1. Anagnostou E, Chaplin W, Watner D, Silverman JM, Smith CJ, Zagursky K, Kryzak LA, Corwin TE, Feirsen N, Tanel N, Hollander E. {{Factor Analysis of Repetitive Behaviors in Autism as Measured by the Y-BOCS}}. {J Neuropsychiatry Clin Neurosci}. 2011; 23(3): 332-9.
The authors carried out a factor analysis of the Yale-Brown Obsessive-Compulsive Scale checklist at the category level in order to reduce the number of variables in this domain and ultimately identify possible endophenotypes; 181 children with autism were enrolled. The authors estimated a tetrachoric correlation matrix among the dichotomous symptom categories and then used exploratory and confirmatory factor analyses to identify a clinically meaningful factor structure for this correlation matrix. Their analysis supported a four-factor solution: obsessions, higher-order repetitive behaviors, lower-order repetitive behaviors, and hoarding. These findings are another step in the effort to identify genetically and biologically distinct groups within this population.
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2. Bakare MO, Munir KM, Kinney DK. {{Association of hypomelanotic skin disorders with autism: links to possible etiologic role of vitamin-D levels in autism?}}. {Hypothesis (Tor)}. 2011; 9(1): 6-14.
Vitamin D is crucial for several key physiological processes, including brain development, DNA repair, and regulation of many genes. Much evidence indicates prenatal and early postnatal vitamin-D deficiency increases autism risk, probably through multiple effects, including impaired brain development and increased de novo mutations. High autism rates in several genetically based hypomelanotic skin disorders are puzzling, because ultraviolet-B radiation (UVB) in sunlight acting on skin is a key source of vitamin-D, and lighter skin protects against vitamin-D deficiency, especially at high latitudes. We consider two hypotheses to help explain autism’s co-morbidity with hypomelanosis. 1) Because genetic and epigenetic variants that produce hypomelanosis help protect against vitamin-D deficiency, they increase reproductive fitness of individuals who also have other autism risk factors. 2) Hypomelanotic children have increased autism risk because photosensitivity and skin-cancer concerns lead families to excessively reduce children’s sun exposure. Hypothesis testing could involve studies comparing genomes, epigenetic markers, skin pigmentation, and vitamin-D levels in autistic individuals with and without hypomelanosis, their relatives and controls. Conducting such studies in samples from regions that differ widely in UVB availability would provide particularly valuable data. Support for either hypothesis would elucidate vitamin-D’s role in autism and suggest vitamin-D enhancement may aid treatment and prevention of autism.
3. Bakouie F, Gharibzadeh S. {{Toward a unifying hypothesis for schizophrenia and autism visual fragmentation}}. {J Neuropsychiatry Clin Neurosci}. 2011; 23(3): E25.
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4. Bakouie F, Gharibzadeh S, Towhidkhah F. {{Does the « dynamic core » approach help to manage autistic behavioral disorders?}}. {J Neuropsychiatry Clin Neurosci}. 2011; 23(3): E1.
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5. Bejerot S, Humble MB, Gardner A. {{Endocrine disruptors, the increase of autism spectrum disorder and its comorbidity with gender identity disorder – a hypothetical association}}. {Int J Androl}. 2011; 34(5 Pt 2): e350.
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6. Birmingham E, Cerf M, Adolphs R. {{Comparing social attention in autism and amygdala lesions: Effects of stimulus and task condition}}. {Soc Neurosci}. 2011.
The amygdala plays a critical role in orienting gaze and attention to socially salient stimuli. Previous work has demonstrated that SM a patient with rare bilateral amygdala lesions, fails to fixate and make use of information from the eyes in faces. Amygdala dysfunction has also been implicated as a contributing factor in autism spectrum disorders (ASD), consistent with some reports of reduced eye fixations in ASD. Yet, detailed comparisons between ASD and patients with amygdala lesions have not been undertaken. Here we carried out such a comparison, using eye tracking to complex social scenes that contained faces. We presented participants with three task conditions. In the Neutral task, participants had to determine what kind of room the scene took place in. In the Describe task, participants described the scene. In the Social Attention task, participants inferred where people in the scene were directing their attention. SM spent less time looking at the eyes and much more time looking at the mouths than control subjects, consistent with earlier findings. There was also a trend for the ASD group to spend less time on the eyes, although this depended on the particular image and task. Whereas controls and SM looked more at the eyes when the task required social attention, the ASD group did not. This pattern of impairments suggests that SM looks less at the eyes because of a failure in stimulus-driven attention to social features, whereas individuals with ASD look less at the eyes because they are generally insensitive to socially relevant information and fail to modulate attention as a function of task demands. We conclude that the source of the social attention impairment in ASD may arise upstream from the amygdala, rather than in the amygdala itself.
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7. Bolling DZ, Pitskel NB, Deen B, Crowley MJ, McPartland JC, Kaiser MD, Wyk BC, Wu J, Mayes LC, Pelphrey KA. {{Enhanced Neural Responses to Rule Violation in Children with Autism: A Comparison to Social Exclusion}}. {Dev Cogn Neurosci}. 2011; 1(3): 280-94.
