1. {{Correction to Supporting Information for Gadad et al., Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology}}. {Proc Natl Acad Sci U S A};2015 (Dec 8);112(49):E6827.
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2. Bagatell N, Mason AE. {{Looking Backward, Thinking Forward: Occupational Therapy and Autism Spectrum Disorders}}. {OTJR (Thorofare N J)};2015 (Jan);35(1):34-41.
As autism spectrum disorders become more prevalent and comprise a growing percentage of occupational therapists’ caseloads, it is important to examine trends in the literature. The purpose of this scoping review is to provide a historical analysis to illuminate changes and gaps in the occupational therapy literature related to autism spectrum disorders to inform the direction of research and practice. A total of 115 articles published in five occupational therapy journals in the United States from 1980 to 2013 were reviewed. Publications were coded by article type, with intervention studies coded in detail. Results indicated a consistent increase in number of publications as years progressed. Analysis by decade highlighted a shift from a biomedical focus to an occupation focus. Suggestions for future research include building a stronger evidence base, developing occupation-based assessments and interventions, and addressing needs of individuals with autism spectrum disorders and their families across the life span.
3. Bercum FM, Rodgers KM, Benison AM, Smith ZZ, Taylor J, Kornreich E, Grabenstatter HL, Dudek FE, Barth DS. {{Maternal Stress Combined with Terbutaline Leads to Comorbid Autistic-Like Behavior and Epilepsy in a Rat Model}}. {J Neurosci};2015 (Dec 2);35(48):15894-15902.
Human autism is comorbid with epilepsy, yet, little is known about the causes or risk factors leading to this combined neurological syndrome. Although genetic predisposition can play a substantial role, our objective was to investigate whether maternal environmental factors alone could be sufficient.We examined the independent and combined effects of maternal stress and terbutaline (used to arrest preterm labor), autism risk factors in humans, on measures of both autistic-like behavior and epilepsy in Sprague-Dawley rats. Pregnant dams were exposed to mild stress (foot shocks at 1 week intervals) throughout pregnancy. Pups were injected with terbutaline on postnatal days 2-5.Either maternal stress or terbutaline resulted in autistic-like behaviors in offspring (stereotyped/repetitive behaviors and deficits in social interaction or communication), but neither resulted in epilepsy. However, their combination resulted in severe behavioral symptoms, as well as spontaneous recurrent convulsive seizures in 45% and epileptiform spikes in 100%, of the rats. Hippocampal gliosis (GFAP reactivity) was correlated with both abnormal behavior and spontaneous seizures.We conclude that prenatal insults alone can cause comorbid autism and epilepsy but it requires a combination of teratogens to achieve this; testing single teratogens independently and not examining combinatorial effects may fail to reveal key risk factors in humans. Moreover, astrogliosis may be common to both teratogens. This new animal model of combined autism and epilepsy permits the experimental investigation of both the cellular mechanisms and potential intervention strategies for this debilitating comorbid syndrome. SIGNIFICANCE STATEMENT: The comorbidity of human autism and epilepsy has been recognized for decades with little understanding of factors that increase risk. We show that two common human risk factors for autism (maternal stress and terbutaline), only when combined, result in severe ASD-like behavior and epilepsy. The significance of this work is fourfold: (1) combinations of teratogens are required to assess true risk in humans; (2) maternal stress and terbutaline, which are frequently combined in pregnant mothers, may be far more of a risk factor than previously appreciated; (3) astrogliosis may be a common mechanism for this syndrome; and (4) this first animal model of environmentally induced autism/epilepsy permits experimental investigation of cellular mechanisms and intervention strategies.
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4. Biamino E, Di Gregorio E, Belligni EF, Keller R, Riberi E, Gandione M, Calcia A, Mancini C, Giorgio E, Cavalieri S, Pappi P, Talarico F, Fea AM, De Rubeis S, Cirillo Silengo M, Ferrero GB, Brusco A. {{A novel 3q29 deletion associated with autism, intellectual disability, psychiatric disorders, and obesity}}. {Am J Med Genet B Neuropsychiatr Genet};2015 (Dec 1)
Copy number variation (CNV) has been associated with a variety of neuropsychiatric disorders, including intellectual disability/developmental delay (ID/DD), autism spectrum disorder (ASD), and schizophrenia (SCZ). Often, individuals carrying the same pathogenic CNV display high clinical variability. By array-CGH analysis, we identified a novel familial 3q29 deletion (1.36 Mb), centromeric to the 3q29 deletion region, which manifests with variable expressivity. The deletion was identified in a 3-year-old girl diagnosed with ID/DD and autism and segregated in six family members, all affected by severe psychiatric disorders including schizophrenia, major depression, anxiety disorder, and personality disorder. All individuals carrying the deletion were overweight or obese, and anomalies compatible with optic atrophy were observed in three out of four cases examined. Amongst the 10 genes encompassed by the deletion, the haploinsufficiency of Optic Atrophy 1 (OPA1), associated with autosomal dominant optic atrophy, is likely responsible for the ophthalmological anomalies. We hypothesize that the haploinsufficiency of ATPase type 13A4 (ATP13A4) and/or Hairy/Enhancer of Split Drosophila homolog 1 (HES1) contribute to the neuropsychiatric phenotype, while HES1 deletion might underlie the overweight/obesity. In conclusion, we propose a novel contiguous gene syndrome due to a proximal 3q29 deletion variably associated with autism, ID/DD, psychiatric traits and overweight/obesity. (c) 2015 Wiley Periodicals, Inc.
