1. 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 (Apr 23)

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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2. Curie A, Lion-François L, Valayannopoulos V, Perreton N, Gavanon M, Touil N, Brun-Laurisse A, Gheurbi F, Buchy M, Halep H, Cheillan D, Mercier C, Brassier A, Desnous B, Kassai B, De Lonlay P, Des Portes V. Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8). Neurology;2024 (Apr 23);102(8):e209243.

BACKGROUND AND OBJECTIVES: Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials. METHODS: As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software. RESULTS: Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence. DISCUSSION: In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials. TRIAL REGISTRATION INFORMATION: ANSM Registration Number 2010-A00327-32.

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3. Dear R, Wagstyl K, Seidlitz J, Markello RD, Arnatkevičiūtė A, Anderson KM, Bethlehem RAI, Raznahan A, Bullmore ET, Vértes PE. Cortical gene expression architecture links healthy neurodevelopment to the imaging, transcriptomics and genetics of autism and schizophrenia. Nat Neurosci;2024 (Apr 22)

Human brain organization involves the coordinated expression of thousands of genes. For example, the first principal component (C1) of cortical transcription identifies a hierarchy from sensorimotor to association regions. In this study, optimized processing of the Allen Human Brain Atlas revealed two new components of cortical gene expression architecture, C2 and C3, which are distinctively enriched for neuronal, metabolic and immune processes, specific cell types and cytoarchitectonics, and genetic variants associated with intelligence. Using additional datasets (PsychENCODE, Allen Cell Atlas and BrainSpan), we found that C1-C3 represent generalizable transcriptional programs that are coordinated within cells and differentially phased during fetal and postnatal development. Autism spectrum disorder and schizophrenia were specifically associated with C1/C2 and C3, respectively, across neuroimaging, differential expression and genome-wide association studies. Evidence converged especially in support of C3 as a normative transcriptional program for adolescent brain development, which can lead to atypical supragranular cortical connectivity in people at high genetic risk for schizophrenia.

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4. Delling JP, Bauer HF, Gerlach-Arbeiter S, Schön M, Jacob C, Wagner J, Pedro MT, Knöll B, Boeckers TM. Combined expansion and STED microscopy reveals altered fingerprints of postsynaptic nanostructure across brain regions in ASD-related SHANK3-deficiency. Mol Psychiatry;2024 (Apr 22)

Synaptic dysfunction is a key feature of SHANK-associated disorders such as autism spectrum disorder, schizophrenia, and Phelan-McDermid syndrome. Since detailed knowledge of their effect on synaptic nanostructure remains limited, we aimed to investigate such alterations in ex11|SH3 SHANK3-KO mice combining expansion and STED microscopy. This enabled high-resolution imaging of mosaic-like arrangements formed by synaptic proteins in both human and murine brain tissue. We found distinct shape-profiles as fingerprints of the murine postsynaptic scaffold across brain regions and genotypes, as well as alterations in the spatial and molecular organization of subsynaptic domains under SHANK3-deficient conditions. These results provide insights into synaptic nanostructure in situ and advance our understanding of molecular mechanisms underlying synaptic dysfunction in neuropsychiatric disorders.

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5. Honybun E, Cockle E, Malpas CB, O’Brien TJ, Vajda FJ, Perucca P, Rayner G. Neurodevelopmental and Functional Outcomes Following In Utero Exposure to Antiseizure Medication: A Systematic Review. Neurology;2024 (Apr 23);102(8):e209175.

BACKGROUND AND OBJECTIVES: To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal neurodevelopmental outcomes, focusing on social, emotional, behavioral, and adaptive domains of human function, and the frequency of neurodevelopmental and psychiatric disorders in ASM-exposed offspring. METHODS: Electronic searches of MEDLINE, PsychINFO, and EMBASE were conducted and limited to studies published between 1990 and 2023 in English. Studies were eligible if they prospectively or retrospectively reported neurodevelopmental outcomes of ASM-exposed offspring. The Newcastle-Ottawa scale was used to conduct methodologic quality assessments of included studies, and a narrative synthesis integrated the review findings. RESULTS: Forty-three studies were included. Valproate has been consistently associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), 2- to 5-fold increased risk of intellectual disability (ID), and poor adaptive functioning. Growing evidence indicates that topiramate is associated with a 2-fold increased risk of ASD and 3- to 4-fold increased risk of ID. The risks of adverse neurodevelopmental outcomes for valproate and topiramate seem to be dose dependent. Phenobarbital has been suggested to be associated with deleterious neurodevelopmental effects, but data are limited. Levetiracetam has recently been linked with an increased risk of attention deficit hyperactivity disorder and anxiety disorders in a single study. Carbamazepine has been associated with variable neurodevelopmental outcomes. Lamotrigine seems to be « safe » in terms of postnatal neurodevelopment. Data for oxcarbazepine, phenytoin, and clonazepam are limited but seem to have little-to-no risk of adverse outcomes. Evidence for the remaining ASMs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. Several methodologic limitations impeded data synthesis, including heterogeneity in outcome measures and small samples of monotherapy exposures. DISCUSSION: The findings of this review support the conclusion that valproate and topiramate use during pregnancy is associated with a significantly increased risk of neurodevelopmental effects on the fetus. Apart from lamotrigine, which seems to be free of adverse neurodevelopmental effects, data for the other ASMs are mixed or inadequate to draw definite conclusions. Further research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed.

