1. Balta B, Gumus H, Bayramov R, Korkmaz Bayramov K, Erdogan M, Oztop DB, Dogan ME, Taheri S, Dundar M. {{Increased vitamin D receptor gene expression and rs11568820 and rs4516035 promoter polymorphisms in autistic disorder}}. {Mol Biol Rep};2018 (May 18)
Although there are a large number of sequence variants of different genes and copy number variations at various loci identified in autistic disorder (AD) patients, the pathogenesis of AD has not been elucidated completely. Recently, in AD patients, a large number of expression array and transcriptome studies have shown an increase in the expression of genes especially related to innate immune response. Antimicrobial effects of vitamin D and VDR are exerted through Toll-Like-Receptors (TLR) which have an important role in the innate immune response, are expressed by antigen presenting cells and recognize foreign microorganisms. In this study, age and gender matched 30 patients diagnosed with AD and 30 healthy controls were included in the study. Comparatively whole blood VDR gene expression and rs11568820 and rs4516035 SNP profile of the promoter region of the VDR gene were investigated by real time PCR. Whole blood VDR gene expression was significantly higher in the AD group compared to control subjects (p < 0.0001). There were no significant differences among allele and genotype distribution of rs11568820 and rs4516035 polymorphisms between AD patients and controls. The increase of VDR gene expression in patients with AD may be in accordance with an increase in the innate immune response in patients with AD. Furthermore, this study will stimulate new studies in order to clarify the relationship among AD, vitamin D, VDR, and innate immunity. Lien vers le texte intégral (Open Access ou abonnement)
2. Bennabi M, Gaman A, Delorme R, Boukouaci W, Manier C, Scheid I, Si Mohammed N, Bengoufa D, Charron D, Krishnamoorthy R, Leboyer M, Tamouza R. {{HLA-class II haplotypes and Autism Spectrum Disorders}}. {Sci Rep};2018 (May 16);8(1):7639.
Infections and autoimmunity are associated with autism spectrum disorders (ASD), with both strongly influenced by the genetic regulation of the human leukocyte antigen (HLA) system. The relationship between ASD and the HLA genetic diversity requires further investigation. Using a case control design, the distribution of HLA class II-DRB1 and DQB1 alleles, genotypes and haplotypes were investigated in ASD patients, versus healthy controls (HC). ASD patients meeting DSM-IV TR criteria and HC (474 and 350 respectively) were genotyped at medium resolution using a Luminex-based SSO technology. Comparisons of genotypes, allele frequencies associated with a haplotype analysis were performed. Results indicate: (i) the HLA-DRB1 *11-DQB1*07 haplotype was more prevalent in ASD patients, versus HC (Pc = 0.001), partially replicating previous data and possibly linking to gastro-intestinal (GI)-related pro-inflammatory processes, given that this haplotype associates with pediatric celiac disorders; (ii) the HLA-DRB1 *17-DQB1*02 haplotype was higher in HC, versus ASD patients (Pc = 0.002), indicating that this is a protective haplotype. Using the Autism Diagnostic Interview to assess clinical dimensions, higher scores on social (Pc = 0.006) and non-verbal functioning (Pc = 0.004) associated with the DRB1 *11 DQB1*07 haplotype. Our results support HLA involvement in ASD, with possible relevance to GI and gut-brain axis dysregulation.
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3. Bertilsson I, Gyllensten AL, Opheim A, Gard G, Sjodahl Hammarlund C. {{Understanding one’s body and movements from the perspective of young adults with autism: A mixed-methods study}}. {Res Dev Disabil};2018 (May 14);78:44-54.
BACKGROUND: There are but a few studies of how persons with autism perceive their bodies and movements. Difficulties in perceiving the surrounding world along with disturbed motor coordination and executive functions may affect physical and psychological development. AIMS: To explore the experiences of body and movements in young adults with autism and how two physiotherapeutic instruments may capture these experiences. PROCEDURES: Eleven young adults (16-22 years) with autism were interviewed and assessed using Bruininks-Oseretsky Test of Motor Proficiency (BOT2) and Body Awareness Scale Movement Quality and Experience (BAS MQ-E). Following a mixed- methods design, the interviews were deductively analyzed and conceptually integrated to the results of the two assessments. RESULTS: Experiencing conflicting feelings about their bodies/movements, led to low understanding of themselves. The assessments captured these experiences relatively well, presenting both movement quality and quantity. Positive experiences and better movement quality related to having access to more functional daily strategies. CONCLUSION: Combining motor proficiency and body awareness assessments was optimal to understand the participants’ experiences. IMPLICATIONS: To capture body and movement functions in persons with autism in this standardized manner will lead to improved and reliable diagnoses, tailored interventions, increased body awareness and activity, and enhanced quality of life.
