1. Craig F, Crippa A, De Giacomo A, Ruggiero M, Rizzato V, Lorenzo A, Fanizza I, Margari L, Trabacca A. {{Differences in Developmental Functioning Profiles Between Male and Female Preschoolers Children With Autism Spectrum Disorder}}. {Autism Res}. 2020.
This study investigated differences in clinical symptoms and developmental functioning profiles as well as sex-specific correlations of clinical characteristics and communication abilities, motor skills, and maladaptive behaviors in male and female preschoolers with autism spectrum disorder (ASD). Fifty-two females (mean age 4.5 +/- 2.16 years old) and 62 males (mean age 4.2 +/- 1.17 years old) with ASD were enrolled and assessed by measures including the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and Psychoeducational Profile-Third Edition (PEP-3). We found intellectual disability in 91.2% of the children. While preschoolers with ASD showed comparable severity of restricted and repetitive behaviors (P = 0.17), females with ASD were less severely affected than age and intelligence quotient-matched males with ASD in the ADOS-2 social affect domain (P value = 0.001) and calibrated severity scores (P = 0.002). Interestingly, sex-specific linear regressions revealed that fine motor skills were predictive of impaired social affect in males but not in females. Specifically, motor skills might be the core feature for sex differences in ASD. Although preliminary, this finding suggests the need for more sex-specific diagnostic and intervention strategies in order to improve early identification efforts and specific intervention targets. LAY SUMMARY: Little is known about differences in developmental and functional profiles in males and females with autism spectrum disorder (ASD). We found important similarities and differences in the core ASD symptoms between male and female preschoolers. In addition, fine motor skills seem to predict social affect impairment and ASD symptom severity in males with ASD.
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2. Filosi M, Kam-Thong T, Essioux L, Muglia P, Trabetti E, Spooren W, Muller-Myshok B, Domenici E. {{Transcriptome signatures from discordant sibling pairs reveal changes in peripheral blood immune cell composition in Autism Spectrum Disorder}}. {Translational psychiatry}. 2020; 10(1): 106.
Notwithstanding several research efforts in the past years, robust and replicable molecular signatures for autism spectrum disorders from peripheral blood remain elusive. The available literature on blood transcriptome in ASD suggests that through accurate experimental design it is possible to extract important information on the disease pathophysiology at the peripheral level. Here we exploit the availability of a resource for molecular biomarkers in ASD, the Italian Autism Network (ITAN) collection, for the investigation of transcriptomic signatures in ASD based on a discordant sibling pair design. Whole blood samples from 75 discordant sibling pairs selected from the ITAN network where submitted to RNASeq analysis and data analyzed by complementary approaches. Overall, differences in gene expression between affected and unaffected siblings were small. In order to assess the contribution of differences in the relative proportion of blood cells between discordant siblings, we have applied two different cell deconvolution algorithms, showing that the observed molecular signatures mainly reflect changes in peripheral blood immune cell composition, in particular NK cells. The results obtained by the cell deconvolution approach are supported by the analysis performed by WGCNA. Our report describes the largest differential gene expression profiling in peripheral blood of ASD subjects and controls conducted by RNASeq. The observed signatures are consistent with the hypothesis of immune alterations in autism and an increased risk of developing autism in subjects exposed to prenatal infections or stress. Our study also points to a potential role of NMUR1, HMGB3, and PTPRN2 in ASD.
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3. Gao F, Huang W, You Y, Huang J, Zhao J, Xue J, Kang H, Zhu Y, Hu Z, Allen EG, Jin P, Xia K, Duan R. {{Development of Chinese genetic reference panel for Fragile X Syndrome and its application to the screen of 10,000 Chinese pregnant women and women planning pregnancy}}. {Molecular genetics & genomic medicine}. 2020: e1236.
BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability caused by a CGG repeat expansion in the 5′ untranslated region of the FMR1 gene. When the number of repeats exceeds 200, the gene becomes hypermethylated and is transcriptionally silenced, resulting in FXS. Other allelic forms of the gene that are studied because of their instability or phenotypic consequence include intermediate alleles (45-54 CGG repeats) and premutation alleles (55-200 repeats). Normal alleles are classified as having <45 CGG repeats. Population screening studies have been conducted among American and Australian populations; however, large population-based studies have not been completed in China. METHODS AND RESULTS: In this work we present FXS screening results from 10,145 women of childbearing age from China. We first created and tested a standard panel that was comprised of normal, intermediate, premutation, and full mutation samples, and we performed the screening after confirming the consistency of genotyping results among laboratories. CONCLUSION: Based on our findings, we have determined the intermediate and premutation carrier prevalence of 1/130 and 1/634, respectively, among Chinese women. Lien vers le texte intégral (Open Access ou abonnement)
4. Garre JM, Silva HM, Lafaille JJ, Yang G. {{P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice}}. {Nat Commun}. 2020; 11(1): 1784.
