1. Ajamian M, Kosofsky BE, Wormser GP, Rajadhyaksha AM, Alaedini A. {{Serologic markers of Lyme disease in children with autism}}. {JAMA};2013 (May 1);309(17):1771-1773.
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2. Crespi B. {{Developmental heterochrony and the evolution of autistic perception, cognition and behavior}}. {BMC Med};2013;11:119.
BACKGROUND: Autism is usually conceptualized as a disorder or disease that involves fundamentally abnormal neurodevelopment. In the present work, the hypothesis that a suite of core autism-related traits may commonly represent simple delays or non-completion of typical childhood developmental trajectories is evaluated. DISCUSSION: A comprehensive review of the literature indicates that, with regard to the four phenotypes of (1) restricted interests and repetitive behavior, (2) short-range and long-range structural and functional brain connectivity, (3) global and local visual perception and processing, and (4) the presence of absolute pitch, the differences between autistic individuals and typically developing individuals closely parallel the differences between younger and older children. SUMMARY: The results of this study are concordant with a model of ‘developmental heterochrony’, and suggest that evolutionary extension of child development along the human lineage has potentiated and structured genetic risk for autism and the expression of autistic perception, cognition and behavior.
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3. Diggle TT, McConachie H. {{WITHDRAWN: Parent-mediated early intervention for young children with autism spectrum disorder}}. {Cochrane Database Syst Rev};2013;4:CD003496.
BACKGROUND: Recent estimates concerning the prevalence of autistic spectrum disorder are much higher than those reported 30 years ago, with at least 1 in 400 children affected. This group of children and families have important service needs. The involvement of parents in implementing intervention strategies designed to help their autistic children has long been accepted as helpful. The potential benefits are increased skills and reduced stress for parents as well as children. OBJECTIVES: The objective of this review was to determine the extent to which parent-mediated early intervention has been shown to be effective in the treatment of children aged 1 year to 6 years 11 months with autistic spectrum disorder. In particular, it aimed to assess the effectiveness of such interventions in terms of the benefits for both children and their parents. SEARCH METHODS: A range of psychological, educational and biomedical databases were searched until January 2002. Bibliographies and reference lists of key articles were searched, field experts were contacted and key journals were hand searched. SELECTION CRITERIA: Only randomised or quasi-randomised studies were included. Study interventions had a significant focus on parent-implemented early intervention, compared to a group of children who received no treatment, a waiting list group or a different form of intervention. There was at least one objective, child related outcome measure. DATA COLLECTION AND ANALYSIS: Appraisal of the methodological quality of included studies was carried out independently by two reviewers. Differences between the included studies in terms of the type of intervention, the comparison groups used and the outcome measures were too great to allow for direct comparison. MAIN RESULTS: The results of this review are based on data from two studies. Two significant results were found to favour parent training in one study: child language and maternal knowledge of autism. In the other, intensive intervention (involving parents, but primarily delivered by professionals) was associated with better child outcomes on direct measurement than were found for parent-mediated early intervention, but no differences were found in relation to measures of parent and teacher perceptions of skills and behaviours. AUTHORS’ CONCLUSIONS: This review has little to offer in the way of implications for practice: there were only two studies, the numbers of participants included were small, and the two studies could not be compared directly to one another. In terms of research, randomised controlled trials involving large samples need to be carried out, involving both short and long-term outcome information and full economic evaluations. Research in this area is hampered by barriers to randomisation, such as availability of equivalent services.
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4. Goubau C, Devriendt K, Van der Aa N, Crepel A, Wieczorek D, Kleefstra T, Willemsen MH, Rauch A, Tzschach A, de Ravel T, Leemans P, Van Geet C, Buyse G, Freson K. {{Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12}}. {Eur J Hum Genet};2013 (May 1)
The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C>G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients’ platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.European Journal of Human Genetics advance online publication, 1 May 2013; doi:10.1038/ejhg.2013.86.
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5. Mullegama SV, Rosenfeld JA, Orellana C, van Bon BW, Halbach S, Repnikova EA, Brick L, Li C, Dupuis L, Rosello M, Aradhya S, Stavropoulos DJ, Manickam K, Mitchell E, Hodge JC, Talkowski ME, Gusella JF, Keller K, Zonana J, Schwartz S, Pyatt RE, Waggoner DJ, Shaffer LG, Lin AE, de Vries BB, Mendoza-Londono R, Elsea SH. {{Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder}}. {Eur J Hum Genet};2013 (May 1)
Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.European Journal of Human Genetics advance online publication, 1 May 2013; doi:10.1038/ejhg.2013.67.
