1. Abujadi C, Croarkin PE, Bellini BB, Brentani H, Marcolin MA. {{Intermittent theta-burst transcranial magnetic stimulation for autism spectrum disorder: an open-label pilot study}}. {Rev Bras Psiquiatr};2017 (Dec 11):0.
OBJECTIVE: Theta-burst stimulation (TBS) modulates synaptic plasticity more efficiently than standard repetitive transcranial magnetic stimulation delivery and may be a promising modality for neuropsychiatric disorders such as autism spectrum disorder (ASD). At present there are few effective interventions for prefrontal cortex dysfunction in ASD. We report on an open-label, pilot study of intermittent TBS (iTBS) to target executive function deficits and restricted, repetitive behaviors in male children and adolescents with ASD. METHODS: Ten right-handed, male participants, aged 9-17 years with ASD were enrolled in an open-label trial of iTBS treatment. Fifteen sessions of neuronavigated iTBS at 100% motor threshold targeting the right dorsolateral prefrontal cortex were delivered over 3 weeks. RESULTS: Parent report scores on the Repetitive Behavior Scale Revised and the Yale-Brown Obsessive Compulsive Scale demonstrated improvements with iTBS treatment. Participants demonstrated improvements in perseverative errors on the Wisconsin Card Sorting Test and total time for the Stroop test. The iTBS treatments were well tolerated with no serious adverse effects. CONCLUSION: These preliminary results suggest that further controlled interventional studies of iTBS for ASD are warranted.
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2. Boivin M, Willemsen R, Hukema RK, Sellier C. {{Potential pathogenic mechanisms underlying Fragile X Tremor Ataxia Syndrome: RAN translation and/or RNA gain-of-function?}}. {Eur J Med Genet};2017 (Dec 6)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disease caused by an expansion of 55-200 CGG repeats located in the FMR1 gene. The main clinical and neuropathological features of FXTAS are progressive intention tremor and gait ataxia associated with brain atrophy, neuronal cell loss and presence of ubiquitin-positive intranuclear inclusions in both neurons and astrocytes. At the molecular level, FXTAS is characterized by increased expression of FMR1 sense and antisense RNA containing expanded CGG or GGC repeats, respectively. Here, we discuss the putative molecular mechanisms underlying FXTAS and notably recent reports that expanded CGG and GGC repeats may be pathogenic through RAN translation into toxic proteins.
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3. Calhoun JD, Vanoye CG, Kok F, George AL, Jr., Kearney JA. {{Characterization of a KCNB1 variant associated with autism, intellectual disability, and epilepsy}}. {Neurol Genet};2017 (Dec);3(6):e198.
Objective: To perform functional characterization of a potentially pathogenic KCNB1 variant identified by clinical exome sequencing of a proband with a neurodevelopmental disorder that included epilepsy and centrotemporal spikes on EEG. Methods: Whole-exome sequencing identified the KCNB1 variant c.595A>T (p.Ile199Phe). Biochemical and electrophysiologic experiments were performed to determine whether this variant affected protein expression, trafficking, and channel functional properties. Results: Biochemical characterization of the variant suggested normal protein expression and trafficking. Functional characterization revealed biophysical channel defects in assembled homotetrameric and heterotetrameric channels. Conclusions: The identification of the KCNB1 variant c.595A>T (p.Ile199Phe) in a neurodevelopmental disorder that included epilepsy with centrotemporal spikes expands the phenotypic spectrum of epilepsies associated with KCNB1 variants. The KCNB1-I199F variant exhibited partial loss of function relative to the wild-type channel. This defect is arguably less severe than previously reported KCNB1 variants, suggesting the possibility that the degree of KCNB1 protein dysfunction may influence disease severity.
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4. Carter Leno V, Chandler S, White P, Pickles A, Baird G, Hobson C, Smith AB, Charman T, Rubia K, Simonoff E. {{Testing the specificity of executive functioning impairments in adolescents with ADHD, ODD/CD and ASD}}. {Eur Child Adolesc Psychiatry};2017 (Dec 9)
Current diagnostic systems conceptualise attention deficit hyperactivity disorder (ADHD), oppositional defiant/conduct disorder (ODD/CD) and autism spectrum disorder (ASD) as separate diagnoses. However, all three demonstrate executive functioning (EF) impairments. Whether these impairments are trans-diagnostic or disorder-specific remains relatively unexplored. Four groups of 10-16 year-olds [typically developing (TD; N = 43), individuals clinically diagnosed with ADHD (N = 21), ODD/CD (N = 26) and ASD (N = 41)] completed Go/NoGo and Switch tasks. Group differences were tested using analysis of co-variance (ANCOVA) including age, IQ, sex, conduct problems and ADHD symptoms as co-variates. Results indicated some disorder-specificity as only the ASD group demonstrated decreased probability of inhibition in the Go/NoGo task compared to all other groups. However, shared impairments were also found; all three diagnostic groups demonstrated increased reaction time variability (RTV) compared to the TD group, and both the ODD/CD and the ASD group demonstrated increased premature responses. When controlling for ADHD symptoms and conduct problems, group differences in RTV were no longer significant; however, the ASD group continued to demonstrate increased premature responses. No group differences were found in cognitive flexibility in the Switch task. A more varied response style was present across all clinical groups, although this appeared to be accounted for by sub-threshold ODD/CD and ADHD symptoms. Only the ASD group was impaired in response inhibition and premature responsiveness relative to TD adolescents. The findings suggest that some EF impairments typically associated with ADHD may also be found in individuals with ASD.
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5. Kaymakcalan H, Yarman Y, Goc N, Toy F, Meral C, Ercan-Sencicek AG, Gunel M. {{Novel compound heterozygous mutations in GPT2 linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia}}. {Am J Med Genet A};2017 (Dec 11)
We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate-dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease-causing by meta-SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ approximately 600) in the whole-exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified.
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6. Kuhlthau KA, Bailey LC, Baer BL, Coury DL, Law JK, Murray DS, Razzaghi H, Forrest CB, Lipkin PH. {{Large Databases for Pediatric Research on Children with Autism Spectrum Disorder}}. {J Dev Behav Pediatr};2017 (Dec 11)
OBJECTIVE: This article reviews the data available in 3 large databases for use in conducting studies of children with autism spectrum disorder (ASD). METHODS: The article describes the data structure, data elements, and strengths and weaknesses of the 3 data sets. RESULTS: Each of the 3 data sets, the Interactive Autism Network (IAN), the Autism Treatment Network (ATN), and PEDSnet have large cohorts of children with ASD. IAN has strengths in patient-reported measures, ATN in clinical characterization, and PEDSnet in health care encounters and electronic medical record data. CONCLUSION: The data sets described here have potential for further studies that could help improve the care and well-being of children with ASD and their families.
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7. Lin LY, Huang PC. {{Quality of life and its related factors for adults with autism spectrum disorder}}. {Disabil Rehabil};2017 (Dec 11):1-8.
PURPOSE: Improved quality of life is an important outcome for adults with autism spectrum disorder. However, little research has examined factors associated with quality of life among adults with autism spectrum disorder. METHOD: This study comparing 66 adults with autism spectrum disorder (intelligence quotient > 70) aged 20-38 years with neuro-typical adults investigated their quality of life and related factors. All the participants were interviewed with questionnaires by a registered occupational therapist. RESULTS: Participants with autism spectrum disorder scored significantly lower in all domains of quality of life than did the controls. Adults with autism spectrum disorder reported higher anxiety level, more loneliness, and higher scores on four sensory quadrants than neuro-typical adults. The predictors of the physical health domain were anxiety and sensation-sensitivity behaviors. Loneliness and sensation-sensitivity behaviors were predictive of the psychological health domain. Comorbid psychiatric disorders and loneliness were predictive of the social relationship domain. CONCLUSIONS: Adults with autism spectrum disorder need more supportive social contexts and interventions to improve their quality of life. Social relationships, psychological health, and sensory processing difficulty must be considered when designing treatment programs for adults with autism spectrum disorder. Implications for Rehabilitation Adults with autism spectrum disorder scored significantly lower in all domains of quality of life than did the neuro-typical adults. Occupational therapy can provide more supportive social contexts and interventions on social relationship and sensory processing difficulty to improve their quality of life. Understanding factors associated with quality of life among adults with autism spectrum disorder can contribute to address their needs. Occupational therapy can facilitate health promotion through working with adults with autism spectrum disorder. Social relationships, psychological health, and sensory processing difficulty must be considered when designing treatment programs for adults with autism spectrum disorder.
