1. Allou L, Julia S, Amsallem D, El Chehadeh S, Lambert L, Thevenon J, Duffourd Y, Saunier A, Bouquet P, Pere S, Moustaine A, Ruaud L, Roth V, Jonveaux P, Philippe C. {{Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease}}. {Clin Genet};2016 (Apr 7)
Several genes have been implicated in Rett syndrome in its typical and variant forms. We applied next-generation sequencing to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease.
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2. Bonatto SJ, Kerner M, Merelles S, Ponde MP. {{The prevalence of symptoms of attention-deficit/hyperactivity disorder in parents of children with autism spectrum disorder}}. {Psychiatry Res};2016 (Apr 5);240:1-3.
This study aims to estimate the prevalence of symptoms of attention-deficit/hyperactivity disorder (ADHD) in parents of children with autism spectrum disorder (ASD). This is a cross-sectional study conducted with the parents of 89 children previously diagnosed with ASD. The research instrument used was the 18-item Adult ADHD Self-Report Scale (ASRS). Symptoms of ADHD were present in 10.4% of the mothers of children with a diagnosis of ASD and in 11.3% of the fathers. These results suggest that the prevalence of symptoms of ADHD in the parents of children with autism is higher than that found in the general adult population.
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3. Bueno C, Tabares-Seisdedos R, Moraleda JM, Martinez S. {{Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands}}. {PLoS One};2016;11(4):e0153262.
Dysfunctions of MeCP2 protein lead to various neurological disorders such as Rett syndrome and Autism. The exact functions of MeCP2 protein is still far from clear. At a molecular level, there exist contradictory data. MeCP2 protein is considered a single immunoreactive band around 75 kDa by western-blot analysis but several reports have revealed the existence of multiple MeCP2 immunoreactive bands above and below the level where MeCP2 is expected. MeCP2 immunoreactive bands have been interpreted in different ways. Some researchers suggest that multiple MeCP2 immunoreactive bands are unidentified proteins that cross-react with the MeCP2 antibody or degradation product of MeCP2, while others suggest that MeCP2 post-transcriptional processing generates multiple molecular forms linked to cell signaling, but so far they have not been properly analyzed in relation to Rett syndrome experimental models. The purpose of this study is to advance understanding of multiple MeCP2 immunoreactive bands in control neural cells and p.T158M MeCP2e1 mutant cells. We have generated stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Application of N- and C- terminal MeCP2 antibodies, and also, RFP antibody minimized concerns about nonspecific cross-reactivity, since they react with the same antigen at different epitopes. We report the existence of multiple MeCP2 immunoreactive bands in control cells, stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Also, MeCP2 immunoreactive bands differences were found between wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Slower migration phosphorylated band around 70kDa disappeared in p.T158M MeCP2e1-RFP mutant expressing cells. These data suggest that threonine 158 could represent an important phosphorylation site potentially involved in protein function. Our results clearly indicate that MeCP2 antibodies have no cross-reactivity with similar epitopes on others proteins, supporting the idea that MeCP2 may exist in multiple different molecular forms and that molecular pattern variations derived from altered post-transcriptional processing may underlay Rett syndrome physiophatology.
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4. Calderoni S, Billeci L, Narzisi A, Brambilla P, Retico A, Muratori F. {{Rehabilitative Interventions and Brain Plasticity in Autism Spectrum Disorders: Focus on MRI-Based Studies}}. {Front Neurosci};2016;10:139.
Clinical and research evidence supports the efficacy of rehabilitative intervention for improving targeted skills or global outcomes in individuals with autism spectrum disorder (ASD). However, putative mechanisms of structural and functional brain changes are poorly understood. This review aims to investigate the research literature on the neural circuit modifications after non-pharmacological intervention. For this purpose, longitudinal studies that used magnetic resonance imaging (MRI)-based techniques at the start and at the end of the trial to evaluate the neural effects of rehabilitative treatment in subjects with ASD were identified. The six included studies involved a limited number of patients in the active group (from 2 to 16), and differed by acquisition method (task-related and resting-state functional MRI) as well as by functional MRI tasks. Overall, the results produced by the selected investigations demonstrated brain plasticity during the treatment interval that results in an activation/functional connectivity more similar to those of subjects with typical development (TD). Repeated MRI evaluation may represent a promising tool for the detection of neural changes in response to treatment in patients with ASD. However, large-scale randomized controlled trials after standardized rehabilitative intervention are required before translating these preliminary results into clinical use.