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5. Bilgic A, Bilgic O, Herguner S, Altinyazar HC. {{Autistic Trait, Empathy, and Attention-Deficit/Hyperactivity Symptoms in Women with Idiopathic Hirsutism}}. {Int J Trichology};2015 (Jul-Sep);7(3):113-118.
AIM: Many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), disruptive behavioral disorders, autism spectrum disorders, and some psychiatric characteristics, such as poor empathizing, are regarded to be related to elevated levels of androgens or androgen sensitivity. Thus, numerous studies have investigated the potential association between androgen-related physical diseases and these psychiatric conditions. Idiopathic hirsutism (IH) is a disease characterized by an increased sensitivity of the pilosebaceous unit to circulating androgens in women. The purpose of this study was to examine whether IH has a relationship with androgen-related psychiatric conditions. MATERIALS AND METHODS: Totally 37 females with IH and 33 healthy female controls were included in this study. Childhood and present ADHD symptoms of the participants were assessed using the Wender Utah Rating Scale (WURS) and the Adult ADHD Self-Report Scale, respectively. The Autism-spectrum quotient and the interpersonal reactivity index were used to assess autistic traits and different aspects of empathy. Hirsutism severity was measured using the Ferriman-Gallwey scoring system. RESULTS: No significant difference was found between the patients and controls on psychiatric questionnaire scores, except for a trend for subjects with IH to show higher levels of the school-associated problems than controls according to WURS. The severity of hirsutism was strongly correlated with the WURS irritability and behavioral problems/impulsivity subscores and WURS total score, and moderately correlated with the WURS attentional deficit subscore. CONCLUSIONS: This study provides preliminary evidence that common etiological factors may be involved in both the severity of IH, ADHD, and coexisting disruptive behavioral problems.
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6. D’Gama AM, Pochareddy S, Li M, Jamuar SS, Reiff RE, Lam AT, Sestan N, Walsh CA. {{Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms}}. {Neuron};2015 (Dec 2);88(5):910-917.
Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.
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7. Habela CW, Song H, Ming GL. {{Modeling synaptogenesis in Schizophrenia and Autism using human iPSC derived neurons}}. {Mol Cell Neurosci};2015 (Dec 2)
Schizophrenia (SCZ) and autism spectrum disorder (ASD) are genetically and phenotypically complex disorders of neural development. Human genetic studies, as well as studies examining structural changes at the cellular level, have converged on glutamatergic synapse formation, function, and maintenance as common pathophysiologic substrates involved in both disorders. Synapses as basic functional units of the brain are continuously modified by experience throughout life, therefore they are particularly attractive candidates for targeted therapy. Until recently we lacked a system to evaluate dynamic changes that lead to synaptic abnormalities. With the development of techniques to generate induced pluripotent stem cells (iPSCs) from patients, we are now able to study neuronal and synaptic development in cells from individual patients in the context of genetic changes conferring disease susceptibility. In this review, we discuss recent studies focusing on neural cells differentiated from SCZ and ASD patient iPSCs. These studies support a central role for glutamatergic synapse formation and function in both disorders and demonstrate that iPSC derived neurons offer a potential system for further evaluation of processes leading to synaptic dysregulation and for the design and screening of future therapies.
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8. Li J, Chai A, Wang L, Ma Y, Wu Z, Yu H, Mei L, Lu L, Zhang C, Yue W, Xu L, Rao Y, Zhang D. {{Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior}}. {Proc Natl Acad Sci U S A};2015 (Dec 15);112(50):E6964-E6972.
Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1alpha (protein phosphase 1alpha)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.
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9. Murshid EZ. {{Dental knowledge of educators and healthcare providers working with children with autism spectrum disorders}}. {Saudi Med J};2015 (Dec);36(12):1477-1485.
