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Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

May 30, 2014 - 8:42am
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Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

Mol Psychiatry. 2013 Oct;18(10):1077-89

Authors: Sowers LP, Loo L, Wu Y, Campbell E, Ulrich JD, Wu S, Paemka L, Wassink T, Meyer K, Bing X, El-Shanti H, Usachev YM, Ueno N, Manak JR, Manak RJ, Shepherd AJ, Ferguson PJ, Darbro BW, Richerson GB, Mohapatra DP, Wemmie JA, Bassuk AG

Abstract
Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.

PMID: 23711981 [PubMed - indexed for MEDLINE]

Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism.

May 30, 2014 - 8:42am
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Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism.

Mol Psychiatry. 2013 Oct;18(10):1054-6

Authors: Ben-David E, Shifman S

PMID: 23147383 [PubMed - indexed for MEDLINE]

Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts.

May 30, 2014 - 8:42am
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Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts.

Mol Psychiatry. 2013 Oct;18(10):1090-5

Authors: Moreno-De-Luca D, Sanders SJ, Willsey AJ, Mulle JG, Lowe JK, Geschwind DH, State MW, Martin CL, Ledbetter DH

Abstract
Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case-control analyses. Nevertheless, current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated 'hotspots') from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD.

PMID: 23044707 [PubMed - indexed for MEDLINE]

Posterior fossa malformation associated with cerebral anomalies: genetic and imaging features.

May 30, 2014 - 8:42am
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Posterior fossa malformation associated with cerebral anomalies: genetic and imaging features.

Top Magn Reson Imaging. 2011 Dec;22(6):295-302

Authors: Bertholdo D, de Carvalho Neto A, Castillo M

Abstract
Many posterior fossa malformations are associated with other malformations particularly supratentorial ones, which tend to affect the prognosis of these patients. The role of the cerebellum in higher learning is just beginning to be understood, but it is obvious that cerebellar abnormalities may result in higher-cognition defects. Studies have demonstrated cerebellar abnormalities in patients with developmental encephalopathies, such as autism, mental retardation, and Rett syndrome. Disorders that affect cell life cycles and result in abnormal cell proliferation and abnormal cell migration disorders (hemimegalencephaly, dystroglicanopathy, lissencephaly, and gray matter heterotopia) can also be accompanied by posterior fossa malformations. In this article, we discuss hindbrain-midbrain malformations associated with developmental encephalopathies and with supratentorial brain abnormalities that result from abnormal cell proliferation and cell migration.

PMID: 24132068 [PubMed - indexed for MEDLINE]

Response to Early Intensive Behavioral Intervention for Autism-an umbrella approach to issues critical to treatment individualization.

May 29, 2014 - 8:23am

Response to Early Intensive Behavioral Intervention for Autism-an umbrella approach to issues critical to treatment individualization.

Int J Dev Neurosci. 2014 May 24;

Authors: Fava L, Strauss K

Abstract
Integrating knowledge across the disciplines of genetics, neurological, and behavioral science targets, so far, early identification of children with autism and thus early access to intervention. Cross-discipline collaboration might be substantially improve treatment efficacy via individualized treatment based on the child and family needs, consistency across treatment providers and careful planning of skill curricula, setting and techniques. This paper documents the current state of five main issues critical to treatment individualization where cross-discipline collaboration is warranted: (1) developmental timing, (2) treatment intensity, (3) heterogeneity in treatment response, (4) program breath and flexibility, and (5) formats of treatment provision.

PMID: 24866707 [PubMed - as supplied by publisher]

Prioritization of neurodevelopmental disease genes by discovery of new mutations.

May 29, 2014 - 8:23am

Prioritization of neurodevelopmental disease genes by discovery of new mutations.

