1. Chen P, Liu Z, Zhang Q, Lin D, Song L, Liu J, Jiao HF, Lai X, Zou S, Wang S, Zhou T, Li BM, Zhu L, Pan BX, Fei E. DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2022; 42(4): 532-51.

Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1β (NRXN1β) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs.SIGNIFICANCE STATEMENT DSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1β interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.

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2. Contractor A, Ethell IM, Portera-Cailliau C. Cortical interneurons in autism. Nature neuroscience. 2021; 24(12): 1648-59.

The mechanistic underpinnings of autism remain a subject of debate and controversy. Why do individuals with autism share an overlapping set of atypical behaviors and symptoms, despite having different genetic and environmental risk factors? A major challenge in developing new therapies for autism has been the inability to identify convergent neural phenotypes that could explain the common set of symptoms that result in the diagnosis. Although no striking macroscopic neuropathological changes have been identified in autism, there is growing evidence that inhibitory interneurons (INs) play an important role in its neural basis. In this Review, we evaluate and interpret this evidence, focusing on recent findings showing reduced density and activity of the parvalbumin class of INs. We discuss the need for additional studies that investigate how genes and the environment interact to change the developmental trajectory of INs, permanently altering their numbers, connectivity and circuit engagement.

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3. Cygan HB, Nowicka MM, Nowicka A. Impaired attentional bias toward one’s own face in autism spectrum disorder: ERP evidence. Autism research : official journal of the International Society for Autism Research. 2022; 15(2): 241-53.

Converging lines of evidence seem to indicate reduced self-referential processing in individuals with autism spectrum disorder (ASD). However, processing of one’s own face has rarely been investigated in the context of ASD. Thus, the aim of the present study was to elucidate the role of attentional biases in the processing of self- and other faces in ASD. To achieve this goal we presented participants with images of their own face, the face of a close-other, and famous and unknown faces in a Stroop-like paradigm. Participants (22 with ASD, 22 typically developing [TD]) were instructed to indicate the color of presented faces while EEG was recorded. Our event-related potential results clearly showed that self-face was associated with larger P3 amplitudes than all other faces in the TD group, thus indicating a strong attentional bias toward one’s own face. In the ASD group, P3 to the self-face and the close-other’s face did not differ, suggesting similar attentional biases in both cases. In line with these P3 findings, nonparametric cluster-based permutation tests showed an analogous pattern of results: significant clusters for the self-face compared with all other faces in the TD group, and no significant cluster in the ASD group. Overall, our findings revealed impaired attentional bias to one’s own face and diminished self versus other differentiation in individuals with ASD. The similar neural underpinnings of the self-face and other faces supports previous findings indicating reduced self-prioritization among individuals with ASD.

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4. Garcia BJ, Simha R, Garvin M, Furches A, Jones P, Gazolla J, Hyatt PD, Schadt CW, Pelletier D, Jacobson D. A k-mer based approach for classifying viruses without taxonomy identifies viral associations in human autism and plant microbiomes. Computational and structural biotechnology journal. 2021; 19: 5911-9.

Viruses are an underrepresented taxa in the study and identification of microbiome constituents; however, they play an essential role in health, microbiome regulation, and transfer of genetic material. Only a few thousand viruses have been isolated, sequenced, and assigned a taxonomy, which limits the ability to identify and quantify viruses in the microbiome. Additionally, the vast diversity of viruses represents a challenge for classification, not only in constructing a viral taxonomy, but also in identifying similarities between a virus’ genotype and its phenotype. However, the diversity of viral sequences can be leveraged to classify their sequences in metagenomic and metatranscriptomic samples, even if they do not have a taxonomy. To identify and quantify viruses in transcriptomic and genomic samples, we developed a dynamic programming algorithm for creating a classification tree out of 715,672 metagenome viruses. To create the classification tree, we clustered proportional similarity scores generated from the k-mer profiles of each of the metagenome viruses to create a database of metagenomic viruses. The resulting Kraken2 database of the metagenomic viruses can be found here: https://www.osti.gov/biblio/1615774 and is compatible with Kraken2. We then integrated the viral classification database with databases created with genomes from NCBI for use with ParaKraken (a parallelized version of Kraken provided in Supplemental Zip 1), a metagenomic/transcriptomic classifier. To illustrate the breadth of our utility for classifying metagenome viruses, we analyzed data from a plant metagenome study identifying genotypic and compartment specific differences between two Populus genotypes in three different compartments. We also identified a significant increase in abundance of eight viral sequences in post mortem brains in a human metatranscriptome study comparing Autism Spectrum Disorder patients and controls. We also show the potential accuracy for classifying viruses by utilizing both the JGI and NCBI viral databases to identify the uniqueness of viral sequences. Finally, we validate the accuracy of viral classification with NCBI databases containing viruses with taxonomy to identify pathogenic viruses in known COVID-19 and cassava brown streak virus infection samples. Our method represents the compulsory first step in better understanding the role of viruses in the microbiome by allowing for a more complete identification of sequences without taxonomy. Better classification of viruses will improve identifying associations between viruses and their hosts as well as viruses and other microbiome members. Despite the lack of taxonomy, this database of metagenomic viruses can be used with any tool that utilizes a taxonomy, such as Kraken, for accurate classification of viruses.