Dysregulated immunity has been implicated in the pathogenesis of neurodevelopmental disorders but its contribution to synaptic and behavioral deficits in Rett syndrome (RTT) remains unknown. P2X7 receptors (P2X7Rs) are unique purinergic receptors with pro-inflammatory functions. Here, we report in a MECP2-deficient mouse model of RTT that the border of the cerebral cortex exhibits increased number of inflammatory myeloid cells expressing cell-surface P2X7Rs. Total knockout of P2X7Rs in MECP2 deficient mice decreases the number of inflammatory myeloid cells, restores cortical dendritic spine dynamics, and improves the animals’ neurological function and social behavior. Furthermore, either genetic depletion of P2X7Rs in bone-marrow derived leukocytes or pharmacological block of P2X7Rs primarily outside of the central nervous system parenchyma, recapitulates the beneficial effects of total P2X7R depletion on the social behavior. Together, our results highlight the pathophysiological roles of P2X7Rs in a mouse model of RTT.
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5. Hilvert E, Hoover J, Sterling A, Schroeder S. {{Comparing Tense and Agreement Productivity in Boys With Fragile X Syndrome, Children With Developmental Language Disorder, and Children With Typical Development}}. {Journal of speech, language, and hearing research : JSLHR}. 2020: 1-14.
Purpose This study compared and characterized the tense and agreement productivity of boys with fragile X syndrome (FXS), children with developmental language disorder (DLD), and children with typical development (TD) matched on mean length of utterance. Method Twenty-two boys with FXS (M age = 12.22 years), 19 children with DLD (M age = 4.81 years), and 20 children with TD (M age = 3.23 years) produced language samples that were coded for their productive use of five tense markers (i.e., third-person singular, past tense -ed, copula BE, auxiliary BE, and auxiliary DO) using the tense and agreement productivity score. Children also completed norm-referenced cognitive and linguistic assessments. Results Children with DLD generally used tense and agreement markers less productively than children with TD, particularly third-person singular and auxiliary BE. However, boys with FXS demonstrated a more complicated pattern of productivity, where they were similar to children with DLD and TD, depending on the tense marker examined. Results revealed that children with DLD and TD showed a specific developmental sequence of the individual tense markers that aligns with patterns documented by previous studies, whereas boys with FXS demonstrated a more even profile of productivity. Conclusions These findings help to further clarify areas of overlap and discrepancy in tense and agreement productivity among boys with FXS and children with DLD. Additional clinical implications of these results are discussed.
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6. Kildahl AN, Helverschou SB, Bakken TL, Oddli HW. {{« If we do not look for it, we do not see it »: Clinicians’ experiences and understanding of identifying post-traumatic stress disorder in adults with autism and intellectual disability}}. {J Appl Res Intellect Disabil}. 2020.
BACKGROUND: Individuals with autism spectrum disorder (ASD) and intellectual disability (ID) are at increased risk of potentially traumatic events and may be at increased risk of post-traumatic stress disorder (PTSD). However, knowledge regarding identification of PTSD in this population is limited. The aim of this study was to investigate clinical experience regarding PTSD and trauma assessment in individuals with co-occurring ASD and ID. METHOD: Interpretative phenomenological analysis was used to explore experiences of identifying PTSD in this population among 18 mental health clinicians working with ASD and ID. RESULTS: Informants viewed PTSD in individuals with ASD and ID as equivalent to PTSD in the general population, but with causes and expressions potentially differing. Several factors were described to contribute to challenges in identification. CONCLUSIONS: Trauma may have severe impact in individuals with ASD and ID. Multidimensional, individualized assessment strategies seem necessary to recognize PTSD or trauma-related symptoms in this population.
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7. Nottingham CL, Vladescu JC, DeBar RM, Deshais M, DeQuinzio J. {{The influence of instructive feedback presentation schedule: A replication with children with autism spectrum disorder}}. {Journal of applied behavior analysis}. 2020.
Instructive feedback (IF) is a modification to discrete trial instruction that may increase instructional efficiency for individuals with autism spectrum disorder. Several variations of IF have recently been evaluated in the literature; however, few studies have assessed the effectiveness and efficiency of presenting secondary targets on continuous versus intermittent presentation schedules. The current study evaluated the effectiveness and efficiency of various presentation schedules of secondary targets during discrete trial instruction. Specifically, we replicated and extended Griffen et al. (1998) by comparing a condition in which secondary targets were presented during each trial of a session, a condition in which secondary targets were presented every other trial, and a condition in which secondary targets were presented about every 4 trials. Within-subject replications were included for both participants. One of the intermittent presentation schedules was associated with the most optimal outcomes in all 4 comparisons.
