studied, their association with genomic loci and genes has not been thoroughly explored. In this review, we focus on 47 CNV regions linked to ASD, encompassing 1,632 genes, including protein-coding genes and long non-coding RNAs (lncRNAs), of which 659 show significant brain expression. Using a list of ASD-associated genes from SFARI, we detect 17 regions harboring at least one known ASD-related protein-coding gene. Of the remaining 30 regions, we identify 24 regions containing at least one protein-coding gene with brain-enriched expression and a nervous system phenotype in mouse mutants, and one lncRNA with both brain-enriched expression and upregulation in iPSC to neuron differentiation. This review not only expands our understanding of the genetic diversity associated with ASD but also underscores the potential of lncRNAs in contributing to its etiology. Additionally, the discovered CNVs will be a valuable resource for future diagnostic, therapeutic, and research endeavors aimed at prioritizing genetic variations in ASD.

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2. Bhattacharya A, Parlanti P, Cavallo L, Farrow E, Spivey T, Renieri A, Mari F, Manzini MC. A novel framework for functional annotation of variants of uncertain significance in ID/ASD risk gene CC2D1A. Hum Mol Genet. 2024; 33(14): 1229-40.

Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous with hundreds of identified risk genes, most affecting only a few patients. Novel missense variants in these genes are being discovered as clinical exome sequencing is now routinely integrated into diagnosis, yet most of them are annotated as variants of uncertain significance (VUS). VUSs are a major roadblock in using patient genetics to inform clinical action. We developed a framework to characterize VUSs in Coiled-coil and C2 domain containing 1A (CC2D1A), a gene causing autosomal recessive ID with comorbid ASD in 40% of cases. We analyzed seven VUSs (p.Pro319Leu, p.Ser327Leu, p.Gly441Val, p.Val449Met, p.Thr580Ile, p.Arg886His and p.Glu910Lys) from four cases of individuals with ID and ASD. Variants were cloned and overexpressed in HEK293 individually and in their respective heterozygous combination. CC2D1A is a signaling scaffold that positively regulates PKA-CREB signaling by repressing phosphodiesterase 4D (PDE4D) to prevent cAMP degradation. After testing multiple parameters including direct interaction between PDE4D and CC2D1A, cAMP levels and CREB activation, we found that the most sensitive readout was CREB transcriptional activity using a luciferase assay. Compared to WT CC2D1A, five VUSs (p.Pro319Leu, p.Gly441Val, p.Val449Met, p.Thr580Ile, and p.Arg886His) led to significantly blunted response to forskolin induced CREB activation. This luciferase assay approach can be scaled up to annotate ~150 CC2D1A VUSs that are currently listed in ClinVar. Since CREB activation is a common denominator for multiple ASD/ID genes, our paradigm can also be adapted for their VUSs.

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3. Castellanos FX. Back to the future: Some similarities and many differences between autism spectrum disorder and early onset schizophrenia. Clues to pathophysiology?. Sci Bull (Beijing). 2024.

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4. Dou JF, Schmidt RJ, Volk HE, Nitta MM, Feinberg JI, Newschaffer CJ, Croen LA, Hertz-Picciotto I, Fallin MD, Bakulski KM. Exposure to heavy metals in utero and autism spectrum disorder at age 3: a meta-analysis of two longitudinal cohorts of siblings of children with autism. Environ Health. 2024; 23(1): 62.

BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts. RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD. CONCLUSION: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

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5. Miles KD, Barker CM, Russell KP, Appel BH, Doll CA. Electrical synapses mediate embryonic hyperactivity in a zebrafish model of Fragile X syndrome. J Neurosci. 2024.

