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Insights into GABAAergic System Deficits in Fragile X Syndrome Lead to Clinical Trials.

July 13, 2014 - 7:11am

Insights into GABAAergic System Deficits in Fragile X Syndrome Lead to Clinical Trials.

Neuropharmacology. 2014 Jul 9;

Authors: Braat S, Kooy RF

Abstract
An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable in unravelling the molecular mechanisms underlying the disorder. Multiple defects in this inhibitory system have been identified in Fmr1 knockout mice, including altered expression of various components, aberrant GABAA receptor-mediated signalling, altered GABA concentrations and anatomical defects in GABAergic neurons. Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated.

PMID: 25016041 [PubMed - as supplied by publisher]

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics.

July 12, 2014 - 6:22am

Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics.

Neuropsychopharmacology. 2014 Jul 11;

Authors: Hernandez LM, Rudie JD, Green SA, Bookheimer S, Dapretto M

Abstract
Neuroimaging investigations of Autism Spectrum Disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered network-level connectivity. Traditional task-based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems-level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD subpopulations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data.Neuropsychopharmacology Reviews accepted article preview online, 11 July 2014; doi:10.1038/npp.2014.172.

PMID: 25011468 [PubMed - as supplied by publisher]

Age-Associated Sperm DNA Methylation Alterations: Possible Implications in Offspring Disease Susceptibility.

July 11, 2014 - 3:05pm
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Age-Associated Sperm DNA Methylation Alterations: Possible Implications in Offspring Disease Susceptibility.

PLoS Genet. 2014 Jul;10(7):e1004458

Authors: Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT

Abstract
Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence that these alterations are more common in offspring sired by older fathers, in most cases the mechanisms that drive these processes are unclear. However, it is commonly believed that epigenetics, and specifically DNA methylation alterations, likely play a role. In this study we have investigated the impact of aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluated changes to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2 samples collected from each individual 9-19 years apart. With this design we have identified 139 regions that are significantly and consistently hypomethylated with age and 8 regions that are significantly hypermethylated with age. A representative subset of these alterations have been confirmed in an independent cohort. A total of 117 genes are associated with these regions of methylation alterations (promoter or gene body). Intriguingly, a portion of the age-related changes in sperm DNA methylation are located at genes previously associated with schizophrenia and bipolar disorder. While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists.

PMID: 25010591 [PubMed - as supplied by publisher]

Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study.

July 11, 2014 - 3:05pm
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Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study.

PLoS One. 2014;9(7):e101784

Authors: Agam Y, Vangel M, Roffman JL, Gallagher PJ, Chaponis J, Haddad S, Goff DC, Greenberg JL, Wilhelm S, Smoller JW, Manoach DS

Abstract
BACKGROUND: Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.
METHODS: We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.
RESULTS: We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.
CONCLUSIONS: DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.

PMID: 25010186 [PubMed - as supplied by publisher]

PACAP and PAC1 receptor in brain development and behavior.

July 11, 2014 - 3:05pm
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PACAP and PAC1 receptor in brain development and behavior.

Neuropeptides. 2013 Dec;47(6):421-30

Authors: Shen S, Gehlert DR, Collier DA

Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) act through three class B G-protein coupled receptors, PAC1, VPAC1 and VPAC2, initiating multiple signaling pathways. In addition to natural peptides ligands, a number of synthetic peptides and a small molecular antagonist have been generated. Genetically modified animals have been produced for the neuropeptides and receptors. Neuroanatomical, electrophysiological, behavioral and pharmacological characterization of the mutants and transgenic mice uncovered diverse roles of PACAP-PAC1-VAPC2 signaling in peripheral tissues and in the central nervous system. Human genetic studies suggest that the PACAP-PAC1-VPAC2 signaling can be associated with psychiatric illness via mechanisms of not only loss-of-function, but also gain-of-function. For example, a duplication of chromosome 7q36.3 (encoding the VPAC2 receptor) was shown to be associated with schizophrenia, and high levels of PACAP-PAC1 signaling are associated with posttraumatic stress disorder. Whereas knockout animals are appropriate to address loss-of-function of human genetics, transgenic mice overexpressing human transgenes in native environment using artificial chromosomes are particularly valuable and essential to address the consequences of gain-of-function. This review focuses on role of PACAP and PAC1 receptor in brain development, behavior of animals and potential implication in human neurodevelopmental disorders. It also encourages keeping an open mind that alterations of VIP/PACAP signaling may associate with psychiatric illness without overt neuroanatomic changes, and that tuning of VIP/PACAP signaling may represent a novel avenue for the treatment of the psychiatric illness.

PMID: 24220567 [PubMed - indexed for MEDLINE]

Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome.

July 9, 2014 - 3:33pm

Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome.

