1. Baum KT, Shear PK, Howe SR, Bishop SL. {{A comparison of WISC-IV and SB-5 intelligence scores in adolescents with autism spectrum disorder}}. {Autism};2014 (Nov 14)
In autism spectrum disorders, results of cognitive testing inform clinical care, theories of neurodevelopment, and research design. The Wechsler Intelligence Scale for Children and the Stanford-Binet are commonly used in autism spectrum disorder evaluations and scores from these tests have been shown to be highly correlated in typically developing populations. However, they have not been compared in individuals with autism spectrum disorder, whose core symptoms can make testing challenging, potentially compromising test reliability. We used a within-subjects research design to evaluate the convergent validity between the Wechsler Intelligence Scale for Children, 4th ed., and Stanford-Binet, 5th ed., in 40 youth (ages 10-16 years) with autism spectrum disorder. Corresponding intelligence scores were highly correlated (r = 0.78 to 0.88), but full-scale intelligence quotient (IQ) scores (t(38) = -2.27, p = 0.03, d = -0.16) and verbal IQ scores (t(36) = 2.23, p = 0.03; d = 0.19) differed between the two tests. Most participants obtained higher full-scale IQ scores on the Stanford-Binet, 5th ed., compared to Wechsler Intelligence Scale for Children, 4th ed., with 14% scoring more than one standard deviation higher. In contrast, verbal indices were higher on the Wechsler Intelligence Scale for Children, 4th ed., Verbal-nonverbal discrepancy classifications were only consistent for 60% of the sample. Comparisons of IQ test scores in autism spectrum disorder and other special groups are important, as it cannot necessarily be assumed that convergent validity findings in typically developing children and adolescents hold true across all pediatric populations.
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2. Buxbaum JD, Bolshakova N, Brownfeld JM, Anney RJ, Bender P, Bernier R, Cook EH, Coon H, Cuccaro M, Freitag CM, Hallmayer J, Geschwind D, Klauck SM, Nurnberger JI, Oliveira G, Pinto D, Poustka F, Scherer SW, Shih A, Sutcliffe JS, Szatmari P, Vicente AM, Vieland V, Gallagher L. {{The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses}}. {Mol Autism};2014;5:34.
BACKGROUND: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. METHODS: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. RESULTS: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). CONCLUSIONS: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
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3. Crider A, Pandya CD, Peter D, Ahmed AO, Pillai A. {{Ubiquitin-proteasome dependent degradation of GABAAalpha1 in autism spectrum disorder}}. {Mol Autism};2014;5:45.
BACKGROUND: Although the neurobiological basis of autism spectrum disorder (ASD) is not fully understood, recent studies have indicated the potential role of GABAA receptors in the pathophysiology of ASD. GABAA receptors play a crucial role in various neurodevelopmental processes and adult neuroplasticity. However, the mechanism(s) of regulation of GABAA receptors in ASD remains poorly understood. METHODS: Postmortem middle frontal gyrus tissues (13 ASD and 13 control subjects) were used. In vitro studies were performed in primary cortical neurons at days in vitro (DIV) 14. The protein levels were examined by western blotting. Immunofluorescence studies were employed for cellular localization. The gene expression was determined by RT-PCR array and qRT-PCR. RESULTS: A significant decrease in GABAAalpha1 protein, but not mRNA levels was found in the middle frontal gyrus of ASD subjects indicating a post-translational regulation of GABAA receptors in ASD. At the cellular level, treatment with proteasomal inhibitor, MG132, or lactacystin significantly increased GABAAalpha1 protein levels and Lys48-linked polyubiquitination of GABAAalpha1, but reduced proteasome activity in mouse primary cortical neurons (DIV 14 from E16 embryos). Moreover, treatment with betulinic acid, a proteasome activator significantly decreased GABAAalpha1 protein levels in cortical neurons indicating the role of polyubiquitination of GABAAalpha1 proteins with their subsequent proteasomal degradation in cortical neurons. Ubiquitination specific RT-PCR array followed by western blot analysis revealed a significant increase in SYVN1, an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase in the middle frontal gyrus of ASD subjects. In addition, the inhibition of proteasomal activity by MG132 increased the expression of GABAAalpha1 in the ER. The siRNA knockdown of SYVN1 significantly increased GABAAalpha1 protein levels in cortical neurons. Moreover, reduced association between SYVN1 and GABAAalpha1 was found in the middle frontal gyrus of ASD subjects. CONCLUSIONS: SYVN1 plays a critical role as an E3 ligase in the ubiquitin proteasome system (UPS)-mediated GABAAalpha1 degradation. Thus, inhibition of the ubiquitin-proteasome-mediated GABAAalpha1 degradation may be an important mechanism for preventing GABAAalpha1 turnover to maintain GABAAalpha1 levels and GABA signaling in ASD.
