1. Chang SC, Pauls DL, Lange C, Sasanfar R, Santangelo SL. {{Sex-specific association of a common variant of the XG gene with autism spectrum disorders}}. {American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics}. 2013 Oct;162(7):742-50.
Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD. In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository. We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp22.33/Yp11.31 in the MO families of predominantly paternal origin (rs2535443, p = 3.8 x 10(-8) ). Five markers that reside within a 550 kb intergenic region on chromosome 13q33.3, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p = 3.3 x 10(-5) to 5.3 x 10(-7) ). In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females. Our results suggest that the pseudoautosomal boundary on Xp22.33/Yp11.31 may harbor male-specific genetic variants for ASD. (c) 2013 Wiley Periodicals, Inc.
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2. Ghaleiha A, Ghyasvand M, Mohammadi MR, Farokhnia M, Yadegari N, Tabrizi M, Hajiaghaee R, Yekehtaz H, Akhondzadeh S. {{Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial}}. {Journal of psychopharmacology (Oxford, England)}. 2013 Oct 15.
The role of cholinergic abnormalities in autism was recently evidenced and there is a growing interest in cholinergic modulation, emerging for targeting autistic symptoms. Galantamine is an acetylcholinesterase inhibitor and an allosteric potentiator of nicotinic receptors. This study aimed to evaluate the possible effects of galantamine as an augmentative therapy to risperidone, in autistic children. In this randomized, double-blind, placebo-controlled, parallel-group study, 40 outpatients aged 4-12 years whom had a diagnosis of autism (DSM IV-TR) and a score of 12 or higher on the Aberrant Behavior Checklist-Community (ABC-C) Irritability subscale were equally randomized to receive either galantamine (up to 24 mg/day) or placebo, in addition to risperidone (up to 2 mg/day), for 10 weeks. We rated participants by ABC-C and a side effects checklist, at baseline and at weeks 5 and 10. By the study endpoint, the galantamine-treated patients showed significantly greater improvement in the Irritability (P = 0.017) and Lethargy/Social Withdrawal (P = 0.005) subscales than the placebo group. The difference between the two groups in the frequency of side effects was not significant. In conclusion, galantamine augmentation was shown to be a relatively effective and safe augmentative strategy for alleviating some of the autism-related symptoms.
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3. Jones RM, Cadby G, Melton PE, Abraham LJ, Whitehouse AJ, Moses EK. {{Genome-wide association study of autistic-like traits in a general population study of young adults}}. {Frontiers in human neuroscience}. 2013;7:658.
Lay abstract: It has been proposed that autistic-like traits in the general population lie on a continuum, with clinical Autism Spectrum Disorder (ASD), representing the extreme end of this distribution. The current study undertook a genome-wide association (GWA) scan of 965 young Western Australian adults to identify novel risk variants associated with autistic-like traits. No associations reached genome-wide significance; however, a review of nominally associated single nucleotide polymorphisms (SNPs) indicated two positional candidate loci that have been previously implicated in autistic-like trait etiology. Scientific abstract: Research has proposed that autistic-like traits in the general population lie on a continuum, with clinical ASD representing the extreme end of this distribution. Inherent in this proposal is that biological mechanisms associated with clinical ASD may also underpin variation in autistic-like traits within the general population. A GWA study using 2,462,046 SNPs was undertaken for ASD in 965 individuals from the Western Australian Pregnancy Cohort (Raine) Study. No SNP associations reached genome-wide significance (p < 5.0 x 10(-8)). However, investigations into nominal observed SNP associations (p < 1.0 x 10(-5)) add support to two positional candidate genes previously implicated in ASD etiology, PRKCB1, and CBLN1. The rs198198 SNP (p = 9.587 x 10(-6)), is located within an intron of the protein kinase C, beta 1 (PRKCB1) gene on chromosome 16p11. The PRKCB1 gene has been previously reported in linkage and association studies for ASD, and its mRNA expression has been shown to be significantly down regulated in ASD cases compared with controls. The rs16946931 SNP (p = 1.78 x 10(-6)) is located in a region flanking the Cerebellin 1 (CBLN1) gene on chromosome 16q12.1. The CBLN1 gene is involved with synaptogenesis and is part of a gene family previously implicated in ASD. This GWA study is only the second to examine SNPs associated with autistic-like traits in the general population, and provides evidence to support roles for the PRKCB1 and CBLN1 genes in risk of clinical ASD.
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4. Liao HM, Gau SS, Tsai WC, Fang JS, Su YC, Chou MC, Liu SK, Chou WJ, Wu YY, Chen CH. {{Chromosomal abnormalities in patients with autism spectrum disorders from taiwan}}. {American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics}. 2013 Oct;162(7):734-41.