Nat Neurosci. 2014 Jun;17(6):764-72

Authors: Hoischen A, Krumm N, Eichler EE

Abstract
Advances in genome sequencing technologies have begun to revolutionize neurogenetics, allowing the full spectrum of genetic variation to be better understood in relation to disease. Exome sequencing of hundreds to thousands of samples from patients with autism spectrum disorder, intellectual disability, epilepsy and schizophrenia provides strong evidence of the importance of de novo and gene-disruptive events. There are now several hundred new candidate genes and targeted resequencing technologies that allow screening of dozens of genes in tens of thousands of individuals with high specificity and sensitivity. The decision of which genes to pursue depends on many factors, including recurrence, previous evidence of overlap with pathogenic copy number variants, the position of the mutation in the protein, the mutational burden among healthy individuals and membership of the candidate gene in disease-implicated protein networks. We discuss these emerging criteria for gene prioritization and the potential impact on the field of neuroscience.

PMID: 24866042 [PubMed - in process]

Genome-scale neurogenetics: methodology and meaning.

May 29, 2014 - 8:23am

Genome-scale neurogenetics: methodology and meaning.

Nat Neurosci. 2014 Jun;17(6):756-63

Authors: McCarroll SA, Feng G, Hyman SE

Abstract
Genetic analysis is currently offering glimpses into molecular mechanisms underlying such neuropsychiatric disorders as schizophrenia, bipolar disorder and autism. After years of frustration, success in identifying disease-associated DNA sequence variation has followed from new genomic technologies, new genome data resources, and global collaborations that could achieve the scale necessary to find the genes underlying highly polygenic disorders. Here we describe early results from genome-scale studies of large numbers of subjects and the emerging significance of these results for neurobiology.

PMID: 24866041 [PubMed - in process]

Neuropsychology and brain morphology in Klinefelter syndrome - the impact of genetics.

May 29, 2014 - 8:23am

Neuropsychology and brain morphology in Klinefelter syndrome - the impact of genetics.

Andrology. 2014 May 28;

Authors: Skakkebaek A, Bojesen A, Kristensen MK, Cohen A, Hougaard DM, Hertz JM, Fedder J, Laurberg P, Wallentin M, Ostergaard JR, Pedersen AD, Gravholt CH

Abstract
Klinefelter syndrome (KS, 47,XXY) is associated with increased psychiatric morbidity and cognitive disabilities, although the neuropsychological phenotype shows great variability. Androgen receptor polymorphism (CAG repeat length), skewed X-chromosome inactivation and parent-of-origin of the extra X-chromosome have been suggested to influence cognitive function and psychological traits. These issues have not been clarified for KS patients. We studied X-chromosome inactivation pattern, CAG repeat length and parent-of-origin in relation to educational and cohabitation status, personality and autism traits, psychological distress, cognitive function and brain volumes in 73 KS patients and 73 controls. Grey matter (GM) volume of left insula was significantly decreased in KS patients with skewed X-inactivation (z = 5.78) and we observed a borderline significant difference in global brain matter volume where KS patients with skewed X-chromosome inactivation tended to have smaller brains. Skewed X-inactivation, CAG repeat length and parent-of-origin were not correlated with educational and marital status, personality traits, autism traits, and psychological distress, prevalence of depression and anxiety or cognitive function. Interestingly our results regarding brain volumes indicate that X-inactivation has an influence on GM volume in left insula and might also be related to global GM volume, indicating a possible effect of X-linked genes on the development of GM volume in KS patient. Skewed X-inactivation, CAG repeat length and parent-of-origin have no impact on the neuropsychological phenotype in KS (http://www.clinicaltrials.gov (Clinical trial NCT00999310)).

PMID: 24865607 [PubMed - as supplied by publisher]

A review of gene-environment correlations and their implications for autism: a conceptual model.

May 29, 2014 - 8:23am
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A review of gene-environment correlations and their implications for autism: a conceptual model.