Although hyperactivity is associated with a wide variety of neurodevelopmental disorders, the early embryonic origins of locomotion have hindered investigation of pathogenesis of these debilitating behaviors. The earliest motor output in vertebrate animals is generated by clusters of early-born motor neurons that occupy distinct regions of the spinal cord, innervating stereotyped muscle groups. Gap junction electrical synapses drive early spontaneous behavior in zebrafish, prior to the emergence of chemical neurotransmitter networks. We use a genetic model of hyperactivity to gain critical insight into the consequences of errors in motor circuit formation and function, finding that Fragile X syndrome (FXS) model mutant zebrafish are hyperexcitable from the earliest phases of spontaneous behavior, show altered sensitivity to blockade of electrical gap junctions, and have increased expression of the gap junction protein Connexin 34/35. We further show that this hyperexcitable behavior can be rescued by pharmacological inhibition of electrical synapses. We also use functional imaging to examine motor neuron and interneuron activity in early embryogenesis, finding genetic disruption of electrical gap junctions uncouples activity between mnx1 (+) motor neurons and interneurons. Taken together, our work highlights the importance of electrical synapses in motor development and suggests that the origins of hyperactivity in neurodevelopmental disorders may be established during the initial formation of locomotive circuits.Significance Statement The origins of hyperactivity in neurodevelopmental disorders are difficult to pinpoint in vertebrate systems. Zebrafish locomotive circuits initiate in early embryogenesis, with defined motor neurons and interneurons driving the earliest locomotive movements. Using a genetic model of hyperactivity, we show that Fragile X syndrome model fmr1 mutant embryos display hyperexcitable behavior and express excess gap junction connexin proteins on motor circuit neurons. We further show that this hyperexcitable behavior can be rescued by pharmacological inhibition of electrical synapses. Taken together, this data suggests hyperactive behavior initiates in the earliest phases of neurodevelopment.

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6. Rozenblat S, Nitzan T, Matz Vaisman T, Shusel R, Rum Y, Ashtamker M, Golan O, Dinstein I, Koller J. Autistic children and their parents in the context of war: Preliminary findings. Stress Health. 2024: e3442.

While existing literature on the intersection of trauma and autism is limited, emerging evidence suggests heightened vulnerability of autistic children to the psychological consequences of traumatic events, including an elevated risk of developing posttraumatic stress disorder (PTSD). Additionally, parents of autistic children often experience elevated levels of negative emotional states, compared to parents of typically developing children. This study investigates the impact of terrorism and war on autistic and non-autistic children and their parents, presenting preliminary results from the initial data collection phase of a year-long longitudinal investigation of the experience of autistic children and their parents following Hamas’ 7 October 2023 attack on Israel. Data gathered within 30 days of the initial attack reveal that both autistic and non-autistic children exhibited clinically significant post-traumatic stress symptoms, with autistic children demonstrating a more pronounced manifestation. Moreover, parents of autistic children reported significantly higher levels of depression, anxiety, and stress in the aftermath of the events, compared to an independent cohort of parents of autistic children assessed prior to the crisis. These results underscore the heightened susceptibility of autistic children to post-traumatic stress and the unique challenges confronted by their parents during times of conflict. The study highlights the imperative for tailored support services for autistic children and their families amidst traumatic incidents and stresses the need for further research in comparable contexts globally.

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7. Sadikova E, Mazurek MO. The Association Between Adverse Childhood Experiences and Sleep in Children with Autism Spectrum Disorder. J Autism Dev Disord. 2024.

Children with autism spectrum disorder are at higher risk for adverse childhood experiences (ACEs). They are also more vulnerable to sleep problems and are less likely to obtain the recommended number of hours of sleep than neurotypical children. In the general population, ACEs have been linked to future sleep difficulties. Despite increased vulnerabilities to both ACEs and sleep problems, no study has examined this association in ASD. Using the National Survey of Children’s Health across four cohorts, we examined whether ACEs were a risk factor to obtaining the recommended number of hours of sleep, while accounting for demographic and health factors typically associated with sleep duration. Findings indicate that children with ASD with more ACEs were less likely to get the recommended number of hours of sleep than children with fewer ACEs. Other factors associated with sleep included race, anxiety, autism severity, and overall health. These findings indicate that sleep problems in children with ASD are complex and multifaceted. Among other considerations, it is important for clinicians to screen children with ASD for ACEs and consider the possible impact of ACEs on sleep.