The present study aimed to explore the neural correlates of two characteristic deficits in autism spectrum disorders (ASD); social impairment and restricted, repetitive behavior patterns. To this end, we used comparable experiences of social exclusion and rule violation to probe potentially atypical neural networks in ASD. In children and adolescents with and without ASD, we used the interactive ball-toss game (Cyberball) to elicit social exclusion and a comparable game (Cybershape) to elicit a non-exclusive rule violation. Using functional magnetic resonance imaging (fMRI), we identified group differences in brain responses to social exclusion and rule violation. Though both groups reported equal distress following exclusion, the right insula and ventral anterior cingulate cortex were hypoactive during exclusion in children with ASD. In rule violation, right insula and dorsal prefrontal cortex were hyperactive in ASD. Right insula showed a dissociation in activation; it was hypoactive to social exclusion and hyperactive to rule violation in the ASD group. Further probed, different regions of right insula were modulated in each game, highlighting differences in regional specificity for which subsequent analyses revealed differences in patterns of functional connectivity. These results demonstrate neurobiological differences in processing social exclusion and rule violation in children with ASD.
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8. Burket JA, Herndon AL, Winebarger EE, Jacome LF, Deutsch SI. {{Complex effects of mGluR5 antagonism on sociability and stereotypic behaviors in mice: Possible implications for the pharmacotherapy of autism spectrum disorders}}. {Brain Res Bull}. 2011; 86(3-4): 152-8.
Balb/c mice display deficits of sociability; for example, they show reduced locomotor activity in the presence of an enclosed or freely-moving social stimulus mouse. Transgenic mice with defective or diminished expression of NMDA receptors manifest impaired sociability, while a partial and full agonist of the obligatory glycine co-agonist binding site on the NMDA receptor improved sociability in the Balb/c mouse strain. Because 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor (mGluR), reduced self-grooming behavior in BTBR T+tfJ (BTBR) mice, another inbred genetic mouse model of autism spectrum disorders (ASDs), and mGluR5 antagonism is emerging as an experimental treatment for the ‘fragile X syndrome, » which has a high prevalence of co-morbid ASDs, we examined the effects of MPEP on sociability and stereotypic behaviors in Balb/c and Swiss Webster mice in a standard paradigm. MPEP had complex effects on sociability, impairing some measures of sociability in both strains, while it reduced the intensity of some spontaneous measures of stereotypic behaviors emerging during free social interaction in Swiss Webster mice. Conceivably, mGluR5 antagonism exacerbates diminished endogenous tone of NMDA receptor-mediated neurotransmission in neural circuits relevant to at least some measures of sociability in Balb/c mice; the mGluR5 receptor contributes to regulation of the phosphorylation status of the NMDA receptor. In any event, although stereotypies are an important therapeutic target in ASDs, medication strategies to attenuate their severity via antagonism of mGluR5 receptors must be pursued cautiously because of their potential to worsen at least some measures of sociability.
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9. Casenhiser DM, Shanker SG, Stieben J. {{Learning Through Interaction in Children With Autism: Preliminary Data From a Social-Communication-Based Intervention}}. {Autism}. 2011.
The study evaluates a social-communication-based approach to autism intervention aimed at improving the social interaction skills of children with autism spectrum disorder. We report preliminary results from an ongoing randomized controlled trial of 51 children aged 2 years 0 months to 4 years 11 months. Participants were assigned to either a target treatment or community treatment group. Families in the target treatment group were given 2 hours of therapy and coaching each week in an intervention emphasizing social-interaction and the parent-child relationship. Children in the community treatment group received a variety of services averaging 3.9 hours per week. After 12 months, outcomes were measured to determine changes in the groups in social interaction and communication. In addition, a regression analysis was conducted to determine whether changes in social interaction skills were associated with language development. Results suggest that children in the treatment group made significantly greater gains in social interaction skills in comparison to the community treatment group, but no between-group differences were found for standard language assessments. Initiation of joint attention, involvement, and severity of language delay were found to be significantly associated with improvement of language skills in children with autism. Finally caregiver skills targeted by the intervention were found to be significantly associated with changes in children’s interaction skills.
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10. Cheon KA, Kim YS, Oh SH, Park SY, Yoon HW, Herrington J, Nair A, Koh YJ, Jang DP, Kim YB, Leventhal BL, Cho ZH, Castellanos FX, Schultz RT. {{Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: A Diffusion Tensor Imaging study}}. {Brain Res}. 2011; 1417C: 77-86.
Background: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI). Methods: We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). Results: The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p<0.05, corrected). We found significantly lower FA in right and left ATR, CC, left UF and right and left ILF and significantly higher MD values of the CC in the ASD group in region of interest-based analyses. We also observed significantly higher RD values of right and left ATR, CC, left UF, left ILF in subjects with ASD compared to typically developing boys and significantly lower AD values of both ILF. Right ATR and right UF FA was significantly negatively correlated with total SRS score within the ASD group (r=-.56, p=.02). Conclusions: Our preliminary findings support evidence implicating disturbances in the thalamo-frontal connections in autism. These findings highlight the role of hypoconnectivity between the frontal cortex and thalamus in ASD.
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11. de Bildt A, Mulder EJ, Van Lang ND, de With SA, Minderaa RB, Stahl SS, Anderson GM. {{The visual rooting reflex in individuals with autism spectrum disorders and co-occurring intellectual disability}}. {Autism Res}. 2011.