Psychol Rev. 2013 Jul;120(3):497-521

Authors: Meek SE, Lemery-Chalfant K, Jahromi LB, Valiente C

Abstract
A conceptual model is proposed that explains how gene-environment correlations and the multiplier effect function in the context of social development in individuals with autism. The review discusses the current state of autism genetic research, including its challenges, such as the genetic and phenotypic heterogeneity of the disorder, and its limitations, such as the lack of interdisciplinary work between geneticists and social scientists. We discuss literature on gene-environment correlations in the context of social development and draw implications for individuals with autism. The review expands upon genes, behaviors, types of environmental exposure, and exogenous variables relevant to social development in individuals on the autism spectrum, and explains these factors in the context of the conceptual model to provide a more in-depth understanding of how the effects of certain genetic variants can be multiplied by the environment to cause largely phenotypic individual differences. Using the knowledge gathered from gene-environment correlations and the multiplier effect, we outline novel intervention directions and implications.

PMID: 23915084 [PubMed - indexed for MEDLINE]

Autism spectrum disorder: advances in evidence-based practice.

May 28, 2014 - 7:53am
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Autism spectrum disorder: advances in evidence-based practice.

CMAJ. 2014 Apr 15;186(7):509-19

Authors: Anagnostou E, Zwaigenbaum L, Szatmari P, Fombonne E, Fernandez BA, Woodbury-Smith M, Brian J, Bryson S, Smith IM, Drmic I, Buchanan JA, Roberts W, Scherer SW

PMID: 24418986 [PubMed - indexed for MEDLINE]

Sex-specific association of a common variant of the XG gene with autism spectrum disorders.

May 28, 2014 - 7:53am
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Sex-specific association of a common variant of the XG gene with autism spectrum disorders.

Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):742-50

Authors: Chang SC, Pauls DL, Lange C, Sasanfar R, Santangelo SL

Abstract
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 × 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 × 10(-5) to 5.3 × 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.

PMID: 24132906 [PubMed - indexed for MEDLINE]

Chromosomal abnormalities in patients with autism spectrum disorders from Taiwan.

May 28, 2014 - 7:53am
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Chromosomal abnormalities in patients with autism spectrum disorders from Taiwan.

Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):734-41

Authors: Liao HM, Gau SS, Tsai WC, Fang JS, Su YC, Chou MC, Liu SK, Chou WJ, Wu YY, Chen CH

Abstract
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.

PMID: 24132905 [PubMed - indexed for MEDLINE]

Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

May 28, 2014 - 7:53am
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Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):671-8

Authors: Schreiber M, Dorschner M, Tsuang D

Abstract
Schizophrenia is a debilitating lifelong illness that lacks a cure and poses a worldwide public health burden. The disease is characterized by a heterogeneous clinical and genetic presentation that complicates research efforts to identify causative genetic variations. This review examines the potential of current findings in schizophrenia and in other related neuropsychiatric disorders for application in next-generation technologies, particularly whole-exome sequencing (WES) and whole-genome sequencing (WGS). These approaches may lead to the discovery of underlying genetic factors for schizophrenia and may thereby identify and target novel therapeutic targets for this devastating disorder.

PMID: 24132899 [PubMed - indexed for MEDLINE]

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

May 27, 2014 - 7:26am

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Mol Autism. 2014;5:31

Authors: Gupta AR, Pirruccello M, Cheng F, Kang HJ, Fernandez TV, Baskin JM, Choi M, Liu L, Ercan-Sencicek AG, Murdoch JD, Klei L, Neale BM, Franjic D, Daly MJ, Lifton RP, De Camilli P, Zhao H, Sestan N, State MW

Abstract
BACKGROUND: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD.
METHODS: We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue.
RESULTS: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10(-16), Wilcoxon test) with a module of genes significantly associated with ASD.
CONCLUSIONS: Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism has been strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism.

PMID: 24860643 [PubMed]

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.

May 27, 2014 - 7:26am

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.

Nat Genet. 2014 May 25;

Authors: Uddin M, Tammimies K, Pellecchia G, Alipanahi B, Hu P, Wang Z, Pinto D, Lau L, Nalpathamkalam T, Marshall CR, Blencowe BJ, Frey BJ, Merico D, Yuen RK, Scherer SW

Abstract
A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10(-38); odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10(-11); OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10(-157); OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.