OBJECTIVES: To evaluate dental knowledge and attitudes toward oral health care among healthcare providers and educators working with children with autism spectrum disorders (ASD) in central Saudi Arabia. METHODS: There were 305 questionnaires distributed to 7 special-needs centers between September and November 2014. A total of 217 questionnaires were collected with a response rate of 71.1%. The study took place in the College of Dentistry, King Saud University, Riyadh, Kingdom of Saudi Arabia. RESULTS: Approximately 50.2% of the participants did not offer any toothbrushing advice, and 73.3% never recommended dental checkup visits to parents, and 75.6% never performed dental examinations to children under their care. Ten percent thought that children should have their first dental visit after 6 years of age. Almost all participants agreed that children should practice oral hygiene, and 60.4% think they should brush twice per day. In general, the participants choose toothbrushes and toothpaste as the main tools to perform oral hygiene. There were 35% of participants who believed that parents should be responsible for the children’s oral hygiene, and a few participants mentioned teachers and therapists to be responsible. Most of the participants (71.4%) did not receive any dental information from dental professional resources, only 14.3% of participants believed bacteria to be the cause of dental cavities. CONCLUSION: There is a clear lack of dental knowledge and attitudes, and its practical application among the participating group of healthcare providers working with children with ASD in Riyadh.
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10. Ulbrich L, Favaloro FL, Trobiani L, Marchetti V, Patel V, Pascucci T, Comoletti D, Marciniak SJ, De Jaco A. {{Autism associated R451C mutation in Neuroligin3 leads to the activation of the unfolded protein response in a PC12 Tet-On inducible system}}. {Biochem J};2015 (Nov 30)
Several forms of monogenic heritable autism spectrum disorders are associated to mutations in the neuroligin genes. The autism-linked substitution arginine 451 to cysteine (R451C) in neuroligin3induces local misfolding of its extracellular domain, causing partial retention in the endoplasmic reticulum (ER) of expressing cells. We have generated a PC12 Tet-On cell model system with inducible expression of wild type or R451C neuroligin3 to investigate if there is activation of the unfolded protein response (UPR) as a result of misfolded protein retention. As a positive control for protein misfolding, we also expressed the severely disrupted mutant G221R neuroligin3, which is known to be completely retained within the ER. Our data show that overexpression of either R451C or G221R mutant proteins leads to the activation of all three signaling branches of the UPR downstream of the stress sensors ATF6, IRE1 and PERK. Each branch displayed different activation profiles that partially correlated with the degree of misfolding caused by each mutation. We also show that upregulation of BiP and CHOP was induced by both mutant proteins but not by wild type neuroligin3, both in proliferative cells and cells differentiated to a neuronal-like phenotype. Collectively, our data show that mutant R451C neuroligin3 activates the UPR in a novel cell model system, suggesting that this cellular response may have a role in monogenic forms of autism characterized by misfolding mutations.
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11. Veatch OJ, Reynolds A, Katz T, Weiss SK, Loh A, Wang L, Malow BA. {{Sleep in Children With Autism Spectrum Disorders: How Are Measures of Parent Report and Actigraphy Related and Affected by Sleep Education?}}. {Behav Sleep Med};2015 (Nov 30):1-12.
Sleep disturbance is common in children with autism, resulting in a great need for effective treatments. To evaluate treatments for sleep disturbance in this population, it is critical to understand the relationship between measures of sleep captured by parent report and objective measures. The Children’s Sleep Habits Questionnaire (CSHQ) and actigraphy-measured data from 80 children with autism and sleep-onset delay were evaluated. Reported problems with sleep-onset delay were concurrent with sleep duration problems in 66% of children, night wakings in 72% of children, and bedtime resistance in 66% of children; 38% of children were reported to have problems with all CSHQ insomnia domains. Actigraphy-measured sleep duration was correlated with estimates using CSHQ-reported bed and wake times.
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12. Vignoli A, La Briola F, Peron A, Turner K, Vannicola C, Saccani M, Magnaghi E, Scornavacca GF, Canevini MP. {{Autism spectrum disorder in tuberous sclerosis complex: searching for risk markers}}. {Orphanet J Rare Dis};2015;10:154.