Autism spectrum disorders (ASD) are childhood-onset neurodevelopmental disorders characterized by verbal communication impairments, social reciprocity deficits, and the presence of restricted interests and stereotyped behaviors. Genetic factors contribute to the incidence of ASD evidently. However, the genetic spectrum of ASD is highly heterogeneous. Chromosomal abnormalities contribute significantly to the genetic deficits of syndromic and non-syndromic ASD. In this study, we conducted karyotyping analysis in a sample of 500 patients (447 males, 53 females) with ASD from Taiwan, the largest cohort in Asia, to the best of our knowledge. We found three patients having sex chromosome aneuploidy, including two cases of 47, XXY and one case of 47, XYY. In addition, we detected a novel reciprocal chromosomal translocation between long arms of chromosomes 4 and 14, designated t(4;14)(q31.3;q24.1), in a patient with Asperger’s disorder. This translocation was inherited from his unaffected father, suggesting it might not be pathogenic or it needs further hits to become pathogenic. In line with other studies, our study revealed that subjects with sex chromosomal aneuploidy are liable to neurodevelopmental disorders, including ASD, and conventional karyotyping analysis is still a useful tool in detecting chromosomal translocation in patients with ASD, given that array-based comparative genomic hybridization technology can provide better resolution in detecting copy number variations of genomic DNA. (c) 2013 Wiley Periodicals, Inc.
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5. McGrath J, Johnson K, O’Hanlon E, Garavan H, Leemans A, Gallagher L. {{Abnormal functional connectivity during visuospatial processing is associated with disrupted organisation of white matter in autism}}. {Frontiers in human neuroscience}. 2013;7:434.
Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD) but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were (1) to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM) in ASD and (2) to examine the relationships between aberrant neural connectivity and behavior in ASD. Twenty-two individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD) based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19) and five paired regions: left caudate head, left caudate body, left uncus, left thalamus, and left cuneus. Measures of WM microstructural organization were extracted from these tracts. Fractional anisotropy (FA) reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant WM microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute (1) to abnormal functional connectivity and (2) to atypical visuospatial processing in ASD.
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6. Percy AK. {{Neuroscience. Path to treat Rett syndrome}}. {Science (New York, NY)}. 2013 Oct 18;342(6156):318-20.
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7. Taylor B, Jick H, Maclaughlin D. {{Prevalence and incidence rates of autism in the UK: time trend from 2004-2010 in children aged 8 years}}. {BMJ open}. 2013;3(10):e003219.
OBJECTIVES: To update UK studies begun in the early 1990s on the annual prevalence and incidence rates of autism in children; undertaken in response to a March 2012 press release, widely covered by the media, from the US Centre for Disease Control (CDC) reporting that the autism prevalence rate in 2008 in 8-year-old US children was 1 in 88, a 78% increase from a CDC estimate in 2004. This finding suggested a continuation of the dramatic increase in children diagnosed as autistic, which occurred in the 1990s. DESIGN: Population study using the UK General Practice Research Database (GPRD). METHODS: Annual autism prevalence rates were estimated for children aged 8 years in 2004-2010 by dividing the number diagnosed as autistic in each or any previous year by the number of children active in the study population that year. We also calculated annual incidence rates for children aged 2-8 years, by dividing the number newly diagnosed in 2004-2010 by the same denominators. RESULTS: Annual prevalence rates for each year were steady at approximately 3.8/1000 boys and 0.8/1000 girls. Annual incidence rates each year were also steady at about 1.2/1000 boys and 0.2/1000 girls. CONCLUSIONS: Following a fivefold increase in the annual incidence rates of autism during the 1990s in the UK, the incidence and prevalence rates in 8-year-old children reached a plateau in the early 2000s and remained steady through 2010. Whether prevalence rates have increased from the early 2000s in the USA remains uncertain.
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8. Yang Y, Vasylyev DV, Dib-Hajj F, Veeramah KR, Hammer MF, Dib-Hajj SD, Waxman SG. {{Multistate Structural Modeling and Voltage-Clamp Analysis of Epilepsy/Autism Mutation Kv10.2-R327H Demonstrate the Role of This Residue in Stabilizing the Channel Closed State}}. {The Journal of neuroscience : the official journal of the Society for Neuroscience}. 2013 Oct 16;33(42):16586-93.
Voltage-gated potassium channel Kv10.2 (KCNH5) is expressed in the nervous system, but its functions and involvement in human disease are poorly understood. We studied a human Kv10.2 channel mutation (R327H) recently identified in a child with epileptic encephalopathy and autistic features. Using multistate structural modeling, we demonstrate that the Arg327 residue in the S4 helix of voltage-sensing domain has strong ionic interactions with negatively charged residues within the S1-S3 helices in the resting (closed) and early-activation state but not in the late-activation and fully-activated (open) state. The R327H mutation weakens ionic interactions between residue 327 and these negatively charged residues, thus favoring channel opening. Voltage-clamp analysis showed a strong hyperpolarizing ( approximately 70 mV) shift of voltage dependence of activation and an acceleration of activation. Our results demonstrate the critical role of the Arg327 residue in stabilizing the channel closed state and explicate for the first time the structural and functional change of a Kv10.2 channel mutation associated with neurological disease.