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8. Tanaka Y, Kurasawa S, Ouchi K, Oi N. Structural associations between self-perception of support and knowledge of disability characteristics of autism spectrum disorder among staff in facilities providing after-school day services. Fukushima J Med Sci. 2024.

BACKGROUND: We constructed a hypothetical model of the knowledge of autism spectrum disorder (ASD) and self-perception of support of staff working in after-school day services to clarify structural relationships. METHODS: A questionnaire survey was conducted at 194 facilities providing after-school day services in Fukushima Prefecture (October 2020), including a basic attributes questionnaire, the Literacy Scale of Characteristics of Autistic Spectrum Disorder (LS-ASD), and a staff questionnaire. We developed a hypothetical model of the relationship between self-perception and LS-ASD total scores of after-school service staff. To obtain latent variables for structural equation modeling (SEM) to confirm factor extraction and the interrelationships among variables, exploratory factor analysis was performed. SEM was used to examine the fit of the hypothetical model to the data and the relationships among variables. RESULTS: The study included 302 staff members from 58 of 194 facilities. Four factors (Factor 1, motivation; 2, self-perception of knowledge; 3, information sharing; 4, self-confidence) were extracted. The final model showed that Factor 2 had a positive direct effect (path coefficient = 0.64) and Factor 4 had a negative direct effect (path coefficient = -0.22) on LS-ASD scores. The model goodness of fit was acceptable (Goodness-of-Fit Index = 0.890; Comparative Fit Index = 0.912; Root Mean Square Error of Approximation = 0.086; Akaike’s Information Criterion = 392.7). CONCLUSION: Self-perception of knowledge contributes greatly to knowledge acquisition, while excessive confidence may hinder knowledge retention.

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9. Wu Y, Ding L, Zhang Q, Dong Y, Tao C, Li Z, Li Z, Lu L. The effect of physical exercise therapy on autism spectrum disorder:a systematic review and meta-analysis. Psychiatry Res. 2024; 339: 116074.

BACKGROUND: Physical Exercise Therapy (PET) is increasingly applied in the treatment of Autism Spectrum Disorders (ASD), yet the empirical evidence supporting its efficacy remains ambiguous. This systematic review and meta-analysis aimed to investigate the effectiveness of PET for individuals with ASD, providing evidence-based support for clinical and scientific research. METHODS: We systematically searched four international databases (Medline via PubMed, Embase, Cochrane Libraries, and Web of Science) and three Chinese databases (CNKI, Wanfang, and VIP Libraries) up to July 31, 2023. The search was conducted in both English and Chinese for original research articles employing randomized-controlled-trial (RCT) designs to study PET’s effects on individuals diagnosed with ASD according to DSM or other established criteria. Co-primary outcomes focused on the overall severity of autism, while secondary outcomes included measures of stereotyped behaviors, social deficits, social skills, and executive functioning. Data from the included studies were synthesized and analyzed using RevMan 5.4. This systematic review is registered with PROSPERO (CRD42023443951). RESULTS: A total of 28 RCTs comprising 1081 participants were analyzed. Of these, only three studies met high-quality standards. Compared to control groups, PET showed improvement in at least one core symptom of autism, including Motor Performance (SMD=1.72, 95%CI[1.01, 2.44], I(2)=90%), Restricted Repetitive Behaviors (SMD=-0.81, 95%CI[-1.00, -0.62], I(2)=0%), Social Dysfunction (SMD=-0.76, 95%CI[-1.06, -0.46], I(2)=47%). CONCLUSIONS: PET may offer benefits in reducing the overall severity and associated symptoms in individuals with ASD. However, given the high overall risk of bias in the included studies, these findings should be interpreted with caution.

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