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6. Khan H, Harripaul R, Mikhailov A, Herzi S, Bowers S, Ayub M, Shabbir MI, Vincent JB. Biallelic variants identified in 36 Pakistani families and trios with autism spectrum disorder. Sci Rep;2024 (Apr 22);14(1):9230.

With its high rate of consanguineous marriages and diverse ethnic population, little is currently understood about the genetic architecture of autism spectrum disorder (ASD) in Pakistan. Pakistan has a highly ethnically diverse population, yet with a high proportion of endogamous marriages, and is therefore anticipated to be enriched for biallelic disease-relate variants. Here, we attempt to determine the underlying genetic abnormalities causing ASD in thirty-six small simplex or multiplex families from Pakistan. Microarray genotyping followed by homozygosity mapping, copy number variation analysis, and whole exome sequencing were used to identify candidate. Given the high levels of consanguineous marriages among these families, autosomal recessively inherited variants were prioritized, however de novo/dominant and X-linked variants were also identified. The selected variants were validated using Sanger sequencing. Here we report the identification of sixteen rare or novel coding variants in fifteen genes (ARAP1, CDKL5, CSMD2, EFCAB12, EIF3H, GML, NEDD4, PDZD4, POLR3G, SLC35A2, TMEM214, TMEM232, TRANK1, TTC19, and ZNF292) in affected members in eight of the families, including ten homozygous variants in four families (nine missense, one loss of function). Three heterozygous de novo mutations were also identified (in ARAP1, CSMD2, and NEDD4), and variants in known X-linked neurodevelopmental disorder genes CDKL5 and SLC35A2. The current study offers information on the genetic variability associated with ASD in Pakistan, and demonstrates a marked enrichment for biallelic variants over that reported in outbreeding populations. This information will be useful for improving approaches for studying ASD in populations where endogamy is commonly practiced.

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7. Le Dréan ME, Le Berre-Scoul C, Paillé V, Caillaud M, Oullier T, Gonzales J, Hulin P, Neunlist M, Talon S, Boudin H. The regulation of enteric neuron connectivity by semaphorin 5A is affected by the autism-associated S956G missense mutation. iScience;2024 (May 17);27(5):109638.

The neural network of the enteric nervous system (ENS) underlies gastrointestinal functions. However, the molecular mechanisms involved in enteric neuronal connectivity are poorly characterized. Here, we studied the role of semaphorin 5A (Sema5A), previously characterized in the central nervous system, on ENS neuronal connectivity. Sema5A is linked to autism spectrum disorder (ASD), a neurodevelopmental disorder frequently associated with gastrointestinal comorbidities, and potentially associated with ENS impairments. This study investigated in rat enteric neuron cultures and gut explants the role of Sema5A on enteric neuron connectivity and the impact of ASD-associated mutations on Sema5A activity. Our findings demonstrated that Sema5A promoted axonal complexity and reduced functional connectivity in enteric neurons. Strikingly, the ASD-associated mutation S956G in Sema5A strongly affected these activities. This study identifies a critical role of Sema5A in the ENS as a regulator of neuronal connectivity that might be compromised in ASD.

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8. Luongo M, Simeoli R, Marocco D, Milano N, Ponticorvo M. Enhancing early autism diagnosis through machine learning: Exploring raw motion data for classification. PLoS One;2024;19(4):e0302238.