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4. Harrop C, Jones D, Zheng S, Nowell S, Boyd BA, Sasson N. {{Circumscribed Interests and Attention in Autism: The Role of Biological Sex}}. {J Autism Dev Disord};2018 (May 18)
Recent studies suggest that circumscribed interests (CI) in females with Autism Spectrum Disorder (ASD) may align more closely with interests reported in typical female development than those typically reported for ASD males. We used eye-tracking to quantify attention to arrays containing combinations of male, female and neutral images in elementary-aged males and females with and without ASD. A number of condition x sex effects emerged, with both groups attending to images that corresponded with interests typically associated with their biological sex. Diagnostic effects reported in similar studies were not replicated in our modified design. Our findings of more typical attention patterns to gender-typical images in ASD females is consistent with evidence of sex differences in CI and inconsistent with the « Extreme Male Brain » theory of ASD.
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5. Kohli JS, Kinnear MK, Fong CH, Fishman I, Carper RA, Muller RA. {{Local Cortical Gyrification is Increased in Children With Autism Spectrum Disorders, but Decreases Rapidly in Adolescents}}. {Cereb Cortex};2018 (May 16)
Extensive MRI evidence indicates early brain overgrowth in autism spectrum disorders (ASDs). Local gyrification may reflect the distribution and timing of aberrant cortical expansion in ASDs. We examined MRI data from (Study 1) 64 individuals with ASD and 64 typically developing (TD) controls (7-19 years), and from (Study 2) an independent sample from the Autism Brain Imaging Data Exchange (n = 31/group). Local Gyrification Index (lGI), cortical thickness (CT), and surface area (SA) were measured. In Study 1, differences in lGI (ASD > TD) were found in left parietal and temporal and right frontal and temporal regions. lGI decreased bilaterally with age, but more steeply in ASD in left precentral, right lateral occipital, and middle frontal clusters. CT differed between groups in right perisylvian cortex (TD > ASD), but no differences were found for SA. Partial correlations between lGI and CT were generally negative, but associations were weaker in ASD in several clusters. Study 2 results were consistent, though less extensive. Altered gyrification may reflect unique information about the trajectory of cortical development in ASDs. While early overgrowth tends to be undetectable in later childhood in ASDs, findings may indicate that a trace of this developmental abnormality could remain in a disorder-specific pattern of gyrification.
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6. Lee KY, Jewett KA, Chung HJ, Tsai NP. {{Loss of Fragile X Protein FMRP Impairs Homeostatic Synaptic Downscaling through Tumor Suppressor p53 and Ubiquitin E3 Ligase Nedd4-2}}. {Hum Mol Genet};2018 (May 16)
Synaptic scaling allows neurons to homeostatically readjust synaptic strength upon chronic neural activity perturbations. Although altered synaptic scaling has been implicated to underlie imbalanced brain excitability in neurological disorders such as autism spectrum disorders and epilepsy, the molecular dysregulation and restoration of synaptic scaling in those diseases have not been demonstrated. Here, we showed that the homeostatic synaptic downscaling is absent in the hippocampal neurons of Fmr1 KO mice, the mouse model of the most common inherited autism, Fragile X Syndrome (FXS). We found that the impaired homeostatic synaptic downscaling in Fmr1 KO neurons is caused by loss-of-function dephosphorylation of an epilepsy-associated ubiquitin E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2. Such dephosphorylation of Nedd4-2 is surprisingly caused by abnormally stable tumor suppressor p53 and subsequently destabilized kinase Akt. Dephosphorylated Nedd4-2 fails to elicit 14-3-3-dependent ubiquitination and down-regulation of the GluA1 subunit of AMPA receptor, and therefore impairs synaptic downscaling. Most importantly, using a pharmacological inhibitor of p53, Nedd4-2 phosphorylation, GluA1 ubiquitination and synaptic downscaling are all restored in Fmr1 KO neurons. Together, our results discover a novel cellular mechanism underlying synaptic downscaling, and demonstrate the dysregulation and successful restoration of this mechanism in the FXS mouse model.
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7. Levy J, Grotto S, Mignot C, Dupont C, Delahaye A, Benzacken B, Keren B, Haye D, Xavier J, Heulin M, Charles E, Verloes A, Maruani A, Pipiras E, Tabet AC. {{NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder}}. {Clin Genet};2018 (May 16)
NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare and only one patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report three additional patients with a de novo deletion encompassing NR4A2: two patients have deletions encompassing only NR4A2 gene and one patient has a deletion including NR4A2 and the first exon of GPD2. Our patients presented a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder. We suggest that NR4A2 haploinsufficiency is implicated in neurodevelopmental disorder with high penetrance. This article is protected by copyright. All rights reserved.
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8. Lutjohann D, Lopez AM, Chuang JC, Kerksiek A, Turley SD. {{Identification of Correlative Shifts in Indices of Brain Cholesterol Metabolism in the C57BL6/Mecp2 (tm1.1Bird) Mouse, a Model for Rett Syndrome}}. {Lipids};2018 (May 17)
Rett syndrome (RS) is a pervasive neurodevelopmental disorder resulting from loss-of-function mutations in the X-linked gene methyl-Cpg-binding protein 2 (MECP2). Using a well-defined model for RS, the C57BL6/Mecp2 (tm1.1Bird) mouse, we have previously found a moderate but persistently lower rate of cholesterol synthesis, measured in vivo, in the brains of Mecp2 (-/y) mice, starting from about the third week after birth. There was no genotypic difference in the total cholesterol concentration throughout the brain at any age. This raised the question of whether the lower rate of cholesterol synthesis in the mutants was balanced by a fall in the rate at which cholesterol was converted via cholesterol 24-hydroxylase (Cyp46A1) to 24S-hydroxycholesterol (24S-OHC), the principal route through which cholesterol is ordinarily removed from the brain. Here, we show that while there were no genotypic differences in the concentrations in plasma and liver of three cholesterol precursors (lanosterol, lathosterol, and desmosterol), two plant sterols (sitosterol and campesterol), and two oxysterols (27-hydroxycholesterol [27-OHC] and 24S-OHC), the brains of the Mecp2 (-/y) mice had significantly lower concentrations of all three cholesterol precursors, campesterol, and both oxysterols, with the level of 24S-OHC being ~20% less than in their Mecp2 (+/y) controls. Together, these data suggest that coordinated regulation of cholesterol synthesis and catabolism in the central nervous system is maintained in this model for RS. Furthermore, we speculate that the adaptive changes in these two pathways conceivably resulted from a shift in the permeability of the blood-brain barrier as implied by the significantly lower campesterol and 27-OHC concentrations in the brains of the Mecp2 (-/y) mice.
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9. Osenberg S, Karten A, Sun J, Li J, Charkowick S, Felice CA, Kritzer M, Nguyen MVC, Yu P, Ballas N. {{Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome}}. {Proc Natl Acad Sci U S A};2018 (May 16)
Rett syndrome (RTT) is a severe neurodevelopmental disorder that affects about 1 in 10,000 female live births. The underlying cause of RTT is mutations in the X-linked gene, methyl-CpG-binding-protein-2 (MECP2); however, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. Specifically, although MeCP2 is known to act as a transcriptional repressor, analyses of the RTT brain at steady-state conditions detected numerous differentially expressed genes, while the changes in transcript levels were mostly subtle. Here we reveal an aberrant global pattern of gene expression, characterized predominantly by higher levels of expression of activity-dependent genes, and anomalous alternative splicing events, specifically in response to neuronal activity in a mouse model for RTT. Notably, the specific splicing modalities of intron retention and exon skipping displayed a significant bias toward increased retained introns and skipped exons, respectively, in the RTT brain compared with the WT brain. Furthermore, these aberrations occur in conjunction with higher seizure susceptibility in response to neuronal activity in RTT mice. Our findings advance the concept that normal MeCP2 functioning is required for fine-tuning the robust and immediate changes in gene transcription and for proper regulation of alternative splicing induced in response to neuronal stimulation.