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5. Guivarch J, Jouve E, Avenel E, Poinso F, Conforti-Roussel L. Effect of physical therapy on 7- to 10-year-old children with autism spectrum disorder: A retrospective study in a university day hospital. Bulletin of the Menninger Clinic. 2021; 85(4): 385-404.

More than half of children who have autism spectrum disorder (ASD) suffer from motor impairment. In a retrospective study, the authors investigated the effect of a body-mediated workshop with dance movement therapy (DMT) on the motor skills and social skills of children with ASD by comparing 10 autistic children aged 7 to 10 years who benefited from DMT with 10 autistic children in a control group. Scores on the Movement Assessment Battery for Children and the Vineland Adaptive Behavior Scale were compared. The body-mediated workshop had significant benefits for motricity, especially manual dexterity, and for relational skills. A body-mediated workshop may have a multimodal effect and requires transmodal training. Regarding the mechanisms that explain the benefits and the cascading effect, the roles of imitation and multimodal connections are important.

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6. Hao K, Chen Y, Yan X, Zhu X. Cilia locally synthesize proteins to sustain their ultrastructure and functions. Nature communications. 2021; 12(1): 6971.

Cilia are microtubule-based hair-like organelles propelling locomotion and extracellular liquid flow or sensing environmental stimuli. As cilia are diffusion barrier-gated subcellular compartments, their protein components are thought to come from the cell body through intraflagellar transport or diffusion. Here we show that cilia locally synthesize proteins to maintain their structure and functions. Multicilia of mouse ependymal cells are abundant in ribosomal proteins, translation initiation factors, and RNA, including 18 S rRNA and tubulin mRNA. The cilia actively generate nascent peptides, including those of tubulin. mRNA-binding protein Fmrp localizes in ciliary central lumen and appears to function in mRNA delivery into the cilia. Its depletion by RNAi impairs ciliary local translation and induces multicilia degeneration. Expression of exogenous Fmrp, but not an isoform tethered to mitochondria, rescues the degeneration defects. Therefore, local translation defects in cilia might contribute to the pathology of ciliopathies and other diseases such as Fragile X syndrome.

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7. Harris L, Gilmore D, Hanks C, Coury D, Moffatt-Bruce S, Garvin JH, Hand BN. « It was surprisingly equivalent to the appointment I had in person »: Advantages and disadvantages of synchronous telehealth for delivering primary care for autistic adults. Autism : the international journal of research and practice. 2021: 13623613211060589.

Autistic adults face many barriers to receiving quality primary health care like clinics that are far away and sensory sensitivities. Real-time telehealth visits, called « virtual visits, » are live video chats between the patient and provider. Virtual visits may minimize barriers to care for autistic adults. We wanted to describe advantages and disadvantages of using virtual visits for delivering primary health care for autistic adults. We interviewed 7 autistic adults and 12 caregivers of autistic adults who receive primary care through one clinic. Autistic adults and caregivers said advantages to virtual visits were that (1) patients were more comfortable at home, (2) patients could get health care while avoiding physical contact with other people during the pandemic, and (3) virtual visits were similar to or better than in-person visits. The disadvantages included that (1) there could be technology problems like grainy video, (2) the doctor could not physically examine the patient (e.g. look in ears), and (3) patients sometimes participated less in the virtual visit than they would in person. Virtual visits may be beneficial for autistic adults by eliminating travel to the clinic and avoiding stressful sensory stimuli. We recognize that virtual visits may not work for all patients or in all situations. However, our study shows that primary care virtual visits may be beneficial for autistic adults during and beyond the pandemic.