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8. Sauna-Aho O, Bjelogrlic-Laakso N, Rautava P, Arvio M. {{Ageing and cognition in men with fragile X syndrome}}. {J Appl Res Intellect Disabil}. 2020.
BACKGROUND: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. The aim of our longitudinal study was to describe ageing-related cognitive changes in men with FXS. METHOD: A neuropsychologist determined the raw scores (RSs) of 19 men with FXS twice with the Leiter International Performance Scale at an average interval of 22 years. The ages of the participants at baseline ranged from 16 to 50 (mean 27) years. RESULTS: At follow-up, the RSs improved in two men, remained the same in two men and declined in 15 men. Overall, the RS of the study group deteriorated by an average 4 points in RSs (p < .001). CONCLUSION: Cognitive ageing in men with FXS started earlier than that in men in the general population; in many cases, cognitive ageing in men with FXS began before middle age, usually without any medical or other underlying cause. Lien vers le texte intégral (Open Access ou abonnement)
9. Schnabel A, Hallford DJ, Stewart M, McGillivray JA, Forbes D, Austin DW. {{An Initial Examination of Post-Traumatic Stress Disorder in Mothers of Children with Autism Spectrum Disorder: Challenging Child Behaviors as Criterion A Traumatic Stressors}}. {Autism Res}. 2020.
Parenting a child with autism spectrum disorder (ASD) is associated with high levels of stress. Several studies have conceptualized this as a traumatic stress response to challenging child behaviors such as self-harm, suicidal ideation, and physical aggression toward caregivers. In the present study, we explored the relevance of a trauma-based diagnostic framework to a sample of 30 mothers (M age = 42.97, SD = 5.82) of children with ASD (M age = 12.43, SD = 3.15). Participants were interviewed using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for post-traumatic stress disorder (PTSD) and an abbreviated Mini International Neuropsychiatric Interview to assess for comorbidity. Three participants were excluded as they met criteria for PTSD from a traumatic event unrelated to their parenting experience. Of the remaining 27 participants, 6 (22.2%) met criteria for PTSD in the context of traumatic parenting experiences. Descriptions of traumatic events experienced are summarized. Results suggest that, for some parents, challenging child behaviors such as physical violence toward the caregiver from the child, self-injurious behaviors, and suicidal behaviors function as traumatic stressors as per Criterion A of PTSD (American Psychiatric Association [2013]. Diagnostic and statistical manual of mental disorders [DSM-5]. Arlington, VA). This has implications for health professionals engaged with parents of children with ASD, who should consider the possibility of PTSD when challenging behaviors of a potentially traumatic nature are present. Autism Res 2020. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study found that some challenging behaviors exhibited by children with autism spectrum disorder can be traumatic for parents and lead to the development of post-traumatic stress disorder. Some of these behaviors included self-harming behaviors like head banging, expressing suicidal urges, and becoming physically aggressive toward parents during meltdowns.
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10. Wilson RB, Elashoff D, Gouelle A, Smith BA, Wilson AM, Dickinson A, Safari T, Hyde C, Jeste SS. {{Quantitative Gait Analysis in Duplication 15q Syndrome and Nonsyndromic ASD}}. {Autism Res}. 2020.
Motor impairments occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD) and in individuals with ASD without a genetic diagnosis (nonsyndromic ASD). In particular, abnormalities in gait in ASD have been linked to language delay, ASD severity, and likelihood of having a genetic disorder. Quantitative measures of motor function can improve our ability to evaluate motor differences in individuals with syndromic and nonsyndromic ASD with varying levels of intellectual disability and adaptive skills. To evaluate this methodology, we chose to use quantitative gait analysis to study duplication 15q syndrome (dup15q syndrome), a genetic disorder highly penetrant for motor delays, intellectual disability, and ASD. We evaluated quantitative gait variables in individuals with dup15q syndrome (n = 39) and nonsyndromic ASD (n = 21) and compared these data to a reference typically developing cohort. We found a gait pattern of slow pace, poor postural control, and large gait variability in dup15q syndrome. Our findings improve characterization of motor function in dup15q syndrome and nonsyndromic ASD. Quantitative gait analysis can be used as a translational method and can improve our identification of clinical endpoints to be used in treatment trials for these syndromes. LAY SUMMARY: Motor impairments, particularly abnormalities in walking, occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD). Here, using quantitative gait analysis, we find that individuals with duplication 15q syndrome have an atypical gait pattern that differentiates them from typically developing and nonsyndromic ASD individuals. Our findings improve motor characterization in dup15q syndrome and nonsyndromic ASD. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Xu ZX, Kim GH, Tan JW, Riso AE, Sun Y, Xu EY, Liao GY, Xu H, Lee SH, Do NY, Lee CH, Clipperton-Allen AE, Kwon S, Page DT, Lee KJ, Xu B. {{Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations}}. {Nat Commun}. 2020; 11(1): 1797.
Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.
