| 41. |
- Orekhova, Elena V, 1967, et al.
(författare)
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Excess of high frequency electroencephalogram oscillations in boys with autism.
- 2007
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223. ; 62:9, s. 1022-1099
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An elevated excitation/inhibition ratio has been suggested as one mechanism underpinning autism. An imbalance between cortical excitation and inhibition may manifest itself in electroencephalogram (EEG) abnormalities in the high frequency range. The aim of this study was to investigate whether beta and gamma range EEG abnormalities are characteristic for young boys with autism (BWA). METHODS: EEG was recorded during sustained visual attention in two independent samples of BWA from Moscow and Gothenburg, aged 3 to 8 years, and in age matched typically developing boys (TDB). High frequency EEG spectral power was analyzed. RESULTS: In both samples, BWA demonstrated a pathological increase of gamma (24.4-44.0 Hz) activity at the electrode locations distant from the sources of myogenic artefacts. In both samples, the amount of gamma activity correlated positively with degree of developmental delay in BWA. CONCLUSIONS: The excess of high frequency oscillations may reflect imbalance in the excitation-inhibition homeostasis in the cortex. Given the important role of high frequency EEG rhythms for perceptual and cognitive processes, early and probably genetically determined abnormalities in the neuronal mechanisms generating high frequency EEG rhythms may contribute to development of the disorder. Further studies are needed to investigate the specificity of the findings for autism.
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| 42. |
- Orekhova, Elena V, 1967, et al.
(författare)
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Sensory gating in young children with autism: relation to age, IQ, and EEG gamma oscillations.
- 2008
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940. ; 434:2, s. 218-223
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Tidskriftsartikel (refereegranskat)abstract
- Unusual reactions to auditory stimuli are often observed in autism and may relate to ineffective inhibitory modulation of sensory input (sensory gating). A previous study of P50 sensory gating did not reveal abnormalities in high-functioning school age children [C. Kemner, B. Oranje, M.N. Verbaten, H. van Engeland, Normal P50 gating in children with autism, J. Clin. Psychiatry 63 (2002) 214-217]. Sensory gating deficit may, however, characterize younger children with autism or be a feature of retarded children with autism, reflecting imbalance of neuronal excitation/inhibition in these cohorts. We applied a paired clicks paradigm to study P50 sensory gating, and its relation to IQ and EEG gamma spectral power (as a putative marker of cortical excitability), in young (3-8 years) children with autism (N=21) and age-matched typically developing children (N=21). P50 suppression in response to the second click was normal in high-functioning children with autism, but significantly (p<0.03) reduced in those with mental retardation. P50 gating improved with age in both typically developing children and those with autism. Higher ongoing EEG gamma power corresponded to lower P50 suppression in autism (p<0.02), but not in control group. The data suggest that ineffective inhibitory control of sensory processing is characteristic for retarded children with autism and may reflect excitation/inhibition imbalance in this clinical group.
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| 43. |
- Orekhova, Elena V, 1967, et al.
(författare)
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The right hemisphere fails to respond to temporal novelty in autism: evidence from an ERP study.
- 2009
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Ingår i: Clinical Neurophysiology. - : Elsevier BV. - 1388-2457. ; 120:3, s. 520-529
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study aimed to investigate electrophysiological correlates of initial attention orienting to temporally novel sound in children with autism (CWA). METHODS: Twenty-one CWA (4-8 years) and 21 age-matched typically developing children (TDC) were presented with pairs of clicks separated by a 0.5s intra-pair interval, with longer (7-9s) intervals between pairs. Children watched a silent movie during click presentation. We assessed EEG perturbations and event-related potentials (ERP) in response to sounds of different temporal novelty - first (S1) and second (S2) clicks in the pair. RESULTS: In TDC, the early attention-modulated midtemporal N1c wave evoked by S1 and corresponding EEG phase locking and power increase were right-lateralized and were bilaterally higher than those evoked by S2. CWA demonstrated abnormal S1 responses, characterized by reduced N1c amplitude and EEG phase locking in the right midtemporal region, reversed leftward lateralization of the phase locking, and diminished later frontal N2 wave. Their brain responses to S2 were essentially normal. CONCLUSIONS: The impaired right hemispheric processing of temporary and contextually novel information and suboptimal lateralization of normally right-lateralized attention networks may be important features of autistic disorder. SIGNIFICANCE: Results of this study contribute to the understanding of autism neurobiology.
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| 44. |
- Pilorge, M, et al.
(författare)
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Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.
- 2016
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 21:7, s. 936-945
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.Molecular Psychiatry advance online publication, 15 September 2015; doi:10.1038/mp.2015.139.
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| 45. |
- Pinto, Dalila, et al.
(författare)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
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Tidskriftsartikel (refereegranskat)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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| 46. |
- Scheid, Isabelle, et al.
(författare)
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Heterozygous FA2H mutations in autism spectrum disorders
- 2013
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD. Methods We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells. Results One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells. Conclusions While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.
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| 47. |
- Stroganova, Tatiana A, et al.
(författare)
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Abnormal EEG lateralization in boys with autism.
- 2007
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Ingår i: Clinical Neurophysiology. - : Elsevier BV. - 1388-2457. ; 118:8, s. 1842-1854
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Functional brain abnormalities associated with autism in 3-8-year-old boys were studied with EEG recorded under controlled experimental condition of sustained visual attention and behavioral stillness. METHODS: EEG was recorded in two independent samples of boys with autism (BWA) from Moscow (N=21) and Gothenburg (N=23) and a corresponding number of age-matched typically developing boys (TDB). EEG spectral power (SP) and SP interhemispheric asymmetry within delta, theta and alpha bands were analyzed. RESULTS: BWA comprised a non-homogeneous group in relation to theta and alpha SP. When four outliers were excluded the only between-group difference in absolute SP was a higher amount of prefrontal delta in BWA. BWA of both samples demonstrated atypical leftward broadband EEG asymmetry with a maximum effect over the mid-temporal regions. Concurrently, the normal leftward asymmetry of mu rhythm was absent in BWA. CONCLUSIONS: The abnormal broadband EEG asymmetry in autism may point to a diminished capacity of right temporal cortex to generate EEG rhythms. The concurrent lack of normal leftward asymmetry of mu rhythm suggests that abnormalities in EEG lateralization in autism may be regionally/functionally specific. SIGNIFICANCE: The data provide evidence for abnormal functional brain lateralization in autism.
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| 48. |
- Tabet, Anne-Claude, et al.
(författare)
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Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.
- 2015
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Ingår i: Molecular autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment. METHODS: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR. RESULTS: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3. CONCLUSIONS: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.
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