1. Abdallah MW, Larsen N, Grove J, Norgaard-Pedersen B, Thorsen P, Mortensen EL, Hougaard DM. {{Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders}}. {World J Biol Psychiatry};2011 (Dec 19)
Objectives. The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy. Methods. AF samples of 331 ASD cases and 698 controls were analyzed for inflammatory cytokines using Luminex xMAP technology utilizing a historic birth cohort. Clinical data were retrieved from nationwide registers, and case-control differences in AF cytokine levels were assessed using chi-square tests, logistic and tobit regression models. Results. Overall, individuals with ASD had significantly elevated AF levels of TNF-alpha and TNF-beta compared to controls. Analyzing individuals diagnosed only with ICD-10 codes yielded significantly elevated levels of IL-4, IL-10, TNF-alpha and TNF-beta in ASD patients. Restricting analysis to infantile autism cases showed significantly elevated levels of IL-4, TNF-alpha and TNF-beta compared to controls with no psychiatric comorbidities. Elevated levels of IL-6 and IL-5 were found in individuals with other childhood psychiatric disorders (OCPD) when compared to controls with no psychiatric comorbidities. Conclusions. AF samples of individuals with ASD or OCPD showed differential cytokine profiles compared to frequency-matched controls. Further studies to examine the specificity of the reported cytokine profiles in ASD and OCPD are required.
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2. Choi J, Ababon MR, Matteson PG, Millonig JH. {{Cut-like Homeobox1 and Nuclear Factor I/B Mediate ENGRAILED2 Autism Spectrum Disorder-associated haplotype function}}. {Hum Mol Genet};2011 (Dec 16)
Both common and rare variants contribute to Autism Spectrum Disorder (ASD) risk, but few variants have been established as functional. Previously we demonstrated that an intronic haplotype (rs1861972-rs1861973 A-C) in the homeobox transcription factor ENGRAILED2 (EN2) is significantly associated with ASD. Positive association has also been reported in six additional datasets, suggesting EN2 is an ASD susceptibility gene. Additional support for this possibility requires the identification of functional variants that affect EN2 regulation or activity. In the present study, we demonstrate that the A-C haplotype is a transcriptional activator. Luciferase (luc) assays in mouse neuronal cultures determined that the A-C haplotype increases expression levels (50%, p<0.01, 24hrs; 250%, p<0.0001, 72hrs). Mutational analysis indicates that the A-C haplotype activator function requires both associated A and C alleles. A minimal 202bp element is sufficient for function and also specifically binds a protein complex. Mass spectrometry identified these proteins as the transcription factors, Cut-like homeobox 1 (Cux1) and Nuclear factor I/B (Nfib). Subsequent antibody supershifts and chromatin immunoprecipitations demonstrated human CUX1 and NFIB bind the A-C haplotype. Co-transfection and knock-down experiments determined that both CUX1 and NFIB are required for the A-C haplotype activator function. These data demonstrate that the ASD-associated A-C haplotype is a transcriptional activator, and both CUX1 and NFIB mediate this activity. These results provide biochemical evidence that the ASD-associated A-C haplotype is functional, further supporting EN2 as an ASD susceptibility gene.
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3. Eigsti IM, Schuh J, Mencl E, Schultz RT, Paul R. {{The neural underpinnings of prosody in autism}}. {Child Neuropsychol};2011 (Dec 19)
This study examines the processing of prosodic cues to linguistic structure and to affect, drawing on fMRI and behavioral data from 16 high-functioning adolescents with autism spectrum disorders (ASD) and 11 typically developing controls. Stimuli were carefully matched on pitch, intensity, and duration, while varying systematically in conditions of affective prosody (angry versus neutral speech) and grammatical prosody (questions versus statement). To avoid conscious attention to prosody, which normalizes responses in young people with ASD, the implicit comprehension task directed attention to semantic aspects of the stimuli. Results showed that when perceiving prosodic cues, both affective and grammatical, activation of neural regions was more generalized in ASD than in typical development, and areas recruited reflect heightened reliance on cognitive control, reading of intentions, attentional management, and visualization. This broader recruitment of executive and « mind-reading » brain areas for a relative simple language-processing task may be interpreted to suggest that speakers with high-functioning autism (HFA) have developed less automaticity in language processing and may also suggest that « mind-reading » or theory of mind deficits are intricately bound up in language processing. Data provide support for both a right-lateralized as well as a bilateral model of prosodic processing in typical individuals, depending upon the function of the prosodic information.
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4. Frazier TW, Youngstrom EA, Speer L, Embacher R, Law P, Constantino J, Findling RL, Hardan AY, Eng C. {{Validation of Proposed DSM-5 Criteria for Autism Spectrum Disorder}}. {J Am Acad Child Adolesc Psychiatry};2012 (Jan);51(1):28-40 e23.