EMBO Mol Med. 2014 Jul 7;

Authors: Camarena V, Cao L, Abad C, Abrams A, Toledo Y, Araki K, Araki M, Walz K, Young JI

Abstract
2q23.1 microdeletion syndrome is characterized by intellectual disability, motor delay, autistic-like behaviors, and a distinctive craniofacial phenotype. All patients carry a partial or total deletion of methyl-CpG-binding domain protein 5 (MBD5), suggesting that haploinsufficiency of this gene is responsible for the phenotype. To confirm this hypothesis and to examine the role of MBD5 in vivo, we have generated and characterized an Mbd5 gene-trap mouse model. Our study indicates that the Mbd5(+/) (GT) mouse model recapitulates most of the hallmark phenotypes observed in 2q23.1 deletion carriers including abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities. In addition, neuronal cultures uncovered a deficiency in neurite outgrowth. These findings support a causal role of MBD5 in 2q23.1 microdeletion syndrome and suggest a role for MBD5 in neuronal processes. The Mbd5(+/) (GT) mouse model will advance our understanding of the abnormal brain development underlying the emergence of 2q23.1 deletion-associated behavioral and cognitive symptoms.

PMID: 25001218 [PubMed - as supplied by publisher]

Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes.

July 9, 2014 - 3:33pm
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Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes.

Nat Commun. 2013;4:2889

Authors: Lambrot R, Xu C, Saint-Phar S, Chountalos G, Cohen T, Paquet M, Suderman M, Hallett M, Kimmins S

Abstract
Epidemiological studies suggest that a father's diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health.

PMID: 24326934 [PubMed - indexed for MEDLINE]

A quantitative framework to evaluate modeling of cortical development by neural stem cells.

July 6, 2014 - 7:37am
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A quantitative framework to evaluate modeling of cortical development by neural stem cells.

Neuron. 2014 Jul 2;83(1):69-86

Authors: Stein JL, de la Torre-Ubieta L, Tian Y, Parikshak NN, Hernández IA, Marchetto MC, Baker DK, Lu D, Hinman CR, Lowe JK, Wexler EM, Muotri AR, Gage FH, Kosik KS, Geschwind DH

Abstract
Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.

PMID: 24991955 [PubMed - in process]

Clinical report of a 17q12 microdeletion with additionally unreported clinical features.

July 6, 2014 - 7:37am
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Clinical report of a 17q12 microdeletion with additionally unreported clinical features.

Case Rep Genet. 2014;2014:264947

Authors: Roberts JL, Gandomi SK, Parra M, Lu I, Gau CL, Dasouki M, Butler MG

Abstract
Copy number variations involving the 17q12 region have been associated with developmental and speech delay, autism, aggression, self-injury, biting and hitting, oppositional defiance, inappropriate language, and auditory hallucinations. We present a tall-appearing 17-year-old boy with marfanoid habitus, hypermobile joints, mild scoliosis, pectus deformity, widely spaced nipples, pes cavus, autism spectrum disorder, intellectual disability, and psychiatric manifestations including physical and verbal aggression, obsessive-compulsive behaviors, and oppositional defiance. An echocardiogram showed borderline increased aortic root size. An abdominal ultrasound revealed a small pancreas, mild splenomegaly with a 1.3 cm accessory splenule, and normal kidneys and liver. A testing panel for Marfan, aneurysm, and related disorders was negative. Subsequently, a 400 K array-based comparative genomic hybridization (aCGH) + SNP analysis was performed which identified a de novo suspected pathogenic deletion on chromosome 17q12 encompassing 28 genes. Despite the limited number of cases described in the literature with 17q12 rearrangements, our proband's phenotypic features both overlap and expand on previously reported cases. Since syndrome-specific DNA sequencing studies failed to provide an explanation for this patient's unusual habitus, we postulate that this case represents an expansion of the 17q12 microdeletion phenotype. Further analysis of the deleted interval is recommended for new genotype-phenotype correlations.

PMID: 24991439 [PubMed]

Prevalence of autism spectrum disorders in China.

July 6, 2014 - 7:37am
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Prevalence of autism spectrum disorders in China.

Shanghai Arch Psychiatry. 2013 Jun;25(3):176-7

Authors: Cubells JF

PMID: 24991154 [PubMed]

Post-transcriptional regulation of the creatine transporter gene: functional relevance of alternative splicing.

July 6, 2014 - 7:37am
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Post-transcriptional regulation of the creatine transporter gene: functional relevance of alternative splicing.