The rooting reflex has long been studied by neurologists and developmentalists and is defined as an orientation toward tactile stimulation in the perioral region or visual stimulation near the face. Nearly, all previous reports of the visual rooting reflex (VRR) concern its presence in adults with neurological dysfunction. Previously, the VRR was reported to be present in a majority of individuals with autism and absent in control subjects. In the present larger study, we examined the presence of the VRR in 155 individuals with ASD and co-occurring Intellectual Disability (ASD + ID: autism, N = 60; Pervasive Developmental Disorder-Not Otherwise Specified (PDD_NOS), N = 95) and in a contrast group of 65 individuals with ID only. The VRR was present significantly more often in the ASD + ID (43.9%) group than in the ID-only group (24.6%; = 7.19; P = 0.007). Individuals with autism displayed a VRR more often (55.0%) than individuals with PDD-NOS (36.8%; = 4.92; P = 0.026) and individuals with ID only (24.6%; = 12.09; P = 0.001). A positive VRR was associated with lower IQ and adaptive functioning; in the ASD + ID group, ADI-R/ADOS domain scores were significantly higher in the VRR-positive subgroup. The results replicate and extend the finding of an increased occurrence of the VRR in autism. Although some association with IQ was observed, the VRR occurred substantially more often in the autism group compared with an intellectually disabled group, indicating some degree of specificity. Additional studies of infants and children with typical development, ASD and ID are needed to determine the utility of the VRR in ASD risk assessment and to elucidate possible specific behavioral associations. Autism Res 2011,4:xxx-xxx. (c) 2011 International Society for Autism Research, Wiley Periodicals, Inc.
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12. De la Marche W, Noens I, Luts J, Scholte E, Van Huffel S, Steyaert J. {{Quantitative Autism Traits in First Degree Relatives: Evidence for the Broader Autism Phenotype in Fathers, but not in Mothers and Siblings}}. {Autism}. 2011.
Autism spectrum disorder (ASD) symptoms are present in unaffected relatives and individuals from the general population. Results are inconclusive, however, on whether unaffected relatives have higher levels of quantitative autism traits (QAT) or not. This might be due to differences in research populations, because behavioral data and molecular genetic research suggest that the genetic etiology of ASD is different in multiplex and simplex families. We compared 117 unaffected siblings and 276 parents of at least one child with ASD with 280 children and 595 adults from the general population on the presence of QAT using the Social Responsiveness Scale (SRS). Mean SRS scores for siblings, control children, parents and control adults were 25.4, 26.6, 33.7 and 32.9. Fathers of children with ASD showed significantly higher levels of QAT than controls, but siblings and mothers did not. We could not detect a statistically significant difference in SRS scores between relatives from simplex and multiplex families. These results do not support the theory of differential (genetic) etiology in multiplex and simplex families and suggest that a carried genetic risk is generally not expressed phenotypically in most relatives, except in fathers.
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13. Estigarribia B, Martin GE, Roberts JE, Spencer A, Gucwa A, Sideris J. {{Narrative Skill in Boys with Fragile X Syndrome with and without Autism Spectrum Disorder}}. {Appl Psycholinguist}. 2011; 32(2): 359-88.
We examined recalled narratives of boys with fragile X syndrome with autism spectrum disorder (FXS-ASD; N=28) and without ASD (FXS-O; N=29), and compared them to those of boys with Down syndrome (DS; N=33) and typically developing boys (TD; N=39). Narratives were scored for mentions of macrostructural Story Grammar elements (Introduction, Relationship, Initiating Events, Internal Response, Attempts/Actions, and Ending). We found that narrative recall is predicted by short-term memory and nonverbal mental age levels in almost all groups (except TD), but not by expressive syntax or caregiver education. After adjusting for these covariates, there were no differences between the three groups with intellectual disability (ID). The FXS-ASD group, however, had significantly poorer performance than the TD group on the overall Story Grammar score, and both the FXS-O and FXS-ASD groups had lower Attempts/Actions scores than the TD group. We conclude that some form of narrative impairment may be associated with FXS, that this impairment may be shared by other forms of ID, and that the presence of ASD has a significantly detrimental effect on narrative recall.
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14. Gauthier J, Siddiqui TJ, Huashan P, Yokomaku D, Hamdan FF, Champagne N, Lapointe M, Spiegelman D, Noreau A, Lafreniere RG, Fathalli F, Joober R, Krebs MO, Delisi LE, Mottron L, Fombonne E, Michaud JL, Drapeau P, Carbonetto S, Craig AM, Rouleau GA. {{Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia}}. {Hum Genet}. 2011; 130(4): 563-73.
Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.
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15. Gebregziabher M, Shotwell MS, Charles JM, Nicholas JS. {{Comparison of Methods for Identifying Phenotype Subgroups Using Categorical Features Data With Application to Autism Spectrum Disorder}}. {Comput Stat Data Anal}. 2012; 56(1): 114-25.
We evaluate the performance of the Dirichlet process mixture (DPM) and the latent class model (LCM) in identifying autism phenotype subgroups based on categorical autism spectrum disorder (ASD) diagnostic features from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision. A simulation study is designed to mimic the diagnostic features in the ASD dataset in order to evaluate the LCM and DPM methods in this context. Likelihood based information criteria and DPM partitioning are used to identify the best fitting models. The Rand statistic is used to compare the performance of the methods in recovering simulated phenotype subgroups. Our results indicate excellent recovery of the simulated subgroup structure for both methods. The LCM performs slightly better than DPM when the correct number of latent subgroups is selected a priori. The DPM method utilizes a maximum a posteriori (MAP) criterion to estimate the number of classes, and yielded results in fair agreement with the LCM method. Comparison of model fit indices in identifying the best fitting LCM showed that adjusted Bayesian information criteria (ABIC) picks the correct number of classes over 90% of the time. Thus, when diagnostic features are categorical and there is some prior information regarding the number of latent classes, LCM in conjunction with ABIC is preferred.
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16. Kavsak PA. {{Autism spectrum disorder: When biochemical and genetic profiles don’t match – Is sample size and selection bias the culprit?}}. {Clin Biochem}. 2011.
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17. Keri S, Benedek G. {{Fragile X protein expression is linked to visual functions in healthy male volunteers}}. {Neuroscience}. 2011; 192: 345-50.