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4. Gadalla KK, Ross PD, Riddell JS, Bailey ME, Cobb SR. {{Gait analysis in a mecp2 knockout mouse model of rett syndrome reveals early-onset and progressive motor deficits}}. {PLoS One};2014;9(11):e112889.
Rett syndrome (RTT) is a genetic disorder characterized by a range of features including cognitive impairment, gait abnormalities and a reduction in purposeful hand skills. Mice harbouring knockout mutations in the Mecp2 gene display many RTT-like characteristics and are central to efforts to find novel therapies for the disorder. As hand stereotypies and gait abnormalities constitute major diagnostic criteria in RTT, it is clear that motor and gait-related phenotypes will be of importance in assessing preclinical therapeutic outcomes. We therefore aimed to assess gait properties over the prodromal phase in a functional knockout mouse model of RTT. In male Mecp2 knockout mice, we observed alterations in stride, coordination and balance parameters at 4 weeks of age, before the onset of other overt phenotypic changes as revealed by observational scoring. These data suggest that gait measures may be used as a robust and early marker of MeCP2-dysfunction in future preclinical therapeutic studies.
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5. Jalnapurkar I, Rafika N, Tassone F, Hagerman R. {{Immune mediated disorders in women with a fragile X expansion and FXTAS}}. {Am J Med Genet A};2014 (Nov 14)
Premutation alleles in fragile X mental retardation 1 (FMR1) can cause the late-onset neurodegenerative disorder, fragile X-associated tremor ataxia syndrome (FXTAS) and/or the fragile X-associated primary ovarian insufficiency in approximately 20% of heterozygotes. Heterozygotes of the FMR1 premutation have a higher incidence of immune mediated disorders such as autoimmune thyroid disorder, especially when accompanied by FXTAS motor signs. We describe the time course of symptoms of immune mediated disorders and the subsequent development of FXTAS in four women with an FMR1 CGG expansion, including three with the premutation and one with a gray zone expansion. These patients developed an immune mediated disorder followed by neurological symptoms that become consistent with FXTAS. In all patients we observed a pattern involving an initial appearance of disease symptoms-often after a period of heightened stress (depression, anxiety, divorce, general surgery) followed by the onset of tremor and/or ataxia. Immune mediated diseases are associated with the manifestations of FXTAS temporally, although further studies are needed to clarify this association. If a cause and effect relationship can be established, treatment of pre-existing immune mediated disorders may benefit patients with pathogenic FMR1 mutations. (c) 2014 Wiley Periodicals, Inc.
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6. Jayarao M, Sohl K, Tanaka T. {{Chiari malformation I and autism spectrum disorder: an underrecognized coexistence}}. {J Neurosurg Pediatr};2014 (Nov 14):1-5.
OBJECT Patients with symptomatic Chiari malformation Type I (CM-I) frequently present with headaches, neck pain, difficulty swallowing, and balance disturbances. In children with autism spectrum disorder (ASD), diagnosing CM-I can be a challenging task. Moreover, even if symptomatic, some patients do not undergo further evaluation or management, as their presentations are attributed to autism and its myriad symptoms. Therefore, cranial MRI findings were reviewed after evaluating and treating patients with coexisting ASD and CM-I. In this paper, the authors report on 5 children with ASD and symptomatic CM-I, including their clinical presentation, imaging studies, management, and outcomes, and discuss the likely underrecognized coexistence of these conditions. METHODS All pediatric patients with ASD and cranial MRI conducted for any reason in the period from 1999 to 2013 were considered for analysis. All cases with concomitant symptomatic CM-I were eligible for this retrospective analysis. RESULTS One hundred twenty-five pediatric patients diagnosed with ASD had undergone MRI, and 9 of them had evidence of cerebellar tonsillar herniation. Five patients were symptomatic and underwent suboccipital craniectomy, a C-1 or a C-1 and C-2 laminectomy, and duraplasty with bovine pericardium or Type I collagen allograft. There were no intraoperative complications. All patients showed symptom improvement and/or resolution of presenting symptoms, which included headache, dysphasia, speech, and irritability. CONCLUSIONS There is no identified cause of autism. Children with ASD can be difficult to assess specifically in a neurological examination. Thus, cranial MRI considered when completing a comprehensive diagnostic evaluation. While cranial MRI is not a routine part of ASD evaluation, this study demonstrates that CM-I and ASD may coexist and be underrecognized. The study reinforces the importance of a comprehensive medical evaluation designed to elucidate neurological findings in children with impaired communication abilities and suggests the judicious use of neuroimaging.
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7. Klintwall L, Macari S, Eikeseth S, Chawarska K. {{Interest level in 2-year-olds with autism spectrum disorder predicts rate of verbal, nonverbal, and adaptive skill acquisition}}. {Autism};2014 (Nov 14)
Recent studies have suggested that skill acquisition rates for children with autism spectrum disorders receiving early interventions can be predicted by child motivation. We examined whether level of interest during an Autism Diagnostic Observation Schedule assessment at 2 years predicts subsequent rates of verbal, nonverbal, and adaptive skill acquisition to the age of 3 years. A total of 70 toddlers with autism spectrum disorder, mean age of 21.9 months, were scored using Interest Level Scoring for Autism, quantifying toddlers’ interest in toys, social routines, and activities that could serve as reinforcers in an intervention. Adaptive level and mental age were measured concurrently (Time 1) and again after a mean of 16.3 months of treatment (Time 2). Interest Level Scoring for Autism score, Autism Diagnostic Observation Schedule score, adaptive age equivalent, verbal and nonverbal mental age, and intensity of intervention were entered into regression models to predict rates of skill acquisition. Interest level at Time 1 predicted subsequent acquisition rate of adaptive skills (R2 = 0.36) and verbal mental age (R2 = 0.30), above and beyond the effects of Time 1 verbal and nonverbal mental ages and Autism Diagnostic Observation Schedule scores. Interest level at Time 1 also contributed (R2 = 0.30), with treatment intensity, to variance in development of nonverbal mental age.
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8. Minshawi NF, Hurwitz S, Morriss D, McDougle CJ. {{Multidisciplinary Assessment and Treatment of Self-Injurious Behavior in Autism Spectrum Disorder and Intellectual Disability: Integration of Psychological and Biological Theory and Approach}}. {J Autism Dev Disord};2014 (Nov 14)
The objective of this review is to consider the psychological (largely behavioral) and biological [neurochemical, medical (including genetic), and pharmacological] theories and approaches that contribute to current thinking about the etiology and treatment of self-injurious behavior (SIB) in individuals with autism spectrum disorder and/or intellectual disability. Algorithms for the assessment and treatment of SIB in this context, respectively, from a multidisciplinary, integrative perspective are proposed and challenges and opportunities that exist in clinical and research settings are discussed.
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9. Mitchell C, Holdt N. {{The search for a timely diagnosis: Parents’ experiences of their child being diagnosed with an Autistic Spectrum Disorder}}. {J Child Adolesc Ment Health};2014 (Jul);26(1):49-62.
Objective This study aimed to describe the experiences of a group of South African parents whose children had received Autistic Spectrum Disorder (ASD) diagnoses. Method A qualitative approach involving semi-structured interviews with a sample of eight parents (seven mothers and one father) of ASD children was used. Results These interviews highlighted key issues in the area of ASD in South Africa, including: a lack of knowledge amongst professionals, an unwillingness to diagnose, and lack of available support and facilities. Many of the parents in the sample reported significant difficulties in obtaining an ASD diagnosis. These findings are discussed in the light of the importance of early intervention in South Africa. Conclusions Practitioners appear to be reluctant to diagnose and label children with ASD at an early age. This reluctance results in lost opportunities for early intervention and years of uncertainty and distress for families. Access to resources for diagnosis and intervention for children with ASD in South Africa appears to be limited to a few families. For this select population, many difficulties and much dissatisfaction with diagnostic processes remain. The study recommends enhancing awareness of ASD to facilitate early identification, and to strengthen the support offered to parents of children with ASD.
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10. Shiozawa BJ. {{It’s About Time for Autism Reform Legislation in Utah}}. {J Autism Dev Disord};2014 (Nov 14)
On 3 April 2014, Governor Gary Herbert signed into law a health insurance reform bill that requires private insurers to cover autism therapy. Specifically, SB57 requires state-regulated health plans to cover applied behavior analysis (ABA) therapy. While early diagnosis and intervention can reduce the long-term cost of autism, families are finding themselves bankrupt in order to pay for ABA therapy. Currently, 37 states, and the District of Columbia have enacted insurance reform laws. Ensuring that children with autism receive proper therapy is a serious public health issue. Utah was right to pass reform legislation because it properly benefits and safeguards the interests of affected children in promoting their well-being and participation in society.
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11. Xing J, Wang C, Kimura H, Takasaki Y, Kunimoto S, Yoshimi A, Nakamura Y, Koide T, Banno M, Kushima I, Uno Y, Okada T, Aleksic B, Ikeda M, Iwata N, Ozaki N. {{Resequencing and Association Analysis of PTPRA, a Possible Susceptibility Gene for Schizophrenia and Autism Spectrum Disorders}}. {PLoS One};2014;9(11):e112531.
BACKGROUND: The PTPRA gene, which encodes the protein RPTP-alpha, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks. METHODS: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3’UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls. RESULTS: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3’UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element. MAJOR CONCLUSIONS: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.
