1. Alvarez-Mora MI, Rodriguez-Revenga L, Madrigal I, Torres-Silva F, Mateu-Huertas E, Lizano E, Friedlander M, Marti E, Estivill X, Mila M. {{MicroRNA expression profiling in blood from fragile X-associated tremor/ataxia syndrome patients}}. {Genes Brain Behav};2013 (Jun 22)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with FMR1 gene premutation alleles (55-200 CGG repeats). FXTAS clinical core features include action tremor, gait ataxia, cognitive deficits progressing to dementia, and frequently parkinsonism. Although the pathogenic molecular mechanism of FXTAS is not completely understood, the restriction of the phenotype to the FMR1 premutation range has given rise to a model based on a RNA toxic gain-of-function. Since the identification of the first microRNAs and their role in normal development, several studies have associated them with neurodegenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, suggesting that they play a key role in brain development, as well as in its morphogenesis. Herein, we present the characterization of microRNA expression profiles in FXTAS male patients using deep sequencing-based technologies and microarray technology. Deep sequencing analysis evidenced 83 microRNAs that were significantly deregulated whereas microarray analysis showed 31. When comparing these results, 14 microRNAs were found deregulated in FXTAS patients. MiR-424 and miR-574-3p showed significant Fold Change adjusted p-values in both platforms in FXTAS patients. MiR-424 has been founded substantially and specifically enriched in human cerebral cortical white matter of Alzheimer disease patients, which, together with cerebral atrophy, is a prominent imaging finding in individuals with FXTAS. The study provides the first systematic evidence of differential microRNA expression changes in FXTAS blood samples. Although further studies are necessary to better characterize the microRNA function in FXTAS disorder, our results suggest that they might contribute to its pathogenesis.
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2. Bringas ME, Carvajal-Flores FN, Lopez-Ramirez TA, Atzori M, Flores G. {{Rearrangement of the dendritic morphology in limbic regions and altered exploratory behavior in a rat model of autism spectrum disorder}}. {Neuroscience};2013 (Jun 25);241:170-187.
Valproic acid (VPA) is a blocker of histone deacetylase widely used to treat epilepsy, bipolar disorders, and migraine; its administration during pregnancy increases the risk of autism spectrum disorder (ASD) in the child. Thus, prenatal VPA exposure has emerged as a rodent model of ASD. In the present study, we aimed to investigate the effect of prenatal administration of VPA (500mg/kg) at E12.5 on the exploratory behavior and locomotor activity in a novel environment, as well as on neuronal morphological rearrangement in the prefrontal cortex (PFC), in the hippocampus, in the nucleus accumbens (NAcc), and in the basolateral amygdala (BLA) at three different ages: immediately after weaning (postnatal day 21 [PD21]), prepubertal (PD35) and postpubertal (PD70) ages. Hyper-locomotion was observed in a novel environment in VPA animals at PD21 and PD70. Interestingly, exploratory behavior assessed by the hole board test at PD70 showed a reduced frequency but an increase in the duration of head-dippings in VPA-animals compared to vehicle-treated animals. In addition, the latency to the first head-dip was longer in prenatal VPA-treated animals at PD70. Quantitative morphological analysis of dendritic spine density revealed a reduced number of spines at PD70 in the PFC, dorsal hippocampus and BLA, with an increase in the dendritic spine density in NAcc and ventral hippocampus, in prenatal VPA-treated rats. In addition, at PD70 increases in neuronal arborization were observed in the NAcc, layer 3 of the PFC, and BLA, with retracted neuronal arborization in the ventral and dorsal hippocampus. Our results extend the list of altered behaviors (exploratory behavior) detected in this model of ASD, and indicate that the VPA behavioral phenotype is accompanied by previously undescribed morphological rearrangement in limbic regions.
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3. Farmer JE, Clark MJ, Mayfield WA, Cheak-Zamora N, Marvin AR, Law JK, Law PA. {{The Relationship Between the Medical Home and Unmet Needs for Children with Autism Spectrum Disorders}}. {Matern Child Health J};2013 (Jun 23)
The purpose of this study was to examine the relationship between having access to a medical home and unmet needs for specialty care services for children with autism spectrum disorders (ASD). Parents of children enrolled in a national autism registry were invited to complete an online Access to Care Questionnaire. The resulting sample consisted of 371 parents-child dyads. Bivariate and hierarchical regression analyses were conducted to determine whether having a medical home was associated with the number of unmet needs for specialty care. Less than one in five children with ASD had a medical home (18.9 %). Nearly all parents reported that their child had a personal doctor or nurse as well as a usual source of care, but less than one-third received coordinated care (29.9 %) and less than one-half received family-centered care (47.1 %). Many children had unmet needs (63 %), and the highest unmet need was for behavioral therapy. Having a medical home was associated with fewer unmet specialty care needs, even after demographic, child and family characteristics were taken into account. Children with ASD who have a medical home are more likely to have adequate access to needed services. Unfortunately, relatively few children have a medical home that includes family-centered and coordinated care. Enhancements in the delivery of primary care for children with ASD may make a real difference in access to needed specialty care services, potentially improving child and family outcomes.
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4. Griesi-Oliveira K, Sunaga DY, Alvizi L, Vadasz E, Passos-Bueno MR. {{Stem Cells as a Good Tool to Investigate Dysregulated Biological Systems in Autism Spectrum Disorders}}. {Autism Res};2013 (Jun 25)
Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n = 7) and control samples (n = 6). Nearly half of the 683 identified DEGs are expressed in the brain (P = 0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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5. Hasegawa N, Kitamura H, Murakami H, Kameyama S, Sasagawa M, Egawa J, Endo T, Someya T. {{Neural activity in the posterior superior temporal region during eye contact perception correlates with autistic traits}}. {Neurosci Lett};2013 (Jun 20)
The present study investigated the relationship between neural activity associated with gaze processing and autistic traits in typically developed subjects using magnetoencephalography. Autistic traits in 24 typically developed college students with normal intelligence were assessed using the Autism Spectrum Quotient (AQ). The Minimum Current Estimates method was applied to estimate the cortical sources of magnetic responses to gaze stimuli. These stimuli consisted of apparent motion of the eyes, displaying direct or averted gaze motion. Results revealed gaze-related brain activations in the 150-250ms time window in the right posterior superior temporal sulcus (pSTS), and in the 150-450ms time window in medial prefrontal regions. In addition, the mean amplitude in the 150-250ms time window in the right pSTS region was modulated by gaze direction, and its activity in response to direct gaze stimuli correlated with AQ score. pSTS activation in response to direct gaze is thought to be related to higher-order social processes. Thus, these results suggest that brain activity linking eye contact and social signals is associated with autistic traits in a typical population.
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6. Kannu P, Campos-Xavier AB, Hull D, Martinet D, Ballhausen D, Bonafe L. {{Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5}}. {Eur J Med Genet};2013 (Jun 20)
Genomic rearrangements at chromosome 13q31.3q32.1 have been associated with digital anomalies, dysmorphic features, and variable degree of mental disability. Microdeletions leading to haploinsufficiency of miR17 approximately 92, a cluster of micro RNA genes closely linked to GPC5 in both mouse and human genomes, has recently been associated with digital anomalies in the Feingold like syndrome. Here, we report on a boy with familial dominant post-axial polydactyly (PAP) type A, overgrowth, significant facial dysmorphisms and autistic traits who carries the smallest germline microduplication known so far in that region. The microduplication encompasses the whole miR17 approximately 92 cluster and the first 5 exons of GPC5. This report supports the newly recognized role of miR17 approximately 92 gene dosage in digital developmental anomalies, and suggests a possible role of GPC5 in growth regulation and in cognitive development.
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7. Kerekes N, Brandstrom S, Lundstrom S, Rastam M, Nilsson T, Anckarsater H. {{ADHD, autism spectrum disorder, temperament, and character: Phenotypical associations and etiology in a Swedish childhood twin study}}. {Compr Psychiatry};2013 (Jun 20)
OBJECTIVE: To explore the links between neurodevelopmental disorders – attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) – and personality in a population-based, genetically sensitive study of children. METHOD: A population-based sample of 1886 twins aged 9 and 12, enriched for childhood mental health problems, was recruited from the Child and Adolescent Twin Study in Sweden (CATSS). Parents were interviewed over the telephone using the Autism-Tics, AD/HD and other Comorbidities (A-TAC) inventory, and in a second step they rated their children according to the Junior Temperament and Character Inventory (JTCI). RESULTS: ADHD was strongly correlated with novelty seeking, while ASD was correlated positively with harm avoidance and negatively with reward dependence. The strongest associations between personality traits and neurodevelopmental disorders were negative correlations between the character dimensions of self-directedness and cooperativeness and ADHD and ASD alike. Cross-twin cross-trait correlations between ADHD, ASD, and personality dimensions in monozygotic twins were more than double those in dizygotic twins, indicating a strong genetic effect behind the phenotypic covariation between neurodevelopmental disorders and personality. CONCLUSIONS: Neurodevelopmental disorders are linked specifically to particular temperament profiles and generally to hampered development of the self-governing strategies referred to as « character. » Poor self-agency and cooperation may be core functional outcomes in the separation of children with handicapping conditions from those with traits only reminiscent of neurodevelopmental disorders. The associations between neurodevelopmental disorders and personality are at least partly due to genetic effects influencing both conditions. As a consequence, personality must be broadly considered in neuropsychiatry, just as neuropsychiatric disorders and their genetic, neurodevelopmental, and cognitive susceptibilities have to be in personality research and clinical treatment.
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8. Lo ST, Siemensma E, Collin P, Hokken-Koelega A. {{Impaired theory of mind and symptoms of Autism Spectrum Disorder in children with Prader-Willi syndrome}}. {Res Dev Disabil};2013 (Jun 18);34(9):2764-2773.