OBJECTIVE: The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for autism spectrum disorder (ASD). METHOD: We analyzed symptoms from 14,744 siblings (8,911 ASD and 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth 2 through 18 years of age were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and subdimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD. RESULTS: A hybrid model that included both a category (ASD versus non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and subsamples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (0.97 versus 0.86); however sensitivity was lower (0.81 versus 0.95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (0.93 versus 0.81), with minimal reduction in specificity (0.95 versus 0.97). CONCLUSIONS: Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I Field Trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources.
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5. Gulhan Ercan-Sencicek A, Davis Wright NR, Frost SJ, Fulbright RK, Felsenfeld S, Hart L, Landi N, Einar Mencl W, Sanders SJ, Pugh KR, State MW, Grigorenko EL. {{Searching for Potocki-Lupski syndrome phenotype: A patient with language impairment and no autism}}. {Brain Dev};2011 (Dec 15)
Potocki-Lupski syndrome (PTLS; OMIM 610883) is a genomic syndrome that arises as a result of a duplication of 17p11.2. Although numerous cases of individuals with PTLS have been presented in the literature, its behavioral characterization is still ambiguous. We present a male child with a de novo dup(17)(p11.2p11.2) and he does not possess any autistic features, but is characterized by severe speech and language impairment. In the context of the analyses of this patient and other cases of PTLS, we argue that the central feature of the syndrome appears to be related to diminished speech and language capacity, rather than the specific social deficits central to autism.
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6. Juneja M, Jain R, Singhal S, Mishra D. {{Availing Services for Developmental Disabilities: Parental Experiences from a Referral Center in Developing Country}}. {Indian J Pediatr};2011 (Dec 17)
OBJECTIVES: To identify the problems faced by parents of children with developmental disabilities in availing rehabilitative services and to find their satisfaction level. METHODS: This study was carried out at a Child Development Clinic (CDC) located in Northern India. Children with developmental disabilities, who were availing services at CDC for at least last 3 mo and had at least 3 follow-up visits, were enrolled. A questionnaire pertaining to the socio-demographic profile, problems faced in availing services and satisfaction level was filled by the parents of the enrolled children. RESULTS: During the study period, 161 parents filled the questionnaire. 77.6% had some problems in getting the services, the major being difficulty in commuting (50%) and financial constraint (21.7%). More than 80% parents use public transport to reach CDC with 19% travelling more than 50 Km. 29.8% had difficulty in bringing their child to the clinic, either due to severe behavioral problems or physical disability. However, majority of the families were well satisfied with the services as 95% of them graded their satisfaction level at 3 or more on the scale of 0-5. CONCLUSIONS: Parents of children with developmental disabilities face many problems in getting rehabilitative services. They travel long distances, face hardships in carrying their child, and lose their day’s earnings, apart from spending time and money for their child’s therapy. However, most of the parents are well satisfied with the services.
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7. Kurita H. {{How to deal with the transition from Pervasive Developmental Disorders in DSM-IV to Autism Spectrum Disorder in DSM-V}}. {Psychiatry Clin Neurosci};2011 (Dec);65(7):609-610.
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8. Larson MJ, South M, Clayson PE, Clawson A. {{Cognitive control and conflict adaptation in youth with high-functioning autism}}. {J Child Psychol Psychiatry};2011 (Dec 16)
Background: Youth diagnosed with autism spectrum disorders (ASD) often show deficits in cognitive control processes, potentially contributing to characteristic difficulties monitoring and regulating behavior. Modification of performance following conflict can be measured by examining conflict adaptation, the adjustment of cognitive resources based on previous-trial conflict. The electrophysiological correlates of these processes can be measured using the N2, a stimulus-locked component of the event-related potential (ERP). Methods: High-density ERPs and behavioral data [i.e. response times (RTs) and error rates] were acquired while 28 youth with ASD and 36 typically developing controls completed a modified Eriksen flanker task. Results: Behaviorally, groups showed similar conflict adaptation effects; youth with ASD showed larger RT slowing on switch trials. For electrophysiology, controls demonstrated larger N2 amplitudes for incongruent (high-conflict) trials following congruent (low-conflict) trials than for incongruent trials following incongruent trials. Importantly, youth with ASD showed no such differences in N2 amplitude based on previous-trial conflict. Conclusions: Lack of electrophysiological conflict adaptation effects in youth with ASD indicates irregular neural processing associated with conflict adaptation. Individuals with ASD show declines in level of conflict evaluation and adaptation. Future research is necessary to accurately characterize and understand the behavioral implications of these cognitive control deficits relative to diagnostic severity, anxiety, and personality.