BACKGROUND: Neuropsychiatric disorders are present in up to 90% of patients with Tuberous Sclerosis Complex (TSC), and represent an important issue for families. Autism Spectrum Disorder (ASD) is the most common neurobehavioral disease, affecting up to 61% of patients. The aims of this study were: 1) to assess the prevalence of ASD in a TSC population; 2) to describe the severity of ASD; 3) to identify potential risk factors associated with the development of ASD in TSC patients. METHODS: We selected 42 individuals over age 4 years with a definite diagnosis of TSC and followed at a TSC clinic in Northern Italy. We collected and reported clinical and genetic data, as well as cognitive level, for each of them. We administered the Social Communication Questionnaire (SCQ) as a reliable screening tool for ASD, and performed comparisons between the average scores and each clinical and genetic feature. RESULTS: Seventeen out of 42 patients (40.5%) had a score at the SCQ suggestive of ASD (>/=15 points). When calculated for each cognitive level category, the average SCQ score tended to be progressively higher in patients with a worse cognitive level, and the number of pathological SCQ scores increased with worsening of intellectual disability. With respect to ASD severity, the scores were equally distributed, indicating that the degree of ASD in TSC patients may have a large variability. By comparing the average SCQ scores with the clinical features, we found statistically significant correlations with epilepsy, seizure onset before age one year, spasms, mutations in TSC2, cognitive level, sleep disorders, and other psychiatric problems, but not with seizure frequency, tubers localization and gender. CONCLUSIONS: Our study showed a prevalence of ASD of 40.5%, confirming the higher risk for this disorder in patients with TSC. However, the severity seems to have a notable variability in TSC patients. Risk factors for ASD are epilepsy, infantile spams, and mutations in TSC2.
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13. Wang Y, Billon C, Walker JK, Burris TP. {{Therapeutic Effect of a Synthetic RORalpha/gamma Agonist in an Animal Model of Autism}}. {ACS Chem Neurosci};2015 (Dec 3)
Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor alpha (RORalpha) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORalpha target genes. Utilizing a synthetic RORalpha/gamma agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORalpha target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORalpha may be a method for treatment of autism.
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14. Wheeler AC, Raspa M, Bishop E, Bailey DB, Jr. {{Aggression in fragile X syndrome}}. {J Intellect Disabil Res};2015 (Dec 2)
BACKGROUND: Individuals with fragile X syndrome (FXS), especially men, have long been described as presenting with significant behavioural challenges. Despite this known aspect of the phenotype, there has been little research exploring the prevalence, frequency, nature or consequences of aggressive behaviour in FXS. METHODS: This study used survey methodology to gather caregiver reports on the types, frequency and severity of aggressive behaviour in 774 individuals with FXS. RESULTS: Based on caregiver report, nearly all (>90%) male and female individuals were reported to have engaged in some aggression over the previous 12 months, with a third of male cases and slightly fewer than 20% of female cases being described as engaging in moderate to severe aggression or being diagnosed or treated for aggression. Further, aggressive behaviours in male individuals were serious enough that 30% had caused injuries to caregivers and 22% had caused injuries to peers or friends. Sensory issues and hyperactivity were significant predictors of the frequency of aggressive acts, while sensory issues and anxiety were predictive of the severity of aggression. Traditional behaviour management techniques as well as medication was described as the most common and successful treatment options. CONCLUSIONS: Aggressive behaviours are a significant concern for a subsample of both male and female individuals with FXS. Given that sensory concerns were predictive of both the frequency and the severity of aggression suggests these behaviours may be a reactive means of escaping uncomfortable situations.
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15. Wolfe FH, Auzias G, Deruelle C, Chaminade T. {{Focal atrophy of the hypothalamus associated with third ventricle enlargement in autism spectrum disorder}}. {Neuroreport};2015 (Dec 2);26(17):1017-1022.
The hypothalamus is a brain structure containing multiple nuclei that mediate essential behavioral, autonomic, and endocrine functions including oxytocin synthesis. Oxytocin is a neuropeptide linked to complex social cognition and behaviors necessary for an effective social interaction. Oxytocinergic system dysfunction has been linked to social deficits in autism spectrum disorders (ASD). Limited studies have been carried out on the hypothalamus because of its small size and methodological constraints in current technologies. This neuroimaging study examines hypothalamic atrophy in ASD in comparison with a typically developing population (a) by directly measuring gray matter (GM) density with a region-of-interest analysis using voxel-based morphometry in a homogenous sample of participants controlled for age and intelligence quotient; (b) for generalization, by measuring third ventricular volume, on the basis of its position bilaterally surrounded by the hypothalamus, using Freesurfer in a heterogeneous sample of participants. A voxel-based morphometry analysis of cerebrospinal fluid density on the first sample provides a link between GM density and third ventricle volume. Our results show decreased hypothalamic GM density and increased third ventricle volume in ASD compared with typically developing patients. Our findings provide neuroanatomical insights into social deficits in ASD within the hypothalamus that might be relevant for other psychiatric conditions.