PMID: 24859339 [PubMed - as supplied by publisher]

Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder.

May 27, 2014 - 7:26am
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Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder.

PLoS One. 2013;8(9):e74167

Authors: Koshimizu E, Miyatake S, Okamoto N, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N

Abstract
Next-generation sequencing (NGS) combined with enrichment of target genes enables highly efficient and low-cost sequencing of multiple genes for genetic diseases. The aim of this study was to validate the accuracy and sensitivity of our method for comprehensive mutation detection in autism spectrum disorder (ASD). We assessed the performance of the bench-top Ion Torrent PGM and Illumina MiSeq platforms as optimized solutions for mutation detection, using microdroplet PCR-based enrichment of 62 ASD associated genes. Ten patients with known mutations were sequenced using NGS to validate the sensitivity of our method. The overall read quality was better with MiSeq, largely because of the increased indel-related error associated with PGM. The sensitivity of SNV detection was similar between the two platforms, suggesting they are both suitable for SNV detection in the human genome. Next, we used these methods to analyze 28 patients with ASD, and identified 22 novel variants in genes associated with ASD, with one mutation detected by MiSeq only. Thus, our results support the combination of target gene enrichment and NGS as a valuable molecular method for investigating rare variants in ASD.

PMID: 24066114 [PubMed - indexed for MEDLINE]

CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder?

May 27, 2014 - 7:26am
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CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder?

J Intellect Disabil Res. 2013 Nov;57(11):993-1000

Authors: Braam W, Keijzer H, Struijker Boudier H, Didden R, Smits M, Curfs L

Abstract
BACKGROUND: In some of our patients with intellectual disabilities (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment. In these patients melatonin levels at noon were extremely high (>50 pg/ml). We hypothesise that the disappearing effectiveness is associated with slow metabolisation of melatonin because of a single nucleotide polymorphism (SNP) of CYP1A2.
METHOD: In this pilot study we analysed DNA extracted from saliva samples of 15 consecutive patients with disappearing effectiveness of melatonin. Saliva was collected at noon and 4 pm for measuring melatonin levels.
RESULTS: In all patients' salivary melatonin levels at noon were >50 or melatonin half time was > 5 h. A SNP was found in eight of 15 patients. The allele 1C was found in two patients and in six patients the 1F allele was found.
CONCLUSIONS: Of 15 patients with disappearing effectiveness of melatonin, seven were diagnosed with autism spectrum disorder, and in four of them a SNP was found. The other eight patients were known with a genetic syndrome. In six of them behaviour was considered to be autistic-type and in three of them a SNP was found. This finding may give a new direction for research into the genetic background of autism.

PMID: 22823064 [PubMed - indexed for MEDLINE]

Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader-Willi syndrome: A comparison between maternal uniparental disomy and deletion cases.

May 23, 2014 - 8:51am

Autism spectrum disorders and hyperactive/impulsive behaviors in Japanese patients with Prader-Willi syndrome: A comparison between maternal uniparental disomy and deletion cases.

Am J Med Genet A. 2014 May 21;

Authors: Ogata H, Ihara H, Murakami N, Gito M, Kido Y, Nagai T

Abstract
This study aims to compare maternal uniparental disomy 15 (mUPD) and a paternal deletion of 15q11-13 (DEL) of Prader-Willi syndrome (PWS) in regard to autism spectrum disorders (ASD). Forty-five Japanese individuals with PWS were recruited from a single recruitment center. The participants consisted of 22 children (aged from 6 to 12) and 23 adolescents (aged from 13 to 19). Six children and seven adolescents were confirmed as having mUPD. Sixteen children and 16 adolescents were confirmed as having DEL. Under blindness to the participants' genotypes, a single psychologist carried out behavioral and psychological assessments, including the Wechsler Intelligence Scales, Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), and ADHD-Rating Scale-IV (ADHD-RS-IV). Two comparisons were made: one between mUPD and DEL children and another between mUPD and DEL adolescents. In children, no significant differences were found between mUPD and DEL participants in terms of autistic (PARS childhood, P = 0.657) and impulsive behaviors (ADHD-RS-IV hyperactive/impulsive, P = 0.275). In adolescents, mUPD patients showed significantly more autistic symptomatology (PARS adolescent, P = 0.027) and significantly more impulsive behavior (ADHD-RS-IV hyperactive/impulsive, P = 0.01) than DEL patients. Our findings about Japanese PWS patients were consistent with previous researches from western countries not focused on Asian patients, indicating that mUPD cases would be more prone to ASD than DEL cases, regardless of ethnoregional differences. In addition, our data suggested that the behavioral difference between mUPD and DEL cases in terms of autistic and impulsive symptoms tend to be unrecognizable in their childhood. © 2014 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