Biochim Biophys Acta. 2014 Jun;1840(6):2070-9

Authors: Ndika JD, Martinez-Munoz C, Anand N, van Dooren SJ, Kanhai W, Smith DE, Jakobs C, Salomons GS

Abstract
BACKGROUND: Aberrations in about 10-15% of X-chromosome genes account for intellectual disability (ID); with a prevalence of 1-3% (Gécz et al., 2009 [1]). The SLC6A8 gene, mapped to Xq28, encodes the creatine transporter (CTR1). Mutations in SLC6A8, and the ensuing decrease in brain creatine, lead to co-occurrence of speech/language delay, autism-like behaviors and epilepsy with ID. A splice variant of SLC6A8-SLC6A8C, containing intron 4 and exons 5-13, was identified. Herein, we report the identification of a novel variant - SLC6A8D, and functional relevance of these isoforms.
METHODS: Via (quantitative) RT-PCR, uptake assays, and confocal microscopy, we investigated their expression and function vis-à-vis creatine transport.
RESULTS: SLC6A8D is homologous to SLC6A8C except for a deletion of exon 9 (without occurrence of a frame shift). Both contain an open reading frame encoding a truncated protein but otherwise identical to CTR1. Like SLC6A8, both variants are predominantly expressed in tissues with high energy requirement. Our experiments reveal that these truncated isoforms do not transport creatine. However, in SLC6A8 (CTR1)-overexpressing cells, a subsequent infection (transduction) with viral constructs encoding either the SLC6A8C (CTR4) or SLC6A8D (CTR5) isoform resulted in a significant increase in creatine accumulation compared to CTR1 cells re-infected with viral constructs containing the empty vector. Moreover, transient transfection of CTR4 or CTR5 into HEK293 cells resulted in significantly higher creatine uptake.
CONCLUSIONS: CTR4 and CTR5 are possible regulators of the creatine transporter since their overexpression results in upregulated CTR1 protein and creatine uptake.
GENERAL SIGNIFICANCE: Provides added insight into the mechanism(s) of creatine transport regulation.

PMID: 24561156 [PubMed - indexed for MEDLINE]

FOXP1 mutations cause intellectual disability and a recognizable phenotype.

July 6, 2014 - 7:37am
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FOXP1 mutations cause intellectual disability and a recognizable phenotype.

Am J Med Genet A. 2013 Dec;161A(12):3166-75

Authors: Le Fevre AK, Taylor S, Malek NH, Horn D, Carr CW, Abdul-Rahman OA, O'Donnell S, Burgess T, Shaw M, Gecz J, Bain N, Fagan K, Hunter MF

Abstract
Mutations in FOXP1, located at 3p13, have been reported in patients with global developmental delay (GDD), intellectual disability (ID), and speech defects. Mutations in FOXP2, located at 7q31, are well known to cause developmental speech and language disorders, particularly developmental verbal dyspraxia (DVD). FOXP2 has been shown to work co-operatively with FOXP1 in mouse development. An overlap in FOXP1 and FOXP2 expression, both in the songbird and human fetal brain, has suggested that FOXP1 may also have a role in speech and language disorders. We report on a male child with a 0.19 MB intragenic deletion that is predicted to result in haploinsufficiency of FOXP1. Review of our patient and others reported in the literature reveals an emerging phenotype of GDD/ID with moderate to severe speech delay where expressive speech is most severely affected. DVD appears not to be a distinct feature in this group. Facial features include a broad forehead, downslanting palpebral fissures, a short nose with broad tip, relative or true macrocephaly, a frontal hair upsweep and prominent digit pads. Autistic traits and other behavioral problems are likely to be associated with haploinsufficiency of FOXP1. Congenital malformations may be associated.

PMID: 24214399 [PubMed - indexed for MEDLINE]

3q29 microdeletion syndrome: Cognitive and behavioral phenotype in four patients.

July 6, 2014 - 7:37am
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3q29 microdeletion syndrome: Cognitive and behavioral phenotype in four patients.

Am J Med Genet A. 2013 Dec;161A(12):3018-22

Authors: Città S, Buono S, Greco D, Barone C, Alfei E, Bulgheroni S, Usilla A, Pantaleoni C, Romano C

Abstract
The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations. A thorough neuropsychiatric evaluation has never been reported in patients with such syndrome. We analyzed the clinical phenotype of four individuals with 3q29 microdeletion syndrome, with special emphasis on the cognitive and behavioral assessment, in order to delineate the neuropsychiatric phenotype related to this condition. We assessed these patients with standardized scales or checklists measuring the cognitive (WISC III or LIPS-R), behavioral (CBCL) and adaptive (VABS) performances. An accurate evaluation in our sample highlights different degrees of ID, variable behavioral disorders, and a preservation of communicative skills among remaining adaptive areas, as the neuropsychiatric hallmark of 3q29 microdeletion syndrome.

PMID: 24214349 [PubMed - indexed for MEDLINE]

Mutations of the synapse genes and intellectual disability syndromes.

July 6, 2014 - 7:37am
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Mutations of the synapse genes and intellectual disability syndromes.

Eur J Pharmacol. 2013 Nov 5;719(1-3):112-6

Authors: Verpelli C, Montani C, Vicidomini C, Heise C, Sala C

Abstract
Intellectual disability syndromes have been found associated to numerous mutated genes that code for proteins functionally involved in synapse formation, the regulation of dendritic spine morphology, the regulation of the synaptic cytoskeleton or the synthesis and degradation of specific synapse proteins. These studies have strongly demonstrated that even mild alterations in synapse morphology and function give rