1. Charman T, Pasco G, Hendry A, Bazelmans T, Narvekar N, Goodwin A, Halkola H, Agyapong M, Holman R, Ali JB, Ersoy M, Johnson MH, Pickles A, Jones EJH. Three year outcomes in infants with a family history of autism and/or attention deficit hyperactivity disorder. JCPP advances. 2023; 3(4): e12189.

BACKGROUND: Most research on early outcomes in infants with a family history (FH) of autism has focussed on categorically defined autism, although some have language and developmental delays. Less is known about outcomes in infants with a FH of attention deficit hyperactivity disorder (ADHD). METHODS: Infants with and without a FH of autism and/or ADHD, due to a first-degree relative with either or both conditions, were recruited at 5 or 10 months. Three year outcomes were characterised using latent profile analysis (LPA) across measures of cognitive ability, adaptive functioning and autism, ADHD and anxiety traits (n = 131). We additionally ran an LPA using only autism and ADHD measures, and the broader LPA in an independent cohort (n = 139) and in both cohorts combined (n = 270). RESULTS: A Low Developmental Level + High Behavioural Concerns class had elevated autism, ADHD and anxiety scores, low cognitive and adaptive function, and included all but one child with autism. A Low Developmental Level + Typical Behaviour class had average cognitive ability and typical behaviour but low adaptive function. A Typical Developmental Level + Some Behavioural Concerns class had average cognitive and adaptive function but slightly elevated behaviour scores. A High Developmental Level + Typical Behaviour class had above average cognitive ability and typical behaviour. All four LPAs identified classes characterised by combinations of either, or both, Low Development Level and elevated behaviour scores, as well as a typically developing class. No classes had elevated autism or ADHD traits in isolation. CONCLUSIONS: Some infants with a FH of autism or ADHD have atypical developmental and behavioural outcomes, but do not show strong autism or ADHD traits in isolation. The field needs to recalibrate aims and methods to embrace the broader transdiagnostic pattern of outcomes seen in these infants.

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2. David LW, Stenberg N, Diseth TH, Helverschou SB, Nyquist CB, Øien RA, Waehre A. Autistic Characteristics in a Nationally Representative Clinical Sample of Adolescents Seeking Medical Gender-Affirming Treatment in Norway. Journal of autism and developmental disorders. 2023.

PURPOSE: Several studies have reported on the intersection of autism and gender incongruence (GI) in clinical populations. This study aims to investigate autistic characteristics and registered autism spectrum diagnoses (ASD) in a clinical cohort of 83 adolescents referred to the National Gender Team for Children and Adolescents in Norway during 2020. METHODS: Parents completed the Social Responsiveness Scale (SRS). Background information and registered psychiatric diagnoses were extracted from patient files. RESULTS: The results showed that 25% of the participants scored within the clinical range on the SRS: 27.4% of adolescents who were assigned female at birth (AFAB) and 19.0% of adolescents who were assigned male at birth (AMAB). AFAB had significantly higher scores on SRS Total Scale and the Social Motivation and Autistic Mannerisms subscales compared to the female norm group. AMAB had higher scores on the Social Motivation subscale and lower scores on the Social Awareness subscale, compared to the male norm population. Information from patient files revealed that 67.5% had one or more registered psychiatric diagnosis. 9.6% had received an ASD diagnosis, all AFAB. 18.1% had received an attention deficit hyperactivity disorder (ADHD) diagnosis. The most common psychiatric diagnoses were depression (25.3%) and anxiety disorders (18.1%). Further, 44.6% had a history of self-harm, and 15.7% had a history of a suicide attempt. CONCLUSION: The results showed an overrepresentation of ASD diagnoses and autistic characteristics measured by SRS for AFAB. There was an overrepresentation of psychiatric diagnoses for both the AFAB and the AMAB group in this study sample. Implications for treatment and future research are discussed.

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3. D’Mello SR. Rett and Rett-related disorders: Common mechanisms for shared symptoms?. Experimental biology and medicine (Maywood, NJ). 2023: 15353702231209419.

Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.

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4. Duarte-Campos JF, Vázquez-Moreno CN, Martínez-Marcial M, Chavarría A, Ramírez-Carreto RJ, Velasco Velázquez MA, De La Fuente-Granada M, González-Arenas A. Changes in neuroinflammatory markers and microglial density in the hippocampus and prefrontal cortex of the C58/J mouse model of autism. The European journal of neuroscience. 2023.

Autism spectrum disorder (ASD) is a diverse group of neurodevelopmental conditions with complex origins. Individuals with ASD present various neurobiological abnormalities, including an altered immune response in the central nervous system and other tissues. Animal models like the C58/J inbred mouse strain are used to study biological characteristics of ASD. This strain is considered an idiopathic autism model because of its demonstrated reduced social preference and repetitive behaviours. Notably, C58/J mice exhibit alterations in dendritic arbour complexity, density and dendritic spines maturation in the hippocampus and prefrontal cortex (PFC), but inflammatory-related changes have not been explored in these mice. In this study, we investigated proinflammatory markers in the hippocampus and PFC of adult male C58/J mice. We discovered elevated levels of interferon gamma (IFN-γ) and monocyte chemoattractant protein 1 (MCP-1) in the hippocampus, suggesting increased inflammation, alongside a reduction in the anti-inflammatory enzyme arginase 1 (ARG1). Conversely, the PFC displayed reduced levels of TNF-α and MCP-1. Microglial analysis revealed higher levels of transmembrane protein 119 (TMEM119) and increased microglial density in a region-specific manner of the autistic-like mice, particularly in the PFC and hippocampus. Additionally, an augmented expression of the fractalkine receptor CX3CR1 was observed in the hippocampus and PFC of C58/J mice. Microglial morphological analysis shows no evident changes in the hippocampus of mice with autistic-like behaviours versus wild-type strain. These region-specific changes can contribute to modulate processes like inflammation or synaptic pruning in the C58/J mouse model of idiopathic autism.

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5. Jiang M, Wang Z, Lu T, Li X, Yang K, Zhao L, Zhang D, Li J, Wang L. Integrative analysis of long noncoding RNAs dysregulation and synapse-associated ceRNA regulatory axes in autism. Translational psychiatry. 2023; 13(1): 375.

Autism spectrum disorder (ASD) is a complex disorder of neurodevelopment, the function of long noncoding RNA (lncRNA) in ASD remains essentially unknown. In the present study, gene networks were used to explore the ASD disease mechanisms integrating multiple data types (for example, RNA expression, whole-exome sequencing signals, weighted gene co-expression network analysis, and protein-protein interaction) and datasets (five human postmortem datasets). A total of 388 lncRNAs and five co-expression modules were found to be altered in ASD. The downregulated co-expression M4 module was significantly correlated with ASD, enriched with autism susceptibility genes and synaptic signaling. Integrating lncRNAs from the M4 module and microRNA (miRNA) dysregulation data from the literature identified competing endogenous RNA (ceRNA) network. We identified the downregulated mRNAs that interact with miRNAs by the miRTarBase, miRDB, and TargetScan databases. Our analysis reveals that MIR600HG was downregulated in multiple brain tissue datasets and was closely associated with 9 autism-susceptible miRNAs in the ceRNA network. MIR600HG and target mRNAs (EPHA4, MOAP1, MAP3K9, STXBP1, PRKCE, and SCAMP5) were downregulated in the peripheral blood by quantitative reverse transcription polymerase chain reaction analysis (false discovery rate <0.05). Subsequently, we assessed the role of lncRNA dysregulation in altered mRNA levels. Experimental verification showed that some synapse-associated mRNAs were downregulated after the MIR600HG knockdown. BrainSpan project showed that the expression patterns of MIR600HG (primate-specific lncRNA) and synapse-associated mRNA were similar in different human brain regions and at different stages of development. A combination of support vector machine and random forest machine learning algorithms retrieved the marker gene for ASD in the ceRNA network, and the area under the curve of the diagnostic nomogram was 0.851. In conclusion, dysregulation of MIR600HG, a novel specific lncRNA associated with ASD, is responsible for the ASD-associated miRNA-mRNA axes, thereby potentially regulating synaptogenesis.

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6. Kolb RL, McComas JJ, Girtler SN, Simacek J, Dimian AF, Unholz-Bowden EK, Shipchandler AH. Teaching Requesting to Individuals with Rett Syndrome Using Alternative Augmentative Communication (AAC) Through Caregiver Coaching via Telehealth. Journal of developmental and physical disabilities. 2023; 35(6): 1063-90.

Rett syndrome is a severe neurodevelopmental disorder that results in both motor and language skill regression with a wide range of severity in symptom presentation. Communication intervention may be particularly challenging for this population due to the decline in speech, motor skills, and motor planning difficulties that characterize the disorder (Townend et al., 2020), often resulting in the need for augmentative and alternative communication (AAC) technology. Very limited research has evaluated communication interventions for individuals with Rett syndrome and even fewer have targeted expressive communication, an important skill required for improved autonomy and quality of life (Sigafoos et al., 2009; Townend et al., 2020). The current study sought to systematically replicate the Simacek et al. (2017) mand training procedures to teach three girls with Rett Syndrome to use AAC to make requests through caregiver coaching by researchers via telehealth. Results suggest that mand training was successful in increasing AAC use for all three participants. Barriers to intervention for this population and implications of results for future research and clinical practice are discussed.

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7. Sapey-Triomphe LA, Sanchez G, Hénaff MA, Sonié S, Schmitz C, Mattout J. Disentangling sensory precision and prior expectation of change in autism during tactile discrimination. NPJ science of learning. 2023; 8(1): 54.

Predictive coding theories suggest that core symptoms in autism spectrum disorders (ASD) may stem from atypical mechanisms of perceptual inference (i.e., inferring the hidden causes of sensations). Specifically, there would be an imbalance in the precision or weight ascribed to sensory inputs relative to prior expectations. Using three tactile behavioral tasks and computational modeling, we specifically targeted the implicit dynamics of sensory adaptation and perceptual learning in ASD. Participants were neurotypical and autistic adults without intellectual disability. In Experiment I, tactile detection thresholds and adaptation effects were measured to assess sensory precision. Experiments II and III relied on two-alternative forced choice tasks designed to elicit a time-order effect, where prior knowledge biases perceptual decisions. Our results suggest a subtler explanation than a simple imbalance in the prior/sensory weights, having to do with the dynamic nature of perception, that is the adjustment of precision weights to context. Compared to neurotypicals, autistic adults showed no difference in average performance and sensory sensitivity. Both groups managed to implicitly learn and adjust a prior that biased their perception. However, depending on the context, autistic participants showed no, normal or slower adaptation, a phenomenon that computational modeling of trial-to-trial responses helped us to associate with a higher expectation for sameness in ASD, and to dissociate from another observed robust difference in terms of response bias. These results point to atypical perceptual learning rather than altered perceptual inference per se, calling for further empirical and computational studies to refine the current predictive coding theories of ASD.

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8. Soares N, VanDerKolk K, Hasan MS, Burge SK, Graves L. Family Medicine Residency Program Directors’ Perception of Curricular Elements Related to Autism: A CERA Study. Family medicine. 2023.

BACKGROUND AND OBJECTIVES: The family medicine (FM) approach to health care across the life span is well-suited to providing care for persons living with autism spectrum disorder (ASD). Little is known about ASD curricula in FM residency training and the characteristics of FM residency programs that prepare their residents to care for persons with this disorder. METHODS: Our study questions were part of a larger omnibus survey by the Council of Academic Family Medicine Educational Research Alliance (CERA) with data collection from November 16 to December 18, 2022, from FM residency program directors (PDs). ASD curricula were investigated using 10 questions, with descriptive analyses and nonparametric comparisons between program variables and ASD curriculum. RESULTS: The response rate was 42.18%, with FM PDs reporting that their programs were preparing residents in the care of youth (71.53%) and adults (68.33%) with ASD, but to a lesser extent (58.89%) in facilitating transitions of care. Programs with faculty champions, access to published curricula, sufficient patients with ASD, and engagement of interprofessional faculty reported a higher proportion of resident preparedness. PDs of community-based programs were most confident in their ability to teach ASD care and transitions of care. CONCLUSIONS: Most FM PDs modestly agreed that they are preparing residents to provide care to patients with ASD and their families. PDs of programs with greater access to resources (ie, published curriculum, faculty champions, sufficient patients with ASD, interprofessional faculty experts) believed that their residents were more prepared. Community-based FM educators may help lead the way in providing models for care and education in this regard.

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9. Wang L, Xu M, Wang Y, Wang F, Deng J, Wang X, Zhao Y, Liao A, Yang F, Wang S, Li Y. Melatonin improves synapse development by PI3K/Akt signaling in a mouse model of autism spectrum disorder. Neural regeneration research. 2024; 19(7): 1618-24.

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10. Wang S, Wang B, Drury V, Drake S, Sun N, Alkhairo H, Arbelaez J, Duhn C, Bal VH, Langley K, Martin J, Hoekstra PJ, Dietrich A, Xing J, Heiman GA, Tischfield JA, Fernandez TV, Owen MJ, O’Donovan MC, Thapar A, State MW, Willsey AJ. Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD. Nature communications. 2023; 14(1): 8077.

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of « male vulnerability », rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of « idiopathic » ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

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11. Wright D, Kenny A, Mizen LAM, McKechanie AG, Stanfield AC. Profiling Autism and Attention Deficit Hyperactivity Disorder Traits in Children with SYNGAP1-Related Intellectual Disability. Journal of autism and developmental disorders. 2023.

SYNGAP1-related ID is a genetic condition characterised by global developmental delay and epilepsy. Individuals with SYNGAP1-related ID also commonly show differences in attention and social communication/interaction and frequently receive additional diagnoses of Autism Spectrum Disorder (ASD) or Attention Deficit Hyperactivity Disorder (ADHD). We thus set out to quantify ASD and ADHD symptoms in children with this syndrome. To assess ASD and ADHD, parents and caregivers of a child with SYNGAP1-related ID (N = 34) or a typically developing control (N = 21) completed the Social Responsiveness Scale-2, the Social Communication Questionnaire with a subset of these also completing the Conners-3. We found that those with SYNGAP1-related ID demonstrated higher levels of autistic traits on both the SRS and SCQ than typically developing controls. On the SRS, those with SYNGAP1-related ID scored highest for restricted repetitive behaviours, and were least impaired in social awareness. On the Conners-3, those with SYNGAP1-related ID also showed a high prevalence of ADHD traits, with scores demonstrating difficulties with peer relations but relatively low occurrence of symptoms for DSM-5 conduct disorder and DSM-5 oppositional defiant disorder. Hierarchical clustering analysis highlighted distinct SYNGAP1-related ID subgroups for both ASD and ADHD traits. These findings provide further characterisation of the SYNGAP1-related ID behavioural phenotype, guiding diagnosis, assessment and potential interventions.

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