1. Arpone M, Baker EK, Bretherton L, Bui M, Li X, Whitaker S, Dissanayake C, Cohen J, Hickerton C, Rogers C, Field M, Elliott J, Aliaga SM, Ling L, Francis D, Hearps SJC, Hunter MF, Amor DJ, Godler DE. {{Intragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X}}. {Sci Rep}. 2018; 8(1): 3644.
Increased intragenic DNA methylation of the Fragile X Related Epigenetic Element 2 (FREE2) in blood has been correlated with lower intellectual functioning in females with fragile X syndrome (FXS). This study explored these relationships in a paediatric cohort of males with FXS using Buccal Epithelial Cells (BEC). BEC were collected from 25 males with FXS, aged 3 to 17 years and 19 age-matched male controls without FXS. Methylation of 9 CpG sites within the FREE2 region was examined using the EpiTYPER approach. Full Scale IQ (FSIQ) scores of males with FXS were corrected for floor effect using the Whitaker and Gordon (WG) extrapolation method. Compared to controls, children with FXS had significant higher methylation levels for all CpG sites examined (p < 3.3 x 10(-7)), and within the FXS group, lower FSIQ (WG corrected) was associated with higher levels of DNA methylation, with the strongest relationship found for CpG sites within FMR1 intron 1 (p < 5.6 x 10(-5)). Applying the WG method to the FXS cohort unmasked significant epi-genotype-phenotype relationships. These results extend previous evidence in blood to BEC and demonstrate FREE2 DNA methylation to be a sensitive epigenetic biomarker significantly associated with the variability in intellectual functioning in FXS. Lien vers le texte intégral (Open Access ou abonnement)
2. Fernandes IR, Cruz AC, Ferrasa A, Phan D, Herai RH, Muotri AR. {{Genetic variations on SETD5 underlying autistic conditions}}. {Dev Neurobiol}. 2018.
The prevalence of autism spectrum disorders (ASD) and the number of identified ASD-related genes have increased in recent years. The SETD5 gene encodes a SET-containing-domain 5 protein, a likely reader enzyme. Genetic evidences suggest that SETD5 malfunction contributes to ASD phenotype, such as on intellectual disability (ID) and facial dysmorphism. In this review, we mapped the clinical phenotypes of individuals carrying mutations on the SETD5 gene that are associated with ASD and other chromatinopathies (mutation in epigenetic modifiers that leads to the development of neurodevelopmental disorders such as ASD). After a detailed systematic literature review and analysis of public disease-related databank, we found so far 42 individuals carrying mutations on the SETD5 gene, with 23.8% presenting autistic-like features. Furthermore, most of mutations occurred between positions 9,480,000-9,500,000 bp on chromosome 3 (3p25.3) at the SETD5 gene locus. In all males, mutations in SETD5 presented high penetrance, while in females the clinical phenotype seems more variable with two reported cases showing normal female carriers and not presenting ASD or any ID-like symptoms. At the molecular level, SETD5 interacts with proteins of PAF1C and N-CoR complexes, leading to a possible involvement with chromatin modification pathway, which plays important roles for brain development. Together, we propose that mutations on the SETD5 gene could lead to a new syndromic condition in males, which is linked to 3p25 syndrome, and can leads to ASD-related intellectual disability and facial dysmorphism. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018.
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3. Ghorbel R, Ghorbel R, Rouissi A, Fendri-Kriaa N, Ben Salah G, Belguith N, Ammar-Keskes L, Gouider-Khouja N, Fakhfakh F. {{First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation}}. {Biochemical and biophysical research communications}. 2018; 497(1): 93-101.
Rett syndrome is an X-linked neurodevelopmental disorder that develops a profound intellectual and motor disability and affects 1 from 10000 to 15000 live female births. This disease is characterized by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress which is caused by mutations occurred in the X-linked MECP2 gene, encoding the methyl-CpG binding protein 2. This research study reports a molecular analysis via an exhaustive gene sequencing which reveals an unusual novel double mutation (c.695G>T; c.880C>T) located in a highly conserved region in MECP2 gene affecting the transcription repression domain (TRD) of MeCP2 protein and leading for the first time to a severe phenotype of Rett syndrome. Moreover, a computational investigation of MECP2 mutations demonstrates that the novel mutation c.695G>T is highly deleterious which affects the MeCP2 protein showing also an adverse impact on MECP2 gene expression and resulting in an affected folding and decreased stability of MECP2 structures. Thus, the altered TRD domain engenders a disrupted process of MECP2 functions. Therefore, this is the first study which highlights a novel double mutation among the transcription repression domain (TRD) of MeCP2 protein in Rett patient with a severe clinical phenotype in North Africa region.