Fragile X syndrome (FXS) is characterized by the impairment of the magnocellular/dorsal visual system. In this study, we explored how fragile X protein (FMRP) expression may affect visual functions in healthy participants. The percentage of FMRP-positive lymphocytes was measured using a rapid antibody test in blood smears of 100 male volunteers. CGG triplet expansion was also determined. Results revealed that participants with fewer FMRP-positive lymphocytes exhibited lower performances on tests biasing information processing toward the magnocellular pathway and dorsal visual stream (contrast sensitivity at low spatial/high temporal frequency and motion coherence). It was not observed in the case of tests biasing information processing toward the parvocellular pathway and ventral stream (contrast sensitivity at high spatial/low temporal frequency and form coherence). These results suggest that healthy persons with lower peripheral FMRP expression display a visual phenotype similar to that described in patients with FXS.
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18. Kliushnik TP, Androsova LV, Simashkova NV, Zozulia SA, Otman IN, Koval’-Zaitsev AA. {{[Innate and adaptive immunity in children with psychotic forms of autism-spectrum disorders.]}}. {Zh Nevrol Psikhiatr Im S S Korsakova}. 2011; 111(8): 41-5.
Leukocyte elastase (LE) activity, functional activity of alpha1-proteinase inhibitor, C-reactive protein, autoantibodies to nerve growth factor and to basic myelin protein have been studied in the blood serum of children with psychotic forms of autistic disorders – children psychosis (F84.02) and atypical children psychosis (F84.11). The activation of innate immunity (the increase in LE activity and acute phase proteins) was seen in children psychosis. The more severe mental disturbances, that are characteristic of endogenous atypical children psychosis, were accompanied by the activation of both innate and adaptive immunity ( the increase of the level of autoantibodies to neuroantigenes in the peripheral blood). Correlations between immunological and clinical parameters suggest the involvement of innate and adaptive immunity in the formation of autistic and cognitive disorders in children.
19. Lou HC. {{Paradigm shift in consciousness research: the child’s self-awareness and abnormalities in autism, ADHD and schizophrenia}}. {Acta Paediatr}. 2011.
Self-awareness is a pivotal component of any conscious experience and conscious self-regulation of behaviour. A paralimbic network is active, specific and causal in self-awareness. Its regions interact by gamma synchrony. Gamma synchrony develops throughout infancy, childhood and adolescence into adulthood and is regulated by dopamine and other neurotransmitters via GABA interneurons. Major derailments of this network and self-awareness occur in developmental disorders of conscious self-regulation like autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia. Conclusion: Recent research on conscious experience is no longer limited to the study of neural ‘correlations’ but is increasingly lending itself to the study of causality. This paradigm shift opens new perspectives for understanding the neural mechanisms of the developing self and the causal effects of their disturbance in developmental disorders.
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20. Lundstrom S, Chang Z, Kerekes N, Gumpert CH, Rastam M, Gillberg C, Lichtenstein P, Anckarsater H. {{Autistic-like traits and their association with mental health problems in two nationwide twin cohorts of children and adults}}. {Psychol Med}. 2011; 41(11): 2423-33.
BACKGROUND: Autistic-like traits (ALTs), that is restrictions in intuitive social interaction, communication and flexibility of interests and behaviors, were studied in two population-based Swedish twin studies, one in children and one in adults: (1) to examine whether the variability in ALTs is a meaningful risk factor for concomitant attention deficit hyperactivity disorder (ADHD), anxiety, conduct problems, depression and substance abuse, and (2) to assess whether common genetic and environmental susceptibilities can help to explain co-existence of ALTs and traits associated with such concomitant problems.MethodTwo nationwide twin cohorts from Sweden (consisting of 11 222 children and 18 349 adults) were assessed by DSM-based symptom algorithms for autism. The twins were divided into six groups based on their degree of ALTs and the risk for concomitant mental health problems was calculated for each group. Genetic and environmental susceptibilities common to ALTs and the other problem types were examined using bivariate twin modeling. RESULTS: In both cohorts, even the lowest degree of ALTs increased the risk for all other types of mental health problems, and these risk estimates increased monotonically with the number of ALTs. For all conditions, common genetic and environmental factors could be discerned. Overall, the phenotypic correlation between ALTs and the traits examined were less pronounced in adulthood than in childhood and less affected by genetic compared with environmental factors. CONCLUSIONS: Even low-grade ALTs are relevant to clinical psychiatry as they increase the risk for several heterotypical mental health problems. The association is influenced partly by common genetic and environmental susceptibilities. Attention to co-existing ALTs is warranted in research on a wide range of mental disorders.
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21. Mandy W, Chilvers R, Chowdhury U, Salter G, Seigal A, Skuse D. {{Sex Differences in Autism Spectrum Disorder: Evidence from a Large Sample of Children and Adolescents}}. {J Autism Dev Disord}. 2011.
Sex differences have been found amongst toddlers and young children with autism spectrum disorder (ASD). We investigated the presence and stability of these ASD sex differences throughout childhood and adolescence. Participants (N = 325, 52 females; aged 3-18 years) consecutively received an ASD diagnosis at a clinic for assessing high-functioning ASD (mean verbal IQ = 92.6). There were no IQ sex differences. By parent report and direct observation, females had less repetitive stereotyped behaviour (RSB), with male-equivalent levels of social and communication impairment. Teachers reported males with ASD as having greater externalising and social problems than females. The female phenotype we describe was stable across our sample’s age range. Their milder RSBs and less severe difficulties at school may lead to under-recognition of ASD in females.
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22. Marcus RN, Owen R, Manos G, Mankoski R, Kamen L, McQuade RD, Carson WH, Findling RL. {{Safety and tolerability of aripiprazole for irritability in pediatric patients with autistic disorder: a 52-week, open-label, multicenter study}}. {J Clin Psychiatry}. 2011; 72(9): 1270-6.