In order to evaluate the social cognitive functioning in children with Prader-Willi syndrome (PWS), Theory of Mind (ToM) and symptoms of Autism Spectrum Disorder were evaluated. Sixty-six children with PWS aged 7-17 years were tested using the Theory of Mind test-R and the Diagnostic Interview for Social Communication disorders. We tested the correlation between Total ToM Standard Deviation Score (Total ToM SDS) and genetic subtype of paternal deletion or maternal uniparental disomy, and total IQ, verbal IQ and performal IQ. Prevalence and symptoms of Autism Spectrum Disorder were assessed. Median (interquartile range) of total ToM SDS of those aged 7-17 years was -3.84 (-5.73, -1.57). Their Total ToM SDS correlated with total IQ (beta=0.662, p<0.001, adj.R2=0.407), in particular with verbal IQ (beta=0.502, p=0.001, adj.R2=0.409), but not with performal IQ (beta=0.241, p>0.05, adj.R2=0.259). No difference in Total ToM SDS was found between children with deletion and maternal uniparental disomy (beta=-0.143, p>0.05, adj.R2=-0.016). Compared to the reference group of healthy children aged 7-12 years, children with PWS in the same age group had a median ToM developmental delay of 4 (3-5) years. One third of children with PWS scored positive for Autism Spectrum Disorder. Most prominent aberrations in Autism Spectrum Disorder were focused on maladaptive behavior. Our findings demonstrate a markedly reduced level of social cognitive functioning, which has consequences for the approach of children with PWS, i.e. adjustment to the child’s level of social cognitive functioning.
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9. Mathersul D, McDonald S, Rushby JA. {{Understanding advanced theory of mind and empathy in high-functioning adults with autism spectrum disorder}}. {J Clin Exp Neuropsychol};2013 (Jun 25)
It has been argued that higher functioning individuals with autism spectrum disorders (ASDs) have specific deficits in advanced but not simple theory of mind (ToM), yet the questionable ecological validity of some tasks reduces the strength of this assumption. The present study employed The Awareness of Social Inference Test (TASIT), which uses video vignettes to assess comprehension of subtle conversational inferences (sarcasm, lies/deception). Given the proposed relationships between advanced ToM and cognitive and affective empathy, these associations were also investigated. As expected, the high-functioning adults with ASDs demonstrated specific deficits in comprehending the beliefs, intentions, and meaning of nonliteral expressions. They also had significantly lower cognitive and affective empathy. Cognitive empathy was related to ToM and group membership whereas affective empathy was only related to group membership.
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10. Nurmi EL, Spilman SL, Whelan F, Scahill LL, Aman MG, McDougle CJ, Arnold LE, Handen B, Johnson C, Sukhodolsky DG, Posey DJ, Lecavalier L, Stigler KA, Ritz L, Tierney E, Vitiello B, McCracken JT. {{Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies}}. {Transl Psychiatry};2013;3:e274.
Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 x 10-6), CNR1 (P=9.6 x 10-5) and the leptin (LEP) promoter (P=1.4 x 10-4) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 x 10-9) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.
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11. Rochat MJ, Veroni V, Bruschweiler-Stern N, Pieraccini C, Bonnet-Brilhault F, Barthelemy C, Malvy J, Sinigaglia C, Stern DN, Rizzolatti G. {{Impaired Vitality Form Recognition In Autism}}. {Neuropsychologia};2013 (Jun 20)
Along with the understanding of the goal of an action (« what » is done) and the intention underlying it (« why » it is done), social interactions largely depend on the appraisal of the action from the dynamics of the movement: « how » it is performed (its « vitality form »). Do individuals with autism, especially children, possess this capacity? Here we show that, unlike typically developing individuals, individuals with autism reveal severe deficits in recognizing vitality forms, and their capacity to appraise them does not improve with age. Deficit in vitality form recognition appears, therefore, to be a newly recognized trait marker of autism.
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12. Zachor DA, Ben-Itzchak E. {{The Relationship Between Clinical Presentation and Unusual Sensory Interests in Autism Spectrum Disorders: A Preliminary Investigation}}. {J Autism Dev Disord};2013 (Jun 25)
Unusual responses to sensory stimuli have been described in autism spectrum disorder (ASD).The study examined the frequencies of ‘unusual sensory interests’ and ‘negative sensory responses’ and their relation to functioning in a large ASD population (n = 679). Having ‘unusual sensory interests’ was reported in 70.4 % and ‘negative sensory responses’ in 66.0 % of the ASD group. Having ‘unusual sensory interests’ was associated with more severe reported and observed autism symptoms, lower cognitive ability and lower adaptive skills. In contrast, having ‘negative sensory responses’ was only associated with more severe reported stereotyped behaviors. It is suggested that having ‘unusual sensory interests’ is a part of a primary more severe type of ASD involving numerous developmental domains that might have a unique neurobiological origin.