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8. Katusic MZ, Myers SM, Weaver AL, Voigt RG. IQ in Autism Spectrum Disorder: A Population-Based Birth Cohort Study. Pediatrics. 2021; 148(6).

OBJECTIVES: We aimed to describe the intellectual ability and ratio of boys to girls with average or higher IQ within autism spectrum disorder (ASD) cases identified in a population-based birth cohort. We hypothesized that research-identified individuals with ASD would be more likely to have average or higher IQ, compared to clinically diagnosed ASD. We also hypothesized the male to female ratio would decrease as the definition of ASD broadened. METHODS: ASD incident cases were identified from 31 220 subjects in a population-based birth cohort. Research-defined autism spectrum disorder, inclusive criteria (ASD-RI) was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, autistic disorder (AD), Asperger Disorder, and pervasive developmental disorder not otherwise specified criteria. Research-defined autism spectrum disorder, narrow criteria (ASD-RN) was a narrower definition based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision AD criteria. Clinical diagnoses of ASD were abstracted from medical and school records. Intellectual ability was based on the last IQ score or on documented diagnoses of intellectual disability if no scores available. Average or higher IQ was defined as IQ ≥86. RESULTS: A total of 59.1% of those with ASD-RI (n = 890), 51.2% of those with ASD-RN (n = 453), and 42.8% of those with clinically diagnosed autism spectrum disorder (n = 187) had average or higher IQ. Within the ASD-RI and ASD-RN groups, boys were more likely than girls to have an average or higher IQ (62.0% vs 51.3% [P = .004] and 54.1% vs. 42.5% [P = .03], respectively). CONCLUSION: Our data suggest that nearly half of individuals with ASD have average or higher IQ. Boys with ASD are more likely to have average or higher IQ than girls. Patients with ASD and higher IQ remain at risk for not being identified.

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9. Li Z, Halls D, Byford S, Tchanturia K. Autistic characteristics in eating disorders: Treatment adaptations and impact on clinical outcomes. European eating disorders review : the journal of the Eating Disorders Association. 2021.

OBJECTIVE: Autistic people with eating disorders (EDs) may have special needs that are not met in standard ED treatment, raising the need for treatment adaptations to accommodate co-existing autism spectrum condition (ASC). Little is currently known about the nature of existing treatment options or adaptations for this population. We conducted a pre-registered systematic review to: (1) identify research articles describing existing interventions for patients with ED and comorbid ASC, and to critically review evidence of their clinical effectiveness and cost-effectiveness (Review 1); (2) review the impact of ASC comorbidity on ED clinical outcomes (Review 2). METHOD: Peer-reviewed studies published until the end of December 2020 were identified through a systematic search of the electronic databases: Medline, Embase, PsycINFO, Web of Science, CINAHL, Scopus and Cochrane Library. RESULTS: Only one clinical pathway of treatment adaptations (the ‘PEACE’ pathway) was identified in Review 1 with early evidence of cost-savings and favourable treatment outcomes. ASC characteristics were shown in Review 2 to have no direct impact on physical outcomes or ED symptoms, but could be associated with higher rates of comorbidities and greater use of intensive ED treatment. Additionally, patients with ASC characteristics may benefit more from individual sessions, rather than group sessions. CONCLUSIONS: Any new treatments or treatment adaptations may not directly impact on ED symptoms, but may be better able to support the complex needs of the ASC population, thus reducing subsequent need for intensive treatment. Future research is warranted to explore evidence of clinical and cost-effectiveness of interventions for this population.

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10. Meir N, Novogrodsky R. Referential expressions in monolingual and bilingual children with and without Autism Spectrum Disorder (ASD): A study of informativeness and definiteness. Journal of child language. 2021: 1-30.

The current study evaluated the separate and combined effects of bilingualism and Autism Spectrum Disorder (ASD) on informativeness and definiteness marking of referential expressions. Hebrew-speaking monolingual children (21 with ASD and 28 with typical language development) and Russian-Hebrew-speaking bilingual children (13 with ASD and 30 with typical language development) aged 4-9 years participated. Informativeness, indexed by referential contrasts, was affected by ASD, but not by bilingualism. Definiteness use was non-target-like in children with ASD and in bilingual children, and it was mainly predicted by children’s morpho-syntactic abilities in Hebrew. Language-universal and language-specific properties of referential use are discussed.