OBJECTIVE: Evaluate the long-term safety and tolerability of aripiprazole in the treatment of irritability in pediatric subjects (6-17 years) with autistic disorder. METHOD: A 52-week, open-label, flexibly dosed (2-15 mg/d) study of the safety and tolerability of aripiprazole in outpatients with a DSM-IV-TR diagnosis of autistic disorder who either had completed 1 of 2 antecedent, 8-week randomized trials or were enrolled de novo (ie, not treated in the randomized trials). Safety and tolerability measures included incidences of adverse events, extrapyramidal symptoms, weight, metabolic measures, vital signs, and other clinical assessments. RESULTS: Subjects were enrolled between September 2006 and June 2009. Three hundred thirty subjects entered the treatment phase: 86 de novo, 174 prior aripiprazole, and 70 prior placebo. A total of 199 (60.3%) subjects completed 52 weeks of treatment. Adverse events were experienced by 286/330 subjects (86.7%). Common adverse events included weight increase, vomiting, nasopharyngitis, increased appetite, pyrexia, upper respiratory tract infection, and insomnia. Discontinuations due to adverse events occurred in 35/330 randomized subjects (10.6%)-most commonly aggression and weight increase. One patient discontinued from the study due to a laboratory-related adverse event (moderately increased alanine transaminase and aspartate transaminase). Nine subjects experienced serious adverse events-most frequently aggression. Extrapyramidal symptoms-related adverse events occurred in 48/330 subjects (14.5%)-most commonly tremor (3.0%), psychomotor hyperactivity (2.7%), akathisia (2.4%), and dyskinesia (not tardive, 2.4%). At > 9 months’ aripiprazole exposure (n = 220), mean change in body weight z score was 0.33 and body mass index z score was 0.31. The percentages of subjects with clinically significant fasting metabolic abnormalities at > 9 months were 2% for glucose, 5% for total cholesterol, 7% for low-density lipoprotein cholesterol, 30% for high-density lipoprotein cholesterol, and 5% for triglycerides. CONCLUSIONS: Aripiprazole was generally safe and well tolerated in the long-term treatment of irritability associated with autistic disorder in pediatric subjects. Weight should be proactively monitored during long-term treatment. TRIAL REGISTRATION: clinical trials.gov Identifier: NCT00365859.
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23. Martos-Perez J, Paula-Perez I. {{[An approach to the executive functions in autism spectrum disorder]}}. {Rev Neurol}. 2011; 52 Suppl 1: S147-53.
INTRODUCTION: The psychological hypothesis of executive dysfunction plays a crucial role in explaining the behavioural phenotype of persons with autism spectrum disorders (ASD), along with other hypotheses such as the deficit in the theory of mind or the weak central coherence hypothesis. Yet, none of these hypotheses are mutually exclusive and behaviours that have their origins in one of these three hypotheses are also shaped and upheld by other processes and factors. DEVELOPMENT: This article reviews the behavioural manifestation and current state of research on the executive functions in persons with ASD. It also examines its impact on planning, mental flexibility and cognitive skills, generativity, response inhibition, mentalist skills and sense of activity. CONCLUSIONS: Although executive dysfunction has become more significant as a hypothesis explaining persons with ASD, there remain some important difficulties in need of further, more detailed research. Moreover, very few intervention programmes have been proved to be effective in minimising the effects of executive dysfunction in autism.
24. McPartland JC, Crowley MJ, Perszyk DR, Naples A, Mukerji CE, Wu J, Molfese P, Bolling DZ, Pelphrey KA, Mayes LC. {{Temporal dynamics reveal atypical brain response to social exclusion in autism}}. {Dev Cogn Neurosci}. 2011; 1(3): 271-9.
Despite significant social difficulties, children with autism spectrum disorder (ASD) are vulnerable to the effects of social exclusion. We recorded EEG while children with ASD and typical peers played a computerized game involving peer rejection. Children with ASD reported ostracism-related distress comparable to typically developing children. Event-related potentials (ERPs) indicated a distinct pattern of temporal processing of rejection events in children with ASD. While typically developing children showed enhanced response to rejection at a late slow wave indexing emotional arousal and regulation, those with autism showed attenuation at an early component, suggesting reduced engagement of attentional resources in the aversive social context. Results emphasize the importance of studying the time course of social information processing in ASD; they suggest distinct mechanisms subserving similar overt behavior and yield insights relevant to development and implementation of targeted treatment approaches and objective measures of response to treatment.
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25. Moskal JR, Burgdorf J, Kroes RA, Brudzynski SM, Panksepp J. {{A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism}}. {Neurosci Biobehav Rev}. 2011; 35(9): 1982-8.
Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist d-cycloserine has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that rats selectively bred for low rates of play-induced pro-social ultrasonic vocalizations (USVs) can be used to model certain core symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play-induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism. We dedicate this paper to Ole Ivar Lovaas (May 8, 1927-August 2, 2010), a pioneer in the field of autism.
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26. Murphy CM, Deeley Q, Daly EM, Ecker C, O’Brien FM, Hallahan B, Loth E, Toal F, Reed S, Hales S, Robertson DM, Craig MC, Mullins D, Barker GJ, Lavender T, Johnston P, Murphy KC, Murphy DG. {{Anatomy and aging of the amygdala and hippocampus in autism spectrum disorder: an in vivo magnetic resonance imaging study of Asperger syndrome}}. {Autism Res}. 2011.
It has been proposed that people with autism spectrum disorder (ASD) have abnormal morphometry and development of the amygdala and hippocampus (AH). However, previous reports are inconsistent, perhaps because they included people of different ASD diagnoses, ages, and health. We compared, using magnetic resonance imaging, the in vivo anatomy of the AH in 32 healthy individuals with Asperger syndrome (12-47 years) and 32 healthy controls who did not differ significantly in age or IQ. We measured bulk (gray + white matter) volume of the AH using manual tracing (MEASURE). We first compared the volume of AH between individuals with Asperger syndrome and controls and then investigated age-related differences. We compared differences in anatomy before, and after, correcting for whole brain size. There was no significant between group differences in whole brain volume. However, individuals with Asperger syndrome had a significantly larger raw bulk volume of total (P<0.01), right (P<0.01), and left amygdala (P<0.05); and when corrected for overall brain size, total (P<0.05), and right amygdala (P<0.01). There was a significant group difference in aging of left amygdala; controls, but not individuals with Asperger syndrome, had a significant age-related increase in volume (r = 0.486, P<0.01, and r = 0.007, P = 0.97, z = 1.995). There were no significant group differences in volume or age-related effects in hippocampus. Individuals with Asperger syndrome have significant differences from controls in bulk volume and aging of the amygdala. Autism Res 2011,4:xxx-xxx. (c) 2011 International Society for Autism Research, Wiley Periodicals, Inc.
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27. Nolin SL, Glicksman A, Ding X, Ersalesi N, Brown WT, Sherman SL, Dobkin C. {{Fragile X analysis of 1112 prenatal samples from 1991 to 2010}}. {Prenat Diagn}. 2011; 31(10): 925-31.
OBJECTIVE: To determine risks of expansion for normal, intermediate, and premutation FMR1 CGG repeats. METHODS: PCR was used to compare the FMR1 alleles in prenatal (chorionic villi and amniocytes) and parental samples collected from 1991 to 2010. Prenatal diagnoses were confirmed by Southern analysis. RESULTS: Fragile X analysis of 1112 pregnancies identified 558 normal, 106 intermediate, 216 premutation, and 232 full mutation fetuses. Of 509 maternal, intermediate, and premutation alleles, 350 (68.7%) were unstable on transmission with expansions ranging from one repeat to the full mutation. The smallest premutation alleles expanding to the full mutation were in mothers with 65 and 66 repeats. Transmissions from women with or without a family history of fragile X suggested greater instability in women from families that included full mutation expansions. CONCLUSIONS: The maternal transmissions of alleles with 55 to 59 CGG repeats summarized here indicate that the risk for expansion to full mutation is substantially less than previous estimates for this size category. Most premutation alleles with no family history of fragile X exhibited less instability than those with a history of fragile X. Thus, lower risk estimates for full mutation expansion may be appropriate for women newly identified as premutation carriers through routine screening. Copyright (c) 2011 John Wiley & Sons, Ltd.
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28. Palau-Baduell M, Valls-Santasusana A, Salvado-Salvado B. {{[Autism spectrum disorders and mu rhythm. A new neurophysiological view]}}. {Rev Neurol}. 2011; 52 Suppl 1: S141-6.
Electroencephalographic studies of subjects with autism spectrum disorders (ASD) provide evidences of brain functional aspects in this pathology. Mu rhythm can be reactive in normal population (mu suppression) to both self-movements and to movements performed by others. These reactivities are considered to be related to mirror neurons activity. Subjects with ASD show significant mu suppression to self-movements but they fail to react to the movements performed by others. These findings support the hypothesis of a dysfunctional mirror neurons system in individuals with ASD. Moreover, dysfunction of mirror neurons would be related to social and communicative impairments, cognitive deficits and impairment imitation skills associated with ASD.
29. Papadopoulos N, McGinley J, Tonge B, Bradshaw J, Saunders K, Murphy A, Rinehart N. {{Motor Proficiency and Emotional/Behavioural Disturbance in Autism and Asperger’s Disorder: Another Piece of the Neurological Puzzle?}}. {Autism}. 2011.
The relationship of motor proficiency with emotional/behavioural disturbance, autistic symptoms and communication disturbance was investigated in children diagnosed with autism and Asperger’s disorder (AD). The Movement Assessment Battery for Children was used as a measure of motor impairment, and the Developmental Behavioural Checklist was used as a measure of emotional/behavioural disturbance in the following groups: AD (n = 22), high functioning autism (HFA) (n = 23), LFA (n = 8) and typically developing children (n = 20). The HFA group had more difficulty with motor items, such as ball skills and balance, than did the AD group. There were significant positive correlations between impairments in motor proficiency (in particular ball skills and balance) and emotional/behavioural disturbance, autistic symptoms and communication disturbance. These findings are consistent with the hypothesis that there are qualitative and quantitative differences in the motor profile between autism and AD. In addition, the association between motor proficiency impairment and emotional/behavioural disturbance in autism and AD emphasizes the importance for screening of co-occurring emotional/behavioural symptoms in individuals with motor difficulties. These findings have implications for the potential use of adjunct motor measures in the diagnosis and definition of autism spectrum disorders.
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30. Petersen JM, Marinova-Todd SH, Mirenda P. {{Brief Report: An Exploratory Study of Lexical Skills in Bilingual Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2011.
Studying lexical diversity in bilingual children with autism spectrum disorders (ASD) can contribute important information to our understanding of language development in this diverse population. In this exploratory study, lexical comprehension and production and overall language skills were investigated in 14 English-Chinese bilingual and 14 English monolingual preschool-age children with ASD. Results indicated that both groups had equivalent scores on all but one measure of language and vocabulary, including English production vocabulary, conceptual production vocabulary, and vocabulary comprehension. When comparing the two languages of bilingual participants, there were no significant differences in production vocabulary size or vocabulary comprehension scores. The results provide evidence that bilingual English-Chinese preschool-age children with ASD have the capacity to function successfully as bilinguals.