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5. Cappuccio G, Vitiello F, Casertano A, Fontana P, Genesio R, Bruzzese D, Ginocchio VM, Mormile A, Nitsch L, Andria G, Melis D. {{New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants}}. {Ital J Pediatr};2016;42(1):39.
BACKGROUND: Array-CGH (aCGH) is presently used into routine clinical practice for diagnosis of patients with intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorder (ASD). ACGH could detect small chromosomal imbalances, copy number variations (CNVs), and closely define their size and gene content. ACGH detects pathogenic imbalances in 14-20 % of patients with ID. The aims of this study were: to establish clinical clues potentially associated with pathogenic CNVs and to identify cytogenetic indicators to predict the pathogenicity of the variants of uncertain significance (VOUS) in a large cohort of paediatric patients. METHODS: We enrolled 214 patients referred for either: ID, and/or ASD and/or MCA to genetic services at the Federico II University of Naples, Department of Translational Medicine. For each patient we collected clinical and imaging data. All the patients were tested with aCGH or as first-tier test or as part of a wider diagnostic work-up. RESULTS: Pathologic data were detected in 65 individuals (30 %) and 46 CNVs revealed a known syndrome. The pathological CNVs were usually deletions showing the highest gene-dosage content. The positive family history for ID/ASD/MCA and ASD were good indicators for detecting pathological chromosomal rearrangements. Other clinical features as eyes anomalies, hearing loss, neurological signs, cutaneous dyscromia and endocrinological problems seem to be potential predictors of pathological CNVs. Among patients carrying VOUS we analyzed genetic features including CNVs size, presence of deletion or duplication, genic density, multiple CNVs, to clinical features. Higher gene density was found in patients affected by ID. This result suggest that higher gene content has more chances to include pathogenic gene involved and causing ID in these patients. CONCLUSION: Our study suggest the use of aCGH as first-tier test in patients with neurdevelopmental phenotypes. The inferred results have been used for building a flow-chart to be applied for children with ID.
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6. Chevreul K, Gandre C, Brigham KB, Lopez-Bastida J, Linertova R, Oliva-Moreno J, Serrano-Aguilar P, Posada-de-la-Paz M, Taruscio D, Schieppati A, Iskrov G, Gulacsi L, von der Schulenburg JM, Kanavos P, Persson U, Fattore G. {{Social/economic costs and health-related quality of life in patients with fragile X syndrome in Europe}}. {Eur J Health Econ};2016 (Apr 12)
OBJECTIVE: To estimate the social/economic costs of fragile X syndrome (FXS) in Europe and to assess the health-related quality of life (HRQOL) of patients and caregivers. METHODS: A cross-sectional study was conducted in a sample of European countries. Patients were recruited through patients’ associations. Data on their resource use and absence from the labour market were retrospectively obtained from an online questionnaire. Costs were estimated by a bottom-up approach and the EuroQol-5 Domain (EQ-5D) questionnaire was used to measure patients’ and caregivers’ HRQOL. RESULTS: Five countries were included in the analysis. The mean annual cost of FXS per patient varied from euro4951 in Hungary to euro58,862 in Sweden. Direct non-healthcare costs represented the majority of costs in all countries but there were differences in the share incurred by formal and informal care among those costs. Costs were also shown to differ between children and adults. Mean EQ-5D utility score for adult patients varied from 0.52 in France (n = 42) to 0.73 in Hungary (n = 2), while for caregivers this score was consistently inferior to 0.87. CONCLUSION: Our findings underline that, although its prevalence is low, FXS is costly from a societal perspective. They support the development of tailored policies to reduce the consequences of FXS on both patients and their relatives.
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7. Dasdemir S, Guven M, Pekkoc KC, Ulucan H, Dogangun B, Kirtas E, Kadak MT, Kucur M, Seven M. {{DNA repair gene XPD Asp312Asn and XRCC4 G-1394T polymorphisms and the risk of autism spectrum disorder}}. {Cell Mol Biol (Noisy-le-grand)};2016;62(3):46-50.
Autism spectrum disorder (ASD) is a complex disorder, and its extreme heterogeneity further complicates our understanding of its biology. Epidemiological evidence from family and twin studies supports a strong genetic component in ASD etiology. Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of ASD. Brain tissues from ASD cases showed higher levels of oxidative stress biomarkers than healthy controls in postmortem analysis. Association between oxidative stress and DNA damage has been well-known. Thus, we sought to investigate a potential link between DNA repair genes and ASD and analyze the role of XPD Asp312Asn and XRCC4 G-1394T gene polymorphisms for ASD in the Turkish population. Genotyping was conducted by PCR-RFLP based on 100 patients and 96 unrelated healthy controls. We, for the first time, demonstrated a positive association between XRCC4 gene variants and ASD risk. Frequencies of XRCC4-1394 T/G+G/G genotypes were higher in patients (%34) than the controls (%18.7). The statistical analysis revealed that the individuals who had XRCC4-1394 T/G+G/G genotype had an increased risk for ASD (OR = 2.23, 95% CI = 1.10-4.55). However, no significant association was found for XPD Asp312Asn polymorphism with the risk of ASD. Our findings suggest that XRCC4 G-1394T polymorphism might be associated with ASD pathogenesis.
8. Edwards A, Brebner C, McCormack PF, Macdougall C. {{« More than blowing bubbles »: What parents want from therapists working with children with autism spectrum disorder}}. {Int J Speech Lang Pathol};2016 (Apr 4):1-13.
PURPOSE: Providing therapy to children with autism spectrum disorder (ASD) often requires therapists to work closely with both the child with ASD and their family. Although there is evidence outlining best practice for therapists when working with families of children with disabilities, few studies have examined the parental perspective. This study investigated the qualities parents seek in therapists who work with their children with ASD. METHOD: Semi-structured interviews were conducted with 14 parents of children with ASD. Thematic analysis was undertaken to analyse the data, with emergence of two core themes; Partnership and Effective Therapy. RESULT: The parents of children with ASD interviewed for this study valued both working in partnership with therapists and therapists delivering effective therapy. Parents ultimately wanted therapists to produce positive outcomes for their children and were willing to sacrifice other desired qualities, as long as the therapy program was effective. CONCLUSION: While parents of children with ASD identified a range of qualities that they want in therapists, a therapist being able to produce positive outcomes for their child was considered most important. The implications of these findings are discussed both in terms of clinical implications for therapists and directions for future research.
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9. Elder JH, Brasher S, Alexander B. {{Identifying the Barriers to Early Diagnosis and Treatment in Underserved Individuals with Autism Spectrum Disorders (ASD) and Their Families: A Qualitative Study}}. {Issues Ment Health Nurs};2016 (Apr 12):1-9.
Clinical accounts indicate that disparities exist among families of children with Autism Spectrum Disorders (ASD), and that these disparities impede timely diagnosis and intervention. Furthermore, families living in rural areas are more likely to have reduced access to proper care and use alternative, unproven, and potentially harmful treatments. The purpose of this project was to begin addressing these needs by engaging providers and families of children with ASD living in rural and typically underserved areas. The investigators established a Community Advisory Board (CAB) of ASD professionals (e.g., community-based healthcare and service providers, director of a center for disabilities, psychologist, autism researcher, and special education professional). Next, they conducted four focus groups comprised of a total of 35 major stakeholders (e.g., individuals with ASD, parents of individuals with ASD, community-based healthcare and service providers, school teachers) to determine potential resources, barriers to early diagnosis/treatment, and alternative treatment use in children with ASD. Focus group sessions were audio-recorded, transcribed verbatim, and analyzed by three trained independent coders. Community participants identified several barriers to early diagnosis and intervention, as well as a variety of alternative treatments used in children with ASD. Thematic analysis of focus group transcripts showed several overarching themes regarding barriers to early diagnosis and treatment. Findings from this study have implications for practice and future research.
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10. Haigh SM, Gupta A, Barb SM, Glass SA, Minshew NJ, Dinstein I, Heeger DJ, Eack SM, Behrmann M. {{Differential sensory fMRI signatures in autism and schizophrenia: Analysis of amplitude and trial-to-trial variability}}. {Schizophr Res};2016 (Apr 12)
Autism and schizophrenia share multiple phenotypic and genotypic markers, and there is ongoing debate regarding the relationship of these two disorders. To examine whether cortical dynamics are similar across these disorders, we directly compared fMRI responses to visual, somatosensory and auditory stimuli in adults with autism (N=15), with schizophrenia (N=15), and matched controls (N=15). All participants completed a one-back letter detection task presented at fixation (to control attention) while task-irrelevant sensory stimulation was delivered to the different modalities. We focused specifically on the response amplitudes and the variability in sensory fMRI responses of the two groups, given the evidence of greater trial-to-trial variability in adults with autism. Both autism and schizophrenia individuals showed weaker signal-to-noise ratios (SNR) in sensory-evoked responses compared to controls (d>0.42), but for different reasons. For the autism group, the fMRI response amplitudes were indistinguishable from controls but were more variable trial-to-trial (d=0.47). For the schizophrenia group, response amplitudes were smaller compared to autism (d=0.44) and control groups (d=0.74), but were not significantly more variable (d<0.29). These differential group profiles suggest (1) that greater trial-to-trial variability in cortical responses may be specific to autism and is not a defining characteristic of schizophrenia, and (2) that blunted response amplitudes may be characteristic of schizophrenia. The relationship between the amplitude and the variability of cortical activity might serve as a specific signature differentiating these neurodevelopmental disorders. Identifying the neural basis of these responses and their relationship to the underlying genetic bases may substantially enlighten the understanding of both disorders. Lien vers le texte intégral (Open Access ou abonnement)
11. Hall DA, Robertson-Dick EE, O’Keefe JA, Hadd AG, Zhou L, Berry-Kravis E. {{X-inactivation in the clinical phenotype of fragile X premutation carrier sisters}}. {Neurol Genet};2016 (Feb);2(1):e45.
OBJECTIVE: The purpose of this study is to describe a case series of 4 sisters with discordant clinical phenotypes associated with fragile X-associated tremor/ataxia syndrome (FXTAS) that may be explained by varying CGG repeat sizes and activation ratios (ARs) (the ratio of cells carrying the normal fragile X mental retardation 1 [FMR1] allele on the active X chromosome). METHODS: Four sisters with premutation size FMR1 gene repeats underwent detailed clinical characterization. CGG repeat length was determined by PCR, and AR was determined using a newly developed commercial methylation PCR assay and was compared with the results from Southern blot with densitometric image analysis. RESULTS: Sister 1 had the largest CGG expansion (82) and the lowest AR (12%), with the most severe clinical presentation. Sister 2 had a lower CGG expansion (70) and an AR of 10% but had a milder clinical presentation.Sister 3 had a similar CGG expansion (79) but a slightly higher AR of 15% and less neurologic involvement. Sister 4 had a similar CGG expansion size of 80 but had the largest AR (40%) and was the only sister not to be affected by FXTAS or have any neurologic signs on examination. CONCLUSIONS: These results suggest that premutation carrier women who have higher ARs may be less likely to show manifestations of FXTAS. If larger studies show similar patterns, AR data could potentially be beneficial to supplement CGG repeat size when counseling premutation carrier women in the clinic.
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12. Hamilton J, Stevens G, Girdler S. {{Becoming a Mentor: The Impact of Training and the Experience of Mentoring University Students on the Autism Spectrum}}. {PLoS One};2016;11(4):e0153204.
While it is widely recognised that the number of young adults diagnosed with Autism Spectrum Disoders (ASD) is increasing, there is currently limited understanding of effective support for the transition to adulthood. One approach gaining increasing attention in the university sector is specialised peer mentoring. The aim of this inductive study was to understand the impact of peer mentor training on seven student mentors working with university students with an ASD. Kirkpatrick’s model framed a mixed methods evaluation of the mentors’ training and description of their experience. Overall, the training was well received by the mentors, who reported on average a 29% increase in their ASD knowledge following the training. Results from the semi-structured interviews conducted three months after the training, found that mentors felt that the general ASD knowledge they gained as part of their training had been essential to their role. The mentors described how their overall experience had been positive and reported that the training and support provided to them was pivotal to their ability to succeed in as peer mentors to students with ASD. This study provides feedback in support of specialist peer-mentoring programs for university students and can inform recommendations for future programs and research.
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13. Igelstrom KM, Webb TW, Graziano MS. {{Functional Connectivity Between the Temporoparietal Cortex and Cerebellum in Autism Spectrum Disorder}}. {Cereb Cortex};2016 (Apr 12)
The neural basis of autism spectrum disorder (ASD) is not yet understood. ASD is marked by social deficits and is strongly associated with cerebellar abnormalities. We studied the organization and cerebellar connectivity of the temporoparietal junction (TPJ), an area that plays a crucial role in social cognition. We applied localized independent component analysis to resting-state fMRI data from autistic and neurotypical adolescents to yield an unbiased parcellation of the bilateral TPJ into 11 independent components (ICs). A comparison between neurotypical and autistic adolescents showed that the organization of the TPJ was not significantly altered in ASD. Second, we used the time courses of the TPJ ICs as spatially unbiased « seeds » for a functional connectivity analysis applied to voxels within the cerebellum. We found that the cerebellum contained a fine-grained, lateralized map of the TPJ. The connectivity of the TPJ subdivisions with cerebellar zones showed one striking difference in ASD. The right dorsal TPJ showed markedly less connectivity with the left Crus II. Disturbed cerebellar input to this key region for cognition and multimodal integration may contribute to social deficits in ASD. The findings might also suggest that the right TPJ and/or left Crus II are potential targets for noninvasive brain stimulation therapies.
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14. Katuwal GJ, Baum SA, Cahill ND, Michael AM. {{Divide and Conquer: Sub-Grouping of ASD Improves ASD Detection Based on Brain Morphometry}}. {PLoS One};2016;11(4):e0153331.
Low success (<60%) in autism spectrum disorder (ASD) classification using brain morphometry from the large multi-site ABIDE dataset and inconsistent findings on brain morphometric abnormalities in ASD can be attributed to the ASD heterogeneity. In this study, we show that ASD brain morphometry is highly heterogeneous, and demonstrate that the heterogeneity can be mitigated and classification improved if autism severity (AS), verbal IQ (VIQ) and age are used with morphometric features. Morphometric features from structural MRIs (sMRIs) of 734 males (ASD: 361, controls: 373) of ABIDE were derived using FreeSurfer. Applying the Random Forest classifier, an AUC of 0.61 was achieved. Adding VIQ and age to morphometric features, AUC improved to 0.68. Sub-grouping the subjects by AS, VIQ and age improved the classification with the highest AUC of 0.8 in the moderate-AS sub-group (AS = 7-8). Matching subjects on age and/or VIQ in each sub-group further improved the classification with the highest AUC of 0.92 in the low AS sub-group (AS = 4-5). AUC decreased with AS and VIQ, and was the lowest in the mid-age sub-group (13-18 years). The important features were mainly from the frontal, temporal, ventricular, right hippocampal and left amygdala regions. However, they highly varied with AS, VIQ and age. The curvature and folding index features from frontal, temporal, lingual and insular regions were dominant in younger subjects suggesting their importance for early detection. When the experiments were repeated using the Gradient Boosting classifier similar results were obtained. Our findings suggest that identifying brain biomarkers in sub-groups of ASD can yield more robust and insightful results than searching across the whole spectrum. Further, it may allow identification of sub-group specific brain biomarkers that are optimized for early detection and monitoring, increasing the utility of sMRI as an important tool for early detection of ASD. Lien vers le texte intégral (Open Access ou abonnement)
15. Kim E, Kyeong S, Cheon KA, Park B, Oh MK, Chun JW, Park HJ, Kim JJ, Dong-Ho S. {{Neural Responses to Affective and Cognitive Theory of Mind in Children and Adolescents with Autism Spectrum Disorder}}. {Neurosci Lett};2016 (Apr 12)
Children and adolescents with Autism Spectrum Disorder (ASD) are characterized by an impaired Theory of Mind (ToM). Recent evidence suggested that two aspects of ToM (cognitive ToM versus affective ToM) are differentially impaired in individuals with ASD. In this study, we examined the neural correlates of cognitive and affective ToM in children and adolescents with ASD compared to typically developing children (TDCs). Twelve children and adolescents with ASD and 12 age, IQ matched TDCs participated in this functional MRI study. The ToM task involved the attribution of cognitive and affective mental states to a cartoon character based on verbal and eye-gaze cues. In cognitive ToM tasks, ASD participants recruited the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and superior temporal gyrus (STG) to a greater extent than did TDCs. In affective ToM tasks, both ASD and TDC participants showed more activation in the insula and other subcortical regions than in cognitive ToM tasks. Correlational analysis revealed that greater activation of the mPFC/ACC regions was associated with less symptom severity in ASD patients. In sum, our study suggests that the recruitment of additional prefrontal resources can compensate for the successful behavioral performance in the ToM task in ASD participants.
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16. Lammert DB, Howell BW. {{RELN Mutations in Autism Spectrum Disorder}}. {Front Cell Neurosci};2016;10:84.
RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, null mutations lead to lissencephaly with cerebellar hypoplasia (LCH), accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD). RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.
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17. Mundy P, Kim K, McIntyre N, Lerro L, Jarrold W. {{Brief Report: Joint Attention and Information Processing in Children with Higher Functioning Autism Spectrum Disorders}}. {J Autism Dev Disord};2016 (Apr 9)
Theory suggests that information processing during joint attention may be atypical in children with Autism Spectrum Disorder (ASD). This hypothesis was tested in a study of school-aged children with higher functioning ASD and groups of children with symptoms of ADHD or typical development. The results indicated that the control groups displayed significantly better recognition memory for pictures studied in an initiating joint attention (IJA) rather than responding to joint attention (RJA) condition. This effect was not evident in the ASD group. The ASD group also recognized fewer pictures from the IJA condition than controls, but not the RJA condition. Atypical information processing may be a marker of the continued effects of joint attention disturbance in school aged children with ASD.
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18. Paucar M, Engvall M, Gordon L, Tham E, Synofzik M, Svenningsson P. {{POLG-Associated Ataxia Presenting as a Fragile X Tremor/Ataxia Phenocopy Syndrome}}. {Cerebellum};2016 (Apr 12)
Hyperintensities in the middle cerebellar peduncles (MCP), known as the MCP sign, and progressive late-onset ataxia constitute major characteristics of the fragile X tremor/ataxia syndrome (FXTAS). Here, we describe a 60-year-old male affected by ataxia due to biallelic mutations in the mitochondrial polymerase gamma (POLG) gene in which hyperintensities of the middle cerebellar peduncles (MCP) were found. The initial suspicion of FXTAS was however ruled out by a normal CGG expansion size in the FMR1 gene. We discuss the features of late-onset POLG-A as a phenocopy of FXTAS.
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19. Shochet IM, Saggers BR, Carrington SB, Orr JA, Wurfl AM, Duncan BM, Smith CL. {{The Cooperative Research Centre for Living with Autism (Autism CRC) Conceptual Model to Promote Mental Health for Adolescents with ASD}}. {Clin Child Fam Psychol Rev};2016 (Apr 12)
Despite an increased risk of mental health problems in adolescents with autism spectrum disorder (ASD), there is limited research on effective prevention approaches for this population. Funded by the Cooperative Research Centre for Living with Autism, a theoretically and empirically supported school-based preventative model has been developed to alter the negative trajectory and promote wellbeing and positive mental health in adolescents with ASD. This conceptual paper provides the rationale, theoretical, empirical and methodological framework of a multilayered intervention targeting the school, parents and adolescents on the spectrum. Two important interrelated protective factors have been identified in community adolescent samples, namely the sense of belonging (connectedness) to school and the capacity for self and affect regulation in the face of stress (i.e. resilience). We describe how a confluence of theories from social psychology, developmental psychology and family systems theory, along with empirical evidence (including emerging neurobiological evidence), supports the interrelationships between these protective factors and many indices of wellbeing. However, the characteristics of ASD (including social and communication difficulties, and frequently difficulties with changes and transitions, and diminished optimism and self-esteem) impair access to these vital protective factors. The paper describes how evidence-based interventions at the school level for promoting inclusive schools (using the Index for Inclusion) and interventions for adolescents and parents to promote resilience and belonging [using the Resourceful Adolescent Program (RAP)] are adapted and integrated for adolescents with ASD. This multisite proof-of-concept study will confirm whether this multilevel school-based intervention is promising, feasible and sustainable.
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20. Smith E, Thurm A, Greenstein D, Farmer C, Swedo S, Giedd J, Raznahan A. {{Cortical thickness change in autism during early childhood}}. {Hum Brain Mapp};2016 (Apr 7)
Structural magnetic resonance imaging (MRI) scans at high spatial resolution can detect potential foci of early brain dysmaturation in children with autism spectrum disorders (ASD). In addition, comparison between MRI and behavior measures over time can identify patterns of brain change accompanying specific outcomes. We report structural MRI data from two time points for a total of 84 scans in children with ASD and 30 scans in typical controls (mean age time one = 4.1 years, mean age at time two = 6.6 years). Surface-based cortical morphometry and linear mixed effects models were used to link changes in cortical anatomy to both diagnostic status and individual differences in changes in language and autism severity. Compared with controls, children with ASD showed accelerated gray matter volume gain with age, which was driven by a lack of typical age-related cortical thickness (CT) decrease within 10 cortical regions involved in language, social cognition, and behavioral control. Greater expressive communication gains with age in children with ASD were associated with greater CT gains in a set of right hemisphere homologues to dominant language cortices, potentially identifying a compensatory system for closer translational study. Hum Brain Mapp, 2016. (c) 2016 Wiley Periodicals, Inc.
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21. Solomon WG, Greenbaum E. {{Case Report on the Use of the Waldon Approach on an Adult with Severe to Moderate Intellectual Disability with Autistic Tendencies}}. {Front Public Health};2016;4:50.
This clinical case report describes a patient diagnosed with severe to moderate intellectual disability with autistic tendencies, resident in a home for adults with a range of disabilities. She had been resident for 18 years prior to intervention by the author when she was 48 years of age. The author worked with her from June 25, 2013 until January 12, 2015 for a total of 55 Waldon Approach (1), movement-based lessons each of about 45 min of which 33 were documented by video. This report describes changes in her cognition and her social behavior at a time when there were no other changes in her life. As far as the author is aware, this is the first clinical case report on the Waldon Approach to appear in a peer-reviewed journal and is unique in that most of the work using the approach is with children who are usually receiving other therapies at the same time as their Waldon Lessons, making it harder to evaluate the attribution of change. During the period of this report, she received no other therapy or intervention beyond that provided at Maon Roglit, which itself had not changed during this period. The patient remains without speech, but there has been real, meaningful, and noticeable change in her life from which she appears to derive pleasure. There has been a significant improvement in the patient’s group participation, facial expression, and general demeanor.
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22. Travers BG, Bigler ED, Duffield TC, Prigge MD, Froehlich AL, Lange N, Alexander AL, Lainhart JE. {{Longitudinal development of manual motor ability in autism spectrum disorder from childhood to mid-adulthood relates to adaptive daily living skills}}. {Dev Sci};2016 (Apr 7)
Many individuals with autism spectrum disorder (ASD) exhibit motor difficulties, but it is unknown whether manual motor skills improve, plateau, or decline in ASD in the transition from childhood into adulthood. Atypical development of manual motor skills could impact the ability to learn and perform daily activities across the life span. This study examined longitudinal grip strength and finger tapping development in individuals with ASD (n = 90) compared to individuals with typical development (n = 56), ages 5 to 40 years old. We further examined manual motor performance as a possible correlate of current and future daily living skills. The group with ASD demonstrated atypical motor development, characterized by similar performance during childhood but increasingly poorer performance from adolescence into adulthood. Grip strength was correlated with current adaptive daily living skills, and Time 1 grip strength predicted daily living skills eight years into the future. These results suggest that individuals with ASD may experience increasingly more pronounced motor difficulties from adolescence into adulthood and that manual motor performance in ASD is related to adaptive daily living skills.
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23. Trembath D, Hawtree R, Arciuli J, Caithness T. {{What do speech-language pathologists think parents expect when treating their children with autism spectrum disorder?}}. {Int J Speech Lang Pathol};2016 (Mar 10):1-9.
PURPOSE: Despite the importance of Speech-Language Pathologists (SLPs) collaborating with parents in the treatment of children with Autism Spectrum Disorder (ASD), few studies have examined the nature of this working relationship and how best to facilitate collaboration. To explore what SLPs think parents of children with ASD expect of them when it comes to the delivery of evidence-based interventions. METHOD: The participants were 22 SLPs from Australia who specialised in ASD and who each participated in a semi-structured interview. Recordings were transcribed and analysed according to the procedures outlined by Braun and Clarke. RESULT: The SLPs expressed strong support for evidence-based practice (EBP) and indicated that they thought parents expected their children would be provided with evidence-based interventions. However, SLPs identified factors that influenced the way and the extent to which they were able to share information as part of a collaborative decision-making process, including the parents’ education level and the amount of time since their children’s diagnoses. CONCLUSION: The results highlight the challenges that SLPs face when engaging with parents in the delivery of EBP. Strategies that the SLPs had developed to cater to the individual needs of each parent are discussed, along with implications for clinical practice.
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24. Tropeano M, Howley D, Gazzellone MJ, Wilson CE, Ahn JW, Stavropoulos DJ, Murphy CM, Eis PS, Hatchwell E, Dobson RJ, Robertson D, Holder M, Irving M, Josifova D, Nehammer A, Ryten M, Spain D, Pitts M, Bramham J, Asherson P, Curran S, Vassos E, Breen G, Flinter F, Ogilvie CM, Collier DA, Scherer SW, McAlonan GM, Murphy DG. {{Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions}}. {J Med Genet};2016 (Apr 12)
BACKGROUND: The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. METHODS: We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). RESULTS: We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18x10-7; OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). CONCLUSIONS: Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment. Lien vers le texte intégral (Open Access ou abonnement)
25. Yang EJ, Ahn S, Lee K, Mahmood U, Kim HS. {{Early Behavioral Abnormalities and Perinatal Alterations of PTEN/AKT Pathway in Valproic Acid Autism Model Mice}}. {PLoS One};2016;11(4):e0153298.
Exposure to valproic acid (VPA) during pregnancy has been linked with increased incidence of autism, and has repeatedly been demonstrated as a useful autism mouse model. We examined the early behavioral and anatomical changes as well as molecular changes in mice prenatally exposed to VPA (VPA mice). In this study, we first showed that VPA mice showed developmental delays as assessed with self-righting, eye opening tests and impaired social recognition. In addition, we provide the first evidence that primary cultured neurons from VPA-treated embryos present an increase in dendritic spines, compared with those from control mice. Mutations in phosphatase and tensin homolog (PTEN) gene are also known to be associated with autism, and mice with PTEN knockout show autistic characteristics. Protein expression of PTEN was decreased and the ratio of p-AKT/AKT was increased in the cerebral cortex and the hippocampus, and a distinctive anatomical change in the CA1 region of the hippocampus was observed. Taken together, our study suggests that prenatal exposure to VPA induces developmental delays and neuroanatomical changes via the reduction of PTEN level and these changes were detectable in the early days of life.