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11. Peck FC, Gabard-Durnam LJ, Wilkinson CL, Bosl W, Tager-Flusberg H, Nelson CA. Prediction of autism spectrum disorder diagnosis using nonlinear measures of language-related EEG at 6 and 12 months. Journal of neurodevelopmental disorders. 2021; 13(1): 57.

BACKGROUND: Early identification of autism spectrum disorder (ASD) provides an opportunity for early intervention and improved developmental outcomes. The use of electroencephalography (EEG) in infancy has shown promise in predicting later ASD diagnoses and in identifying neural mechanisms underlying the disorder. Given the high co-morbidity with language impairment, we and others have speculated that infants who are later diagnosed with ASD have altered language learning, including phoneme discrimination. Phoneme learning occurs rapidly in infancy, so altered neural substrates during the first year of life may serve as early, accurate indicators of later autism diagnosis. METHODS: Using EEG data collected at two different ages during a passive phoneme task in infants with high familial risk for ASD, we compared the predictive accuracy of a combination of feature selection and machine learning models at 6 months (during native phoneme learning) and 12 months (after native phoneme learning), and we identified a single model with strong predictive accuracy (100%) for both ages. Samples at both ages were matched in size and diagnoses (n = 14 with later ASD; n = 40 without ASD). Features included a combination of power and nonlinear measures across the 10‑20 montage electrodes and 6 frequency bands. Predictive features at each age were compared both by feature characteristics and EEG scalp location. Additional prediction analyses were performed on all EEGs collected at 12 months; this larger sample included 67 HR infants (27 HR-ASD, 40 HR-noASD). RESULTS: Using a combination of Pearson correlation feature selection and support vector machine classifier, 100% predictive diagnostic accuracy was observed at both 6 and 12 months. Predictive features differed between the models trained on 6- versus 12-month data. At 6 months, predictive features were biased to measures from central electrodes, power measures, and frequencies in the alpha range. At 12 months, predictive features were more distributed between power and nonlinear measures, and biased toward frequencies in the beta range. However, diagnosis prediction accuracy substantially decreased in the larger, more behaviorally heterogeneous 12-month sample. CONCLUSIONS: These results demonstrate that speech processing EEG measures can facilitate earlier identification of ASD but emphasize the need for age-specific predictive models with large sample sizes to develop clinically relevant classification algorithms.

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12. Qiu T, Dai Q, Wang Q. A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report. The Journal of international medical research. 2021; 49(11): 3000605211058372.

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing (trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

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13. Schwartzman JM, Smith JR, Bettis AH. Safety Planning for Suicidality in Autism: Obstacles, Potential Solutions, and Future Directions. Pediatrics. 2021; 148(6).

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14. Thi Vui L, Duc DM, Thuy Quynh N, Giang NTH, Mai VTT, Ha BTT, Van Minh H. Early screening and diagnosis of autism spectrum disorders in Vietnam: A population-based cross-sectional survey. Journal of public health research. 2021; 11(2).

BACKGROUND: Early detection of autism spectrum disorders (ASDs) is essential given the under-reported cases in low- and middle-income countries. This first national representative survey was conducted to explore the prevalence of ASDs amongst 18 and 30 months in seven provinces in Vietnam. DESIGN AND METHODS: During 2017- 2018, a national cross-sectional and population-based survey for autism spectrum disorder (ASD) amongst 40,243 children aged 18 to 30 months was conducted in 7 provinces representing the socio-economic regions of Vietnam. M-CHAT was used to screen children and then confirmed by diagnostic assessment using DSM-IV criteria. RESULTS: The prevalence of ASDs amongst children aged 18 and 30 months in Vietnam was high (0.758% or 1 in 132 children). Urban setting, male gender, and hereditable genes were associated with ASD prevalence. CONCLUSIONS: ASDs amongst children aged 18 and 30 months in Vietnam tend to be increasing and are similar to this rate in other middle-income countries but lower than that in Western countries. This under-recognized public health problem amongst children should be addressed by early detection and intervention for families with affected children.

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15. Wallace-Thompson L, Rose J. Improving support for children with autism and their families using a 100 day challenge framework. BMJ (Clinical research ed). 2021; 375: n2954.

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