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6. Nava C, Keren B, Mignot C, Rastetter A, Chantot-Bastaraud S, Faudet A, Fonteneau E, Amiet C, Laurent C, Jacquette A, Whalen S, Afenjar A, Perisse D, Doummar D, Dorison N, Leboyer M, Siffroi JP, Cohen D, Brice A, Heron D, Depienne C. {{Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders}}. {Eur J Hum Genet};2013 (May 1)
Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.European Journal of Human Genetics advance online publication, 1 May 2013; (2013) 0, 000-000. doi:10.1038/ejhg.2013.88.
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7. Oono IP, Honey EJ, McConachie H. {{Parent-mediated early intervention for young children with autism spectrum disorders (ASD)}}. {Cochrane Database Syst Rev};2013;4:CD009774.
BACKGROUND: Young children with autism spectrum disorders (ASD) have impairments in the areas of communication and social interaction and often display repetitive or non-compliant behaviour. This early pattern of difficulties is a challenge for parents. Therefore, approaches that help parents develop strategies for interaction and management of behaviour are an obvious route for early intervention in ASD. This review updates a Cochrane review first published in 2002 but is based on a new protocol. OBJECTIVES: To assess the effectiveness of parent-mediated early interventions in terms of the benefits for both children with ASD and their parents and to explore some potential moderators of treatment effect. SEARCH METHODS: We searched a range of psychological, educational and biomedical databases including CENTRAL, MEDLINE, Embase, PsycINFO and ERIC in August 2012. As this is an update of a previous review, we limited the search to the period following the original searches in 2002. Bibliographies and reference lists of key articles were searched, field experts were contacted and key journals were handsearched. SELECTION CRITERIA: We included only randomised controlled trials of early intervention for children with ASD. The interventions in the experimental condition were mediated by parents; the control conditions included no treatment, treatment as usual, waiting list, alternative child-centred intervention not mediated by parents, or alternative parent-mediated intervention of hypothesised lesser effect than the experimental condition. DATA COLLECTION AND ANALYSIS: Two review authors (HM and IPO) independently screened articles identified in the search and decided which articles should be retrieved in full. For each included study, two review authors (IPO and EH) extracted and recorded data, using a piloted data collection form. Two review authors (IPO and HM) assessed the risk of bias in each study. We performed data synthesis and analysis using The Cochrane Collaboration’s Review Manager 5.1 software. MAIN RESULTS: The review includes 17 studies from six countries (USA, UK, Australia, Canada, Thailand and China), which recruited 919 children with ASD. Not all 17 studies could be compared directly or combined in meta-analyses due to differences in the theoretical basis underpinning interventions, the duration and intensity of interventions, and the outcome measurement tools used. Data from subsets of 10 studies that evaluated interventions to enhance parent interaction style and thereby facilitate children’s communication were included in meta-analyses. The largest meta-analysis combined data from 316 participants in six studies and the smallest combined data from 55 participants in two studies. Findings from the remaining seven studies were reported narratively.High risk of bias was evident in the studies in relation to allocation concealment and incomplete outcome data; blinding of participants was not possible.Overall, we did not find statistical evidence of gains from parent-mediated approaches in most of the primary outcomes assessed (most aspects of language and communication – whether directly assessed or reported; frequency of child initiations in observed parent-child interaction; child adaptive behaviour; parents’ stress), with findings largely inconclusive and inconsistent across studies. However, the evidence for positive change in patterns of parent-child interaction was strong and statistically significant (shared attention: standardised mean difference (SMD) 0.41; 95% confidence interval (CI) 0.14 to 0.68, P value < 0.05; parent synchrony: SMD 0.90; 95% CI 0.56 to 1.23, P value < 0.05). Furthermore, there is some evidence suggestive of improvement in child language comprehension, reported by parents (vocabulary comprehension: mean difference (MD 36.26; 95% CI 1.31 to 71.20, P value < 0.05). In addition, there was evidence suggesting a reduction in the severity of children’s autism characteristics (SMD -0.30, 95% CI -0.52 to -0.08, P value < 0.05). However, this evidence of change in children’s skills and difficulties as a consequence of parent-mediated intervention is uncertain, with small effect sizes and wide CIs, and the conclusions are likely to change with future publication of high-quality RCTs. AUTHORS’ CONCLUSIONS: The review finds some evidence for the effectiveness of parent-mediated interventions, most particularly in proximal indicators within parent-child interaction, but also in more distal indicators of child language comprehension and reduction in autism severity. Evidence of whether such interventions may reduce parent stress is inconclusive. The review reinforces the need for attention to be given to early intervention service models that enable parents to contribute skilfully to the treatment of their child with autism. However, practitioners supporting parent-mediated intervention require to monitor levels of parent stress. The ability to draw conclusions from studies would be improved by researchers adopting a common set of outcome measures as the quality of the current evidence is low.