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4. Hadjikhani N, Asberg Johnels J, Lassalle A, Zurcher NR, Hippolyte L, Gillberg C, Lemonnier E, Ben-Ari Y. {{Bumetanide for autism: more eye contact, less amygdala activation}}. {Sci Rep}. 2018; 8(1): 3602.
We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism.
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5. Li J, Zhu L, Chen Z. {{The association between punishment and cooperation in children with high-functioning autism}}. {Journal of experimental child psychology}. 2018; 171: 1-13.
This study examined judgment about punishment and whether punishment promoted cooperation in the prisoner’s dilemma game (PDG) in children with high-functioning autism (HFA) and typically developing (TD) children. In total, 66 6- to 12-year-olds participated in this study. Children were first asked about judgments regarding rewards and punishment in stories, and then they were asked to play the PDG with a partner in conditions with and without punishment. Results showed that children with HFA believed that hitting others should deserve punishment to a greater extent than TD children did. It indicated that children with HFA understood that bad acts should be punished, suggesting that these children have already acquired the general concept of « punishment. » Children displayed higher levels of cooperation in the condition with punishment than in the condition without punishment in the PDG, suggesting that punishment promoted cooperation in the PDG in both children with HFA and TD children.
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6. Neubauer BA. {{Erratum: Rett Syndrome}}. {Neuropediatrics}. 2018.
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7. Romero-Garcia R, Warrier V, Bullmore ET, Baron-Cohen S, Bethlehem RAI. {{Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism}}. {Mol Psychiatry}. 2018.
Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (DeltaCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of DeltaCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in DeltaCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected 10(-14)), driven entirely by downregulated genes (OR = 1.87, Pcorrected 10(-15)). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism.
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8. Woodman AC, Breviglia E, Mori Y, Golden R, Maina J, Wisniewski H. {{The Effect of Music on Exercise Intensity among Children with Autism Spectrum Disorder: A Pilot Study}}. {J Clin Med}. 2018; 7(3).
Children with autism spectrum disorder (ASD) are at risk for obesity, commonly have sleep disorders, and exhibit stereotypic behaviors that disrupt their learning. Vigorous levels of exercise have been shown to ameliorate these issues in children with ASD, but little research exists to provide techniques for motivating children with ASD to engage in exercise. The present study examined the effect of music on exercise intensity in a group of 13 elementary school students with ASD. Data were collected across six days during structured (e.g., verbal and physical prompts) and unstructured (e.g., minimal prompting) exercise periods. During these exercise periods, three music conditions were randomized: no music, slow-tempo music, and fast-tempo music. Exercise intensity, measured in Metabolic Equivalent of Tasks by triaxial accelerometers, was greatest during the structured exercise periods and during the slow music condition. Student characteristics moderated the impact of music condition on exercise intensity, such that students with high levels of adaptive behavior or lower levels of maladaptive behavior displayed greater exercise intensity during the fast music condition.
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9. Zhu Z, Fang X, Chen H, Zhu X, Zhang L, Zhai X, Cui Z, Gao Q. {{Alterations in volumes and MRI features of amygdala in Chinese autistic preschoolers associated with social and behavioral deficits}}. {Brain Imaging Behav}. 2018.
To examine the amygdala volume in 2-5-year-old preschool children with autism and explore the relationship between amygdala volumes based on MRI findings and clinical features. A total of 39 cases with clinically diagnosed autism were collected. The oblique coronal T1 weighted image (T1WI) sequence was used to measure the volume of amygdala and the MRI signals were measured and analyzed. The data were compared to that of 24 age-matched healthy children and correlated to the clinical manifestations. The autism and the control groups were subject to brain scanning in 1 week after Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) review. The 39 cases, diagnosed with autism, were associated with social and behavioral deficits through clinical observation, physical and neurological examination, and assessments according to DSM IV, and the range of ABC scores in the autism group was 47-124, with an average score of 84.7 +/- 24.1. Abnormal MRI signals were found in 19/78 (24.4%) amygdala in the autism group, the amygdala lesions showed punctuate or flaky low signal, slightly low signal, low to iso-signal, slightly high signal, or iso to high-signal intensity on T1 weighted three-dimendional fast low angle shot(T1FL3D) images. The right amygdala volume average was 1.088 +/- 0.38 cm(3), while that of the left amygdala was 1.04 +/- 0.41 cm(3), without any statistically significant difference (t = 0.533, p = 0.596) in the autism group. Among the 24 cases in the control group, the right amygdala volume average was 0.754 +/- 0.194 cm(3), while that of the left amygdala was 0.666 +/- 0.252 cm(3); the autism group had a significantly larger right and left amygdala volumes as compared to the age-matched typically developing group with a significant positive correlation between age and right amygdala volume (r = 0.406, p = 0.01). The preschool children with autism had significantly larger bilateral amygdala volumes as compared to age-matched typically developing children, the amygdala lesions may show abnormal signal. A relationship between age and right amygdala volume in the preschool children with autism was established.