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10. Patrick KE, Hurewitz F, McCurdy MD, Agate FT, Daly BP, Tarazi RA, Chute DL, Schultheis MT. {{Driving Comparisons Between Young Adults with Autism Spectrum Disorder and Typical Development}}. {J Dev Behav Pediatr};2018 (May 18)
OBJECTIVE: Many individuals with autism spectrum disorder (ASD) are reluctant to pursue driving because of concerns about their ability to drive safely. This study aimed to assess differences in simulated driving performance in young adults with ASD and typical development, examining relationships between driving performance and the level of experience (none, driver’s permit, licensed) across increasingly difficult driving environments. METHOD: Participants included 50 English-speaking young adults (16-26 years old) with ASD matched for sex, age, and licensure with 50 typically-developing (TD) peers. Participants completed a structured driving assessment using a virtual-reality simulator that included increasingly complex environmental demands. Differences in mean speed and speed and lane variability by diagnostic group and driving experience were analyzed using multilevel linear modeling. RESULTS: Young adults with ASD demonstrated increased variability in speed and lane positioning compared with controls, even during low demand tasks. When driving demands became more complex, group differences were moderated by driving experience such that licensed drivers with ASD drove similarly to TD licensed drivers for most tasks, whereas unlicensed drivers with ASD had more difficulty with speed and lane management than TD drivers. CONCLUSION: Findings suggest that young adults with ASD may have more difficulty with basic driving skills than peers, particularly in the early stages of driver training. Increased difficulty compared with peers increases as driving demands become more complex, suggesting that individuals with ASD may benefit from a slow and gradual approach to driver training. Future studies should evaluate predictors of driving performance, on-road driving, and ASD-specific driving interventions.
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11. Vagenas D, Totsika V. {{Modelling correlated data: Multilevel models and generalized estimating equations and their use with data from research in developmental disabilities}}. {Res Dev Disabil};2018 (May 18)
BACKGROUND: The use of Multilevel Models (MLM) and Generalized Estimating Equations (GEE) for analysing clustered data in the field of intellectual and developmental disability (IDD) research is still limited. METHOD: We present some important features of MLMs and GEEs: main function, assumptions, model specification and estimators, sample size and power. We provide an overview of the ways MLMs and GEEs have been used in IDD research. RESULTS: While MLMs and GEEs are both appropriate for longitudinal and/or clustered data, they differ in the assumptions they impose on the data, and the inferences made. Estimators in MLMs require appropriate model specification, while GEEs are more resilient to misspecification at the expense of model complexity. Studies on sample size seem to suggest that Level 1 coefficients are robust to small samples/clusters, with any higher-level coefficients less so. MLMs have been used more frequently than GEEs in IDD research, especially for fitting developmental trajectories. CONCLUSIONS: Clustered data from research in the IDD field can be analysed flexibly using MLMs and GEEs. These models would be more widely used if journals required the inclusion of technical specification detail, simulation studies examined power for IDD study characteristics, and researchers developed core skills during basic studies.
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12. Veliskova J, Silverman JL, Benson M, Lenck-Santini PP. {{Autistic traits in epilepsy models: Why, when and how?}}. {Epilepsy Res};2018 (May 18);144:62-70.
Autism spectrum disorder (ASD) is a common comorbidity of epilepsy and seizures and/or epileptiform activity are observed in a significant proportion of ASD patients. Current research also implies that autistic traits can be observed to a various degree in mice and rats with seizures. This suggests that there are shared mechanisms in both ASD and epilepsy syndromes. Here, we first review the standard, validated methods used to assess autistic traits in animal models as well as their limitations with regards to epilepsy models. We then discuss two of the potential pathological processes that could be shared between ASD and epilepsy. We first focus on functional implications of neuroinflammation including changes to excitable networks mediated by inflammatory regulators. Finally we examine mechanisms at the cellular and network level involved in neuronal excitability, timing and network coordination that may directly lead to behavioral disturbances present in both epilepsy and ASD. This mini-review summarizes the work first presented at an Investigators Workshop at the 2016 American Epilepsy Society meeting.