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8. Paneth N. {{Restoring science to the National Children’s Study}}. {JAMA};2013 (May 1);309(17):1775-1776.
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9. Plenty S, Heurlin D, Arlinde C, Bejerot S. {{Applying an ESSENCE Framework to Understanding Adult Autism Spectrum Disorder and ADHD: Retrospective Parent Reports of Childhood Problems}}. {ScientificWorldJournal};2013;2013:469594.
Diagnoses of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are increasingly being made in adulthood. However, assessments can fail to address the diverse range of problems that patients have experienced. The current study applied an early symptomatic syndromes eliciting neurodevelopmental clinical examinations (ESSENCE) framework to explore retrospectively reported childhood developmental and behavioral problems. It examined if adult ASD and ADHD patients would show problems outside those reflected in the respective diagnostic criteria, and also if these patient groups would show more extensive childhood problems than other psychiatric patients. Parents of adults with ADHD (n = 130), ASD (n = 57), coexisting ADHD and ASD (n = 38), and other psychiatric disorders (n = 56) reported on a range of childhood problems. Descriptions of the ADHD, ASD, and ADHD+ASD groups reflected greater impairment than descriptions for patients with other psychiatric disorders in most problem areas. Although differences were observed between ADHD and ASD patients in the core diagnostic areas, these syndromes also shared a number of childhood difficulties. The ESSENCE approach can assist in understanding the symptom history of adult ADHD and ASD patients and can be helpful to distinguish their childhood experiences from other psychiatric patients’ experiences.
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10. Sasson NJ, Lam KS, Parlier M, Daniels JL, Piven J. {{Autism and the broad autism phenotype: familial patterns and intergenerational transmission}}. {J Neurodev Disord};2013;5(1):11.
BACKGROUND: Features of the Broad Autism Phenotype (BAP) are disproportionately prevalent in parents of a child with autism, highlighting familial patterns indicative of heritability. It is unclear, however, whether the presence of BAP features in both parents confers an increased liability for autism. The current study explores whether the presence of BAP features in two biological parents occurs more frequently in parents of a child with autism relative to comparison parents, whether parental pairs of a child with autism more commonly consist of one or two parents with BAP features, and whether these features are associated with severity of autism behaviors in probands. METHOD: Seven hundred eleven parents of a child with an autism spectrum disorder and 981 comparison parents completed the Broad Autism Phenotype Questionnaire. Parents of a child with autism also completed the Social Communication Questionnaire. RESULTS: Although parental pairs of a child with autism were more likely than comparison parental pairs to have both parents characterized by the presence of the BAP, they more commonly consisted of a single parent with BAP features. The presence of the BAP in parents was associated with the severity of autism behaviors in probands, with the lowest severity occurring for children of parental pairs in which neither parent exhibited a BAP feature. Severity did not differ between children of two affected parents and those of just one. CONCLUSIONS: Collectively, these findings indicate that parental pairs of children with autism frequently consist of a single parent with BAP characteristics and suggest that future studies searching for implicated genes may benefit from a more narrow focus that identifies the transmitting parent. The evidence of intergenerational transmission reported here also provides further confirmation of the high heritability of autism that is unaccounted for by the contribution of de novo mutations currently emphasized in the field of autism genetics.
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11. Serenius F, Kallen K, Blennow M, Ewald U, Fellman V, Holmstrom G, Lindberg E, Lundqvist P, Marsal K, Norman M, Olhager E, Stigson L, Stjernqvist K, Vollmer B, Stromberg B. {{Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden}}. {JAMA};2013 (May 1);309(17):1810-1820.