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9. Mandy WP, Charman T, Skuse DH. {{Testing the Construct Validity of Proposed Criteria for DSM-5 Autism Spectrum Disorder}}. {J Am Acad Child Adolesc Psychiatry};2012 (Jan);51(1):41-50.
OBJECTIVE: To use confirmatory factor analysis to test the construct validity of the proposed DSM-5 symptom model of autism spectrum disorder (ASD), in comparison to alternative models, including that described in DSM-IV-TR. METHOD: Participants were 708 verbal children and young persons (mean age, 9.5 years) with mild to severe autistic difficulties. Autistic symptoms were measured using the Developmental, Dimensional and Diagnostic interview (3Di). The fit of the two-factor DSM-5 model, which has a social communication and a restricted, repetitive behavior (RRB) factor, was compared with that of alternative models. In one half of the sample, properties of the DSM-5 model were examined to investigate the validity of specific diagnostic criteria, informing the development of a better fitting DSM-5 model. This was then cross-validated in the remaining « hold-out » half of the sample; and its stability was tested across groups defined by age, sex, and symptom severity. RESULTS: The DSM-5 model was superior to the three-factor DSM-IV-TR model. It was improved by the removal of items measuring « play and imagination » and « stereotyped and repetitive use of language. » A scale measuring sensory abnormalities was added to the model, and loaded onto its RRB factor. This DSM-5 model fit well in the hold-out sample; was stable across age and sex; and fit adequately in those with clinical and sub-threshold autistic presentations. CONCLUSIONS: Among higher-functioning individuals, ASD is a dyad, not a triad, with distinct social communication and repetitive behavior dimensions. As suggested in the proposed DSM-5 criteria, sensory abnormalities are part of the RRB symptom cluster.
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10. Polsek D, Jagatic T, Cepanec M, Hof PR, Simic G. {{RECENT DEVELOPMENTS IN NEUROPATHOLOGY OF AUTISM SPECTRUM DISORDERS}}. {Transl Neurosci};2011;2(3):256-264.
Autism spectrum disorders (ASD) represent complex neurodevelopmental disorders characterized by impairments in reciprocal social interactions, abnormal development and use of language, and monotonously repetitive behaviors. With an estimated heritability of more than 90%, it is the most strongly genetically influenced psychiatric disorder of the young age. In spite of the complexity of this disorder, there has recently been much progress in the research on etiology, early diagnosing, and therapy of autism. Besides already advanced neuropathologic research, several new technological innovations, such as sleep functional MRI, diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy imaging ((1)H-MRS) divulged promising breakthroughs in exploring subtle morphological and neurochemical changes in the autistic brain. This review provides a comprehensive summary of morphological and neurochemical alterations in autism known to date, as well as a short introduction to the functional research that has begun to advance in the last decade. Finally, we mention the progress in establishing new standardized diagnostic measures and its importance in early recognition and treatment of ASD.
11. Puleo CM, Schmeidler J, Reichenberg A, Kolevzon A, Soorya LV, Buxbaum JD, Silverman JM. {{Advancing paternal age and simplex autism}}. {Autism};2011 (Dec 16)
De novo events appear more common in female and simplex autism spectrum disorder (ASD) cases and may underlie greater ASD risk in older fathers’ offspring. This study examined whether advancing paternal age predicts an increase in simplex (n = 90) versus multiplex ASD cases (n = 587) in 677 participants (340 families). Whether or not controlling for maternal age, results support a significant interaction of linear paternal age and sex of the child on simplex family type. Female ASD cases were significantly more likely to be simplex as paternal age increased, but the increase for males was not significant. Findings suggest that ASD arising from non-familial, de novo events may be far less prominent in males than in females, even if more prevalent in males, due to the substantially larger number of male cases attributable to other, more strongly male-biased risk factors.
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12. Whyatt CP, Craig CM. {{Motor Skills in Children Aged 7-10 Years, Diagnosed with Autism Spectrum Disorder}}. {J Autism Dev Disord};2011 (Dec 17)
This study used the Movement Assessment Battery for Children (M-ABC2) to assess motor skills in children aged 7-10 years with autism (n = 18) in comparison to two groups of age-matched typically developing children; a receptive vocabulary matched group (n = 19) and a nonverbal IQ matched group (n = 22). The results supported previous work, as indicated by a significant general motor impairment in the group with autism. However, sub-analysis of the M-ABC2 revealed that there were only 2 out of 8 subcomponent skills which showed universal significant specific deficits for the autism group; i.e. catching a ball and static balance. These results suggest that motor skill deficits associated with autism may not be pervasive but more apparent in activities demanding complex, interceptive actions or core balance ability.