PMID: 24850752 [PubMed - as supplied by publisher]

No increase in autism-associated genetic events in children conceived by assisted reproduction.

May 21, 2014 - 8:12am

No increase in autism-associated genetic events in children conceived by assisted reproduction.

Fertil Steril. 2014 May 17;

Authors: Ackerman S, Wenegrat J, Rettew D, Althoff R, Bernier R

Abstract
OBJECTIVE: To understand the rate of genetic events in patients with autism spectrum disorder (ASD) who were exposed to assisted reproduction.
DESIGN: Case control study using genetics data.
SETTING: Twelve collaborating data collection sites across North America as part of the Simons Simplex Collection.
PATIENT(S): 2,760 children with ASD, for whom 1,994 had published copy number variation data and 424 had published gene mutation status available.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Rates of autism-associated genetic events in children with ASD conceived with assisted reproduction versus those conceived naturally.
RESULT(S): No statistically significant differences in copy number variations or autism-associated gene-disrupting events were found when comparing ASD patients exposed to assisted reproduction with those not exposed to assisted reproduction.
CONCLUSION(S): This is the first large genetic association to concurrently examine the genotype of individuals with ASD in relation to their exposure to ART versus natural conception, and it adds reassuring evidence to the argument that ART does not increase the risk of ASD.

PMID: 24842673 [PubMed - as supplied by publisher]

Maternal inflammation promotes fetal microglial activation and increased cholinergic expression in the fetal basal forebrain: role of interleukin-6.

May 20, 2014 - 7:55am
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Maternal inflammation promotes fetal microglial activation and increased cholinergic expression in the fetal basal forebrain: role of interleukin-6.

Pediatr Res. 2013 Oct;74(4):393-401

Authors: Pratt L, Ni L, Ponzio NM, Jonakait GM

Abstract
BACKGROUND: Perinatal exposure to infectious agents with associated maternal immune activation (MIA) leads to neuroanatomical and behavioral dysregulation reminiscent of autism spectrum disorders. Persistent microglial activation as well as increased choline acetyltransferase (ChAT) activity in the basal forebrain (BF) are characteristic of autistic subjects. Previous studies have shown that medium from activated microglia promotes cholinergic differentiation of precursors in the BF. We sought to determine whether MIA in vivo would lead to a similar effect on developing BF neurons.
METHODS: Pregnant mice were treated with the viral mimic polyinosinic-polycytidylic acid (poly(I:C)) or saline.
RESULTS: Poly(I:C) treatment resulted in increased production of cytokines and chemokines in fetal microglia and increased ChAT activity and cholinergic cell number in the perinatal BF. Whether microglial activation causes these changes is unclear. Examination of fetal brains from mice lacking interleukin-6 (IL-6 KOs) revealed an elevation in non-microglial-derived cytokines and chemokines over wild-type controls. Moreover, IL-6 KO offspring showed an elevation of ChAT activity even in the absence of poly(I:C) administration.
CONCLUSION: These data suggest that elevations in cytokines and/or chemokines caused either by maternal poly(I:C) administration or by the absence of IL-6 are associated with alterations in cholinergic development in the BF.

PMID: 23877071 [PubMed - indexed for MEDLINE]

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