IMPORTANCE: Active perinatal care increases survival of extremely preterm infants; however, improved survival might be associated with increased disability among survivors. OBJECTIVE: To determine neurodevelopmental outcome in extremely preterm children at 2.5 years (corrected age). DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective cohort of consecutive extremely preterm infants born before 27 weeks of gestation in Sweden between 2004 and 2007. Of 707 live-born infants, 491 (69%) survived to 2.5 years. Survivors were assessed and compared with singleton control infants who were born at term and matched by sex, ethnicity, and municipality. Assessments ended in February 2010 and comparison estimates were adjusted for demographic differences. MAIN OUTCOMES AND MEASURES: Cognitive, language, and motor development was assessed with Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-lll), which are standardized to mean (SD) scores of 100 (15). Clinical examination and parental questionnaires were used for diagnosis of cerebral palsy and visual and hearing impairments. Assessments were made by week of gestational age. RESULTS: At a median age of 30.5 months (corrected), 456 of 491 (94%) extremely preterm children were evaluated (41 by chart review only). For controls, 701 had information on health status and 366 had Bayley-lll assessments. Mean (SD) composite Bayley-III scores (cognition, 94 [12.3]; language, 98 [16.5]; motor, 94 [15.9]) were lower than the corresponding mean scores for controls (cognition, 104 [10.6]; P < .001; adjusted difference in mean scores, 9.2 [99% CI, 6.9-11.5]; language, 109 [12.3]; P < .001; adjusted difference in mean scores, 9.3 [99% Cl, 6.4-12.3]; and motor, 107 [13.7]; P < .001; adjusted difference in mean scores, 12.6 [99% Cl, 9.5-15.6]). Cognitive disability was moderate in 5% of the extremely preterm group vs 0.3% in controls (P < .001) and it was severe in 6.3% of the extremely preterm group vs 0.3% in controls (P < .001). Language disability was moderate in 9.4% of the extremely preterm group vs 2.5% in controls (P < .001) and severe in 6.6% of the extremely preterm group vs 0% in controls (P < .001). Other comparisons between the extremely preterm group vs controls were for cerebral palsy (7.0% vs 0.1%; P < .001), for blindness (0.9% vs 0%; P = .02), and for hearing impairment (moderate and severe, 0.9% vs 0%; P = .02, respectively). Overall, 42% (99% CI, 36%-48%) of extremely preterm children had no disability, 31% (99% CI, 25%-36%) had mild disability, 16% (99% CI, 12%-21%) had moderate disability, and 11% (99% CI, 7.2%-15%) had severe disability. Moderate or severe overall disability decreased with gestational age at birth (22 weeks, 60%; 23 weeks, 51%; 24 weeks, 34%; 25 weeks, 27%; and 26 weeks, 17%; P for trend < .001). CONCLUSIONS AND RELEVANCE: Of children born extremely preterm and receiving active perinatal care, 73% had mild or no disability and neurodevelopmental outcome improved with each week of gestational age. These results are relevant for clinicians counseling families facing extremely preterm birth.
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12. Teng BL, Nonneman RJ, Agster KL, Nikolova VD, Davis TT, Riddick NV, Baker LK, Pedersen CA, Jarstfer MB, Moy SS. {{Prosocial effects of oxytocin in two mouse models of autism spectrum disorders}}. {Neuropharmacology};2013 (May 3)
Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin.
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13. Wolff JJ, Hazlett HC, Lightbody AA, Reiss AL, Piven J. {{Repetitive and self-injurious behaviors: associations with caudate volume in autism and fragile X syndrome}}. {J Neurodev Disord};2013;5(1):12.
BACKGROUND: Following from previous work suggesting that neurobehavioral features distinguish fragile X and idiopathic variants of autism, we investigated the relationships between four forms of repetitive behavior (stereotypy, self-injury, compulsivity, ritual behavior) and caudate nuclei volume in two groups: boys with fragile X syndrome, a subset of whom met criteria for autism, and a comparison group of boys with idiopathic autism. METHODS: Bilateral caudate nuclei volumes were measured in boys aged 3 to 6 years with fragile X syndrome (n = 41), the subset of boys with fragile X syndrome and autism (n = 16), and boys with idiopathic autism (n = 30). Repetitive behaviors were measured using the Repetitive Behavior Scales-Revised. RESULTS: For boys with idiopathic autism, left caudate volume was modestly associated with self-injury, while both compulsive and ritual behaviors showed significant positive correlations with bilateral caudate nuclei volumes, replicating previous results. For boys with fragile X syndrome, there was no such association between caudate volume and compulsive behaviors. However, we did identify significant positive correlations between self-injury total scores and number of self-injury topographies with bilateral caudate nuclei volumes. CONCLUSIONS: These findings suggest a specific role for the caudate nucleus in the early pathogenesis of self-injurious behavior associated with both idiopathic autism and fragile X syndrome. Results further indicate that the caudate may be differentially associated with compulsive behavior, highlighting the utility of isolating discrete brain-behavior associations within and between subtypes of autism spectrum disorder.