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31. Rayner C. {{Teaching students with autism to tie a shoelace knot using video prompting and backward chaining}}. {Dev Neurorehabil}. 2011.
Purpose: To evaluate the effects of video prompting and backward chaining for teaching students with autism to tie a shoelace knot. Method: Videos featuring an adult and a peer or sibling model were used as part of the video prompting procedures to teach three boys with autism to tie a shoelace knot. A backward chaining procedure involving live modelling and verbal instruction was introduced following the video prompting phases. Results: Although the video prompting interventions increased the number of steps in the shoelace tying task completed by each of the participants, the backward chaining procedure was more effective, enabling one participant to reach mastery and a second participant to approach mastery. Conclusion: Practitioners should consider the pre-requisite skills of the participants and the nature of the target behaviour when selecting an intervention to teach daily living skills to individuals with autism.
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32. Rayner C. {{Sibling and adult video modelling to teach a student with autism: Imitation skills and intervention suitability}}. {Dev Neurorehabil}. 2011.
Purpose: To investigate the effectiveness of adult-as-model and sibling-as-model video modelling procedures for an individual with autism who demonstrated limited imitation skills. Methods: This study assessed the imitation ability of Matthew, a 15 year-old boy with autism, and then used video modelling, with his sibling and an adult as models, in order to teach him to match coins, respond to questions in a group discussion time and prepare a snack of noodles. Results: Matthew seldom responded to imitative opportunities in the assessment. Also, minimal changes in his ability to perform the target behaviours resulted from either of the video modelling conditions. Conclusion: An individual’s imitation skills are an important pre-requisite for successful video modelling intervention.
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33. Reed P, Staytom L, Stott S, Truzoli R. {{Comparison of conditioning impairments in children with Down syndrome, autistic spectrum disorders and mental age-matched controls}}. {J Intellect Disabil Res}. 2011; 55(10): 988-97.
Background This study investigated the relative ease of learning across four tasks suggested by an adaptation of Thomas’s hierarchy of learning in children with Down syndrome, autism spectrum disorders and mental age-matched controls. Methods Learning trials were carried out to investigate observational learning, instrumental learning, reversal learning and conditional discrimination. Results The sample with autism spectrum disorders performed worse than the other two groups on the observational learning and conditional discrimination tasks, while the Down syndrome sample performed worse on the instrumental learning task. Conclusions These findings are discussed in terms of there implications for reward-based educational intervention programmes.
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34. Reiersen AM, Handen B. {{Commentary on ‘Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD)’}}. {Evid Based Child Health}. 2011; 6(4): 1082-5.
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35. Reynolds KE. {{Autism spectrum disorders in childhood: a clinical update}}. {Community Pract}. 2011; 84(7): 36-8.
Autism spectrum disorders refer to a range of conditions such as autism disorder and Asperger syndrome that may affect about 1% of children in the UK. This paper aims to consider diagnosis and to provide an overview of potentially useful therapies and support.
36. Samios CM, Pakenham KI, Sofronoff K. {{Sense Making and Benefit Finding in Couples who Have a Child With Asperger Syndrome: An Application of the Actor-Partner Interdependence Model}}. {Autism}. 2011.
Parents of children with Asperger syndrome face many challenges that may lead them to search for meaning by developing explanations for (sense making) and finding benefits (benefit finding) in having a child with special needs. Although family theorists have proposed that finding meaning occurs interpersonally, there is a dearth of empirical research that has examined finding meaning at the couple level. This study examined sense making and benefit finding in 84 couples who have a child with Asperger syndrome by using the Actor-Partner Interdependence Model (Kenny et al., 2006) to examine actor effects (i.e. the extent to which an individual’s score on the predictor variable impacts his or her own level of adjustment) and partner effects (i.e. the extent to which an individual’s score on the predictor variable has an impact on his or her partner’s level of adjustment) of sense making and benefit finding on parental adjustment. Results demonstrated that parents’ benefit finding related to greater anxiety and parents’ sense making related to not only their own adjustment but also their partner’s adjustment. Results highlight the importance of adopting an interpersonal perspective on finding meaning and adjustment. Limitations, future research and clinical implications are also discussed.
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37. Sasamoto A, Miyata J, Hirao K, Fujiwara H, Kawada R, Fujimoto S, Tanaka Y, Kubota M, Sawamoto N, Fukuyama H, Takahashi H, Murai T. {{Social impairment in schizophrenia revealed by Autism-Spectrum Quotient correlated with gray matter reduction}}. {Soc Neurosci}. 2011.
One of the difficulties facing schizophrenia patients is a failure to construct appropriate relationships with others in social situations. This impairment of social cognition is also found in autism-spectrum disorder (ASD). Considering such commonality between the two disorders, in this study we adopted the Autism-Spectrum Quotient (AQ) score to assess autistic traits, and explored the association between such traits and gray matter (GM) alterations of the brain in schizophrenia. Twenty schizophrenia patients and 25 healthy controls underwent structural magnetic resonance imaging (MRI), and AQ was assessed, comprising five subscales measuring different facets of autistic traits. Voxel-based morphometry (VBM) was applied to investigate the correlation between these AQ scores and regional GM alterations. Schizophrenia patients showed significantly higher scores in total AQ, and in four of the five subscales, compared to healthy controls. The total AQ score in schizophrenia showed significant negative correlation with GM volume reduction in the cortical area surrounding the left superior temporal sulcus (STS), which is considered to be important in social perception. Our findings suggest a possible neuroanatomical basis of autistic tendencies in schizophrenia. This research was supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, Japan (20691401 to T. M. and 21890119 to J. M.), a grant from the Ministry of Health, Labor and Welfare, Japan (20E-3 to T. M.), and a research grant from the Research Group for Schizophrenia sponsored by Astellas Pharma, Inc., and the Mitsubishi Pharma Research Foundation. We thank Ms Miho Yoshizumi and Drs Mitsuaki Shimizu, Keita Ueda, and Akiko Hayashi for assistance and support, and the patients and volunteers for participating in the study.