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8. Mahdi S, Viljoen M, Yee T, Selb M, Singhal N, Almodayfer O, Granlund M, de Vries PJ, Zwaigenbaum L, Bolte S. {{An international qualitative study of functioning in autism spectrum disorder using the World Health Organization international classification of functioning, disability and health framework}}. {Autism Res};2017 (Dec 11)
This is the third in a series of four empirical studies designed to develop International Classification of Functioning, Disability and Health (ICF) Core Sets for Autism Spectrum Disorder (ASD). The present study aimed to describe functioning in ASD (as operationalized by the ICF) derived from the perspectives of diagnosed individuals, family members, and professionals. A qualitative study using focus groups and semi-structured interviews were conducted with 19 stakeholder groups (N = 90) from Canada, India, Saudi Arabia, South Africa, and Sweden. Meaningful concepts from the focus groups and individual interviews were linked to ICF categories using a deductive qualitative approach with standardized linking procedures. The deductive qualitative content analysis yielded meaningful functioning concepts that were linked to 110 ICF categories across all four ICF components. Broad variation of environmental factors and activities and participation categories were identified in this study, while body functions consisted mainly of mental functions. Body structures were sparsely mentioned by the participants. Positive aspects of ASD included honesty, attention to detail, and memory. The experiences provided by international stakeholders support the need to understand individuals with ASD in a broader perspective, extending beyond diagnostic criteria into many areas of functioning and environmental domains. This study is part of a larger systematic effort that will provide the basis to define ICF Core Sets for ASD, from which assessment tools can be generated for use in clinical practice, research, and health care policy making. Autism Res 2017. (c) 2017 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: The study findings support the need to understand the living experiences of individuals with Autism Spectrum Disorder (ASD) from a broader perspective, taking into account many areas of an individual’s functioning and environment. The ICF can serve as foundation for exploring these living experiences more extensively by offering tools that enable wide variety of individual difficulties and strengths to be captured along with important environmental influences. As such, these tools can facilitate interventions that meet the needs and goals of the individual.
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9. Pardo CA, Meffert MK. {{Animal models in autism research: The legacy of Paul H. Patterson}}. {Exp Neurol};2018 (Jan);299(Pt A):197-198.
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10. Raveau M, Shimohata A, Amano K, Miyamoto H, Yamakawa K. {{DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures}}. {Neurobiol Dis};2017 (Dec 6);110:180-191.
Mutations and copy number variants affecting DYRK1A gene encoding the dual-specificity tyrosine phosphorylation-regulated kinase 1A are among the most frequent genetic causes of neurodevelopmental disorders including autism spectrum disorder (ASD) associated with microcephaly, febrile seizures and severe speech acquisition delay. Here we developed a mouse model harboring a frame-shift mutation in Dyrk1a resulting in a protein truncation and elimination of its kinase activity site. Dyrk1a(+/-) mice showed significant impairments in cognition and cognitive flexibility, communicative ultrasonic vocalizations, and social contacts. Susceptibility to hyperthermia-induced seizures was also significantly increased in these mice. The truncation leading to haploinsufficiency of DYRK1A in mice thus recapitulates the syndromic phenotypes observed in human patients and constitutes a useful model for further investigations of the mechanisms leading to ASD, speech delay and febrile seizures.
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11. Walsh E, Holloway J, Lydon H. {{An Evaluation of a Social Skills Intervention for Adults with Autism Spectrum Disorder and Intellectual Disabilities preparing for Employment in Ireland: A Pilot Study}}. {J Autism Dev Disord};2017 (Dec 9)
Individuals with autism spectrum disorder (ASD) are faced with significant barriers relating to employment opportunities and workplace participation. This study evaluated the effectiveness of the Walker social skills curriculum: the ACCESS program and video modeling to increase social communication skills necessary for workplace inclusion. Participants attended two sessions (i.e., 3 h) per week across a period of 20 weeks. A multiple-probe design was used to demonstrate social skills outcomes across three broad curricular areas (i.e., peer-related, adult-related, and self-related social skills). Pre-and post-intervention standardized assessments were also taken. Results showed significant increases in target social skills and a significant decrease in problem behaviors following intervention. Evidence of maintenance and generalization were also demonstrated. Implications for practice and research are discussed.