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13. Wong DF, Blue ME, Brasic JR, Nandi A, Valentine H, Stansfield KH, Rousset O, Bibat G, Yablonski ME, Johnston MV, Gjedde A, Naidu S. {{Are dopamine receptor and transporter changes in Rett syndrome reflected in Mecp2-deficient mice?}}. {Exp Neurol};2018 (May 18)
In the present study we tested the claim that the dopaminergic dysfunction of Rett Syndrome (RTT) also occurs in Mecp2-deficient mice that serve as a model of the syndrome. We used positron emission tomography (PET) to image dopamine D2 receptors (D2R) and transporters (DAT) in women with RTT and in Mecp2-deficient mice, and D1R and D2R density was measured in postmortem human tissue by autoradiography. Results showed 1) significantly reduced D2R density in the striatum of women with RTT compared to control subjects. 2) PET imaging of mouse striatum similarly demonstrated significant reductions in D2R density of 7-10week-old hemizygous (Mecp2-null) and heterozygous (HET) mice compared to wild type (WT) mice. With age, the density of D2R declined in WT mice but not HET mice. 3) In contrast, postmortem autoradiography revealed no group differences in the density of D1R and D2R in the caudate and putamen of RTT versus normal control subjects. 4) In humans and in the mouse model, PET revealed only marginal group differences in DAT. The results confirm that dopaminergic dysfunction in RTT is also present in Mecp2-deficient mice and that reductions in D2R more likely explain the impaired ambulation and progressive rigidity observed rather than alterations in DAT.
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14. Yenkoyan K, Harutyunyan H, Harutyunyan A. {{A certain role of SOD/CAT imbalance in pathogenesis of autism spectrum disorders}}. {Free Radic Biol Med};2018 (May 19);123:85-95.
The real impact of reactive oxygen species, antioxidant enzymes, mitochondrial dysfunction and chronic inflammation on the development of autism spectrum disorders (ASD) remains unclear, and even controversial. In this study we compared the plasma levels of antioxidant enzymes and their cofactors, markers of oxidative damage, and the respiratory burst in peripheral blood polymorphonuclear leucocytes (PMNL) as surrogate marker of chronic inflammation obtained from 10 children (4-10 year old) who met DSM-5 criteria and their siblings. We demonstrated diminished superoxide dismutase (SOD) and enhanced catalase (CAT) activities resulting in a markedly decreased SOD/CAT ratio and enhanced carbonyl content in the plasma of ASD patients. A strong correlation was present between SOD and CAT activities in the control group, which was not noted in ASD patients. Moreover, in autistic patients, we observed negative correlation between SOD activity on one side, and carbonyl content in plasma, 8-Hydroxy-2-deoxyguanosin content in urine, and respiratory burst intensity in PMNL on the other side. At the same time, low SOD level in autistic children was positively correlated with the magnesium content in the packed RBCs, which might indicate the involvement of the mitochondrial MnSOD in ASD pathogenesis, and therefore the consequent partaking of mitochondrial dysfunction in the development of ASD. Altogether, these results indicate that decreased antioxidant capacity and increased oxidative stress in ASD patients may have functional consequence in terms of increased superoxide leakage, oxidative protein damage, chronic inflammatory response, and, finally, neuronal cell abnormal functioning or death.
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15. Yorke I, White P, Weston A, Rafla M, Charman T, Simonoff E. {{The Association Between Emotional and Behavioral Problems in Children with Autism Spectrum Disorder and Psychological Distress in Their Parents: A Systematic Review and Meta-analysis}}. {J Autism Dev Disord};2018 (May 18)
This review (Prospero Registration Number: CRD42017057915) aimed to systematically identify and summarize existing research on the relationship between additional emotional and behavioral problems (EBP) in children with autism, and parenting stress (PS) and mental health problems (MHP) in their parents. Sixty-seven studies met criteria for inclusion in the review, 61 of which were included in the meta-analysis. Pooled correlation coefficients were in the low to moderate range ([Formula: see text]). Some evidence for moderation by measurement characteristics was found. Narrative review of concurrent adjusted associations showed some evidence for shared relationships with other factors, most notably ASD severity and parent perception of own parenting. Longitudinal studies showed mixed evidence for bidirectional predictive relationships between child EBP and parent psychological distress variables.