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38. Thomke H, Boser K. {{« Language construction in an autistic child: thoughts regarding language acquisition and language therapy »: translation, update, and commentary on a 1977 case report}}. {Cogn Behav Neurol}. 2011; 24(3): 156-67.
A 1977 Swiss case study is presented in English translation: a mute child with infantile autism is taught to speak starting at the relatively late age of 6. The author, who is the primary therapist and the child’s father, details the conditioning procedure, discusses theoretical considerations in speech acquisition, and outlines the limits of the training. The author and translator update the child’s status and add commentary.
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39. van Balkom ID, Shaw A, Vuijk PJ, Franssens M, Hoek HW, Hennekam RC. {{Development and behaviour in Marshall-Smith syndrome: an exploratory study of cognition, phenotype and autism}}. {J Intellect Disabil Res}. 2011; 55(10): 973-87.
Background Marshall-Smith syndrome (MSS) is an infrequently described entity characterised by failure to thrive, developmental delay, abnormal bone maturation and a characteristic face. In studying the physical features of a group of patients, we noticed unusual behavioural traits. This urged us to study cognition, behavioural phenotype and autism in six patients. Methods Information on development, behavioural characteristics, autism symptoms, and adaptive and psychological functioning of six MSS children was collected through in-person examinations, questionnaires, semi-structured interviews of parents and neuropsychological assessments. Results Participants showed moderate to severe delays in mental age, motor development and adaptive functioning, with several similarities in communication, social interactions and behaviour. There was severe delay of speech and motor milestones, a friendly or happy demeanour and enjoyment of social interactions with familiar others. They exhibited minimal maladaptive behaviours. Deficits in communication and social interactions, lack of reciprocal social communication skills, limited imaginary play and the occurrence of stereotyped, repetitive behaviours were noted during assessments. Conclusions Systematic collection of developmental and behavioural data in very rare entities such as MSS allows recognition of specific patterns in these qualities. Clinical recognition of physical,developmental and behavioural features is important not only for diagnosis, prognosis and counselling of families, but also increases our understanding of the biological basis of the human physical and behavioural phenotype.
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40. Veeraragavan S, Bui N, Perkins JR, Yuva-Paylor LA, Paylor R. {{The modulation of fragile X behaviors by the muscarinic M4 antagonist, tropicamide}}. {Behav Neurosci}. 2011; 125(5): 783-90.
Muscarinic acetylcholine receptors (mAChR) are G protein-coupled receptors (M1-M5), grouped together into two functional classes, based on their G protein interaction. Although ubiquitously expressed in the CNS, the M4 protein shows highest expression in the neostriatum, cortex, and hippocampus. Electrophysiological and biochemical studies have provided evidence for overactive mAChR signaling in the fragile X knock-out (Fmr1KO) mouse model, and this has been hypothesized to contribute to the phenotypes seen in Fmr1KO mice. To address this hypothesis we used an M4 antagonist, tropicamide, to reduce the activity through the M4 mAChR and investigated the behavioral response in the Fmr1KO animals. Data from the marble-burying assay have shown that tropicamide treatment resulted in a decreased number of marbles buried in the wild-type (WT) and in the knockout (KO) animals. Results from the open field assay indicated that tropicamide increases activity in both the WT and KO mice. In the passive avoidance assay, tropicamide treatment resulted in the improvement of performance in both the WT and the KO animals at the lower doses (2 and 5 mg/kg), and the drug was shown to be important for the acquisition and not the consolidation process. Lastly, we observed that tropicamide causes a significant decrease in the percentage of audiogenic seizures in the Fmr1KO animals. These results suggest that pharmacological antagonism of the M4 receptor modulates select behavioral responses in the Fmr1KO mice. (PsycINFO Database Record (c) 2011 APA, all rights reserved).
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41. Wan CY, Schlaug G. {{Neural pathways for language in autism: the potential for music-based treatments}}. {Future Neurol}. 2010; 5(6): 797-805.
Language deficits represent the core diagnostic characteristics of autism, and some of these individuals never develop functional speech. The language deficits in autism may be due to structural and functional abnormalities in certain language regions (e.g., frontal and temporal), or due to altered connectivity between these brain regions. In particular, a number of anatomical pathways that connect auditory and motor brain regions (e.g., the arcuate fasciculus, the uncinate fasciculus and the extreme capsule) may be altered in individuals with autism. These pathways may also provide targets for experimental treatments to facilitate communication skills in autism. We propose that music-based interventions (e.g., auditory-motor mapping training) would take advantage of the musical strengths of these children, and are likely to engage, and possibly strengthen, the connections between frontal and temporal regions bilaterally. Such treatments have important clinical potential in facilitating expressive language in nonverbal children with autism.
42. Welch MG. {{Review: secretin is not effective for the treatment of children with autism spectrum disorders}}. {Evid Based Ment Health}. 2011.
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43. Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick I, Bennett A, Jabado O, Hirschberg DL, Lipkin WI. {{Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances}}. {PLoS One}. 2011; 6(9): e24585.
Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism.