In recent years, research has been demonstrating that movement analysis, utilizing machine learning methods, can be a promising aid for clinicians in supporting autism diagnostic process. Within this field of research, we aim to explore new models and delve into the detailed observation of certain features that previous literature has identified as prominent in the classification process. Our study employs a game-based tablet application to collect motor data. We use artificial neural networks to analyze raw trajectories in a « drag and drop » task. We compare a two-features model (utilizing only raw coordinates) with a four-features model (including velocities and accelerations). The aim is to assess the effectiveness of raw data analysis and determine the impact of acceleration on autism classification. Our results revealed that both models demonstrate promising accuracy in classifying motor trajectories. The four-features model consistently outperforms the two-features model, as evidenced by accuracy values (0.90 vs. 0.76). However, our findings support the potential of raw data analysis in objectively assessing motor behaviors related to autism. While the four-features model excels, the two-features model still achieves reasonable accuracy. Addressing limitations related to sample size and noise is essential for future research. Our study emphasizes the importance of integrating intelligent solutions to enhance and assist autism traditional diagnostic process and intervention, paving the way for more effective tools in assessing motor skills.

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9. Minhas A, Whitlock K, Rosenfelt C, Shatto J, Finlay B, Zwicker J, Lippe S, Jacquemont S, Hagerman R, Murias K, Bolduc FV. Analyzing the Quality of Life in Individuals with Fragile X Syndrome in Relation to Sleep and Mental Health. J Autism Dev Disord;2024 (Apr 23)

The purpose of this paper was to examine the physical, emotional, social and school functioning domains of quality of life of individuals with Fragile X Syndrome, in relation to mental health and sleep patterns to gain a better understanding of how these aspects are affected by the disorder. This study included 119 individuals with Fragile X Syndrome who were given different cognitive examinations by a neuropsychologist or by parent-proxy questionnaires. This study focused on the Pediatric Quality of Life Inventory (PedsQoL), the Anxiety, Depression and Mood Scale (ADAMS), the Children’s Sleep Habits Questionnaire (CSHQ), but did include other cognitive tests (Vineland Adaptive Behaviour Scales, Nonverbal IQ, Autism Diagnostic Observation Schedule). We identified significant associations between decreases in emotional, social and school domains of PedsQoL and the ADAMS subtests of Generalized Anxiety, Manic/Hyperactivity and Obsessive/Compulsivity, with the subtest of Depressed Mood having associations with lower physical and emotional domains. We also identified a significant impact between CSHQ subtests of Sleep Anxiety, Night Wakings, Daytime Sleepiness, and Parasomnia with the emotional and school domains of PedsQoL. There were associations connecting school functioning with Bedtime Resistance, and additional associations connecting emotional functioning with Sleep Duration and Sleep Onset Delay. Physical functioning was also associated with Sleep Anxiety. Our study shows how mental health and sleep defects impact improper sleep patterns and mental health which leads to decreases in the quality of life for individuals with FXS, and how it is important to screen for these symptoms in order to alleviate issues.

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10. Nasir AK, Strong-Bak W, Bernard M. Diagnostic Evaluation of Autism Spectrum Disorder in Pediatric Primary Care. J Prim Care Community Health;2024 (Jan-Dec);15:21501319241247997.

BACKGROUND AND OBJECTIVES: Children with autism spectrum disorder (ASD) continue to experience significant delays in diagnosis and interventions. One of the main factors contributing to this delay is a shortage of developmental-behavioral specialists. Diagnostic evaluation of ASD by primary care pediatricians (PCPs) has been shown to be reliable and to decrease the interval from first concern to diagnosis. In this paper, we present the results of a primary care ASD diagnosis program in which the PCP serves as the primary diagnostician and leverages the infrastructure of the primary care medical home to support the child and family during the pre- and post-diagnostic periods, along with data on parental satisfaction with this model. METHODS: Retrospective data from a cohort of patients evaluated through this program were analyzed to determine the mean age at diagnosis and interval from referral for evaluation to diagnosis. We used survey methodology to obtain data from parents regarding their satisfaction with the process. RESULTS: Data from 8 of 20 children evaluated from April 2021 through May 2022 showed a median age of diagnosis of 34.5 months compared to the national average of 49 months. Mean interval from referral for evaluation to diagnosis was 3.5 months. Parental survey responses indicated high satisfaction. CONCLUSIONS: This model was successful in shortening the interval from referral to diagnosis resulting in significant decrease of age at diagnosis compared with the national average. Widespread implementation could improve access to timely diagnostic services and improve outcomes for children with ASD.

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11. O’Loghlen J, McKenzie M, Lang C, Paynter J. Repetitive Behaviors in Autism and Obsessive-Compulsive Disorder: A Systematic Review. J Autism Dev Disord;2024 (Apr 23)

PURPOSE: Obsessive-compulsive disorder (OCD) and autism are characterized by the presence of repetitive behaviors. Differentiating between repetitive behaviors attributable to a diagnosis of autism, and those attributable to OCD, poses challenges for differential and co-occurring diagnosis. Differentiation is important to inform appropriate supports and interventions for phenotypically similar but functionally distinct behaviors. In this systematic review, the quantitative literature was examined to explore the similarities and differences in repetitive behaviors (including restricted and repetitive behaviors and interests, and obsessive-compulsive behaviors) in autistic individuals and those with OCD, and those with co-occurring diagnoses, in terms of: (1) expression, (2) content, and (3) associated factors. METHODS: Thirty-one studies were identified that compared repetitive behaviors in autistic individuals, individuals with OCD, or individuals with both diagnoses. RESULTS: The results suggest considerable overlap in the intensity and content of repetitive behaviors between groups. The findings of this review highlight that research aimed specifically at understanding similarities and differences in repetitive behaviors between autistic individuals and individuals with OCD is limited and frequently only compare at total score or composite measure levels. CONCLUSION: Further research into differences in the presentation of repetitive behaviors at a subscale and item level is required to inform clearer differentiation of specific behaviors in autism versus OCD. Understanding and more accurately differentiating is essential for efficient diagnosis, effective treatment, and better outcomes.

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12. Shan G, Wang HT, Juan CY, Chang CH. Using a visual support package to facilitate independent leisure engagement and choice-making for individuals with moderate to severe autism in Taiwan. Autism;2024 (Apr 22):13623613241245596.

Self-determination encompasses various components, including decision-making and independence, making it a complex process. While the importance of self-determination for individuals with autism spectrum disorder has been explored in previous studies, there is limited research focusing on individuals with moderate to severe autism spectrum disorder. Evidence-based practices such as visual activity schedules and video modeling have shown effectiveness in promoting independence among individuals with autism spectrum disorder. To address the need for independence and choice-making among individuals with moderate to severe autism spectrum disorder, this study developed a visual support package incorporating visual activity schedules, video modeling, preference assessments, and prompt procedures. By investigating the intervention’s effectiveness in three participants, this study contributes to the existing literature on the use of a visual activity schedule and video modeling in enhancing choice-making and independent leisure engagement. Following the intervention, all participants were able to select three leisure activities, develop their own visual schedules, and complete them. Notably, this study conducted preference assessments to determine participants’ preferred leisure activities and did not provide additional reinforcement. Practical implications of this research include incorporating video prompting as needed and adjusting activity engagement time. Future research should explore the long-term effectiveness of the visual support package and its application in developing novel skills or vocational activities for individuals with moderate to severe autism spectrum disorder. This study fills a critical gap in the literature, providing important insights for practices and research in the field of autism spectrum disorder interventions.

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13. Tsang T, Green SA, Liu J, Lawrence K, Jeste S, Bookheimer SY, Dapretto M. Salience network connectivity is altered in 6-week-old infants at heightened likelihood for developing autism. Commun Biol;2024 (Apr 22);7(1):485.

Converging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network – an early-emerging neural network involved in orienting attention to the most salient aspects of one’s internal and external environment – may predict the development of ASD symptoms such as reduced social attention and atypical sensory processing. Six-week-old infants at high likelihood of developing ASD based on family history exhibited stronger Salience Network connectivity with sensorimotor regions; infants at typical likelihood of developing ASD demonstrated stronger Salience Network connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in Salience Network connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with vulnerability to ASD.

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14. Zhao C, Ong JH, Veic A, Patel AD, Jiang C, Fogel AR, Wang L, Hou Q, Das D, Crasto C, Chakrabarti B, Williams TI, Loutrari A, Liu F. Predictive processing of music and language in autism: Evidence from Mandarin and English speakers. Autism Res;2024 (Apr 23)

Atypical predictive processing has been associated with autism across multiple domains, based mainly on artificial antecedents and consequents. As structured sequences where expectations derive from implicit learning of combinatorial principles, language and music provide naturalistic stimuli for investigating predictive processing. In this study, we matched melodic and sentence stimuli in cloze probabilities and examined musical and linguistic prediction in Mandarin- (Experiment 1) and English-speaking (Experiment 2) autistic and non-autistic individuals using both production and perception tasks. In the production tasks, participants listened to unfinished melodies/sentences and then produced the final notes/words to complete these items. In the perception tasks, participants provided expectedness ratings of the completed melodies/sentences based on the most frequent notes/words in the norms. While Experiment 1 showed intact musical prediction but atypical linguistic prediction in autism in the Mandarin sample that demonstrated imbalanced musical training experience and receptive vocabulary skills between groups, the group difference disappeared in a more closely matched sample of English speakers in Experiment 2. These findings suggest the importance of taking an individual differences approach when investigating predictive processing in music and language in autism, as the difficulty in prediction in autism may not be due to generalized problems with prediction in any type of complex sequence processing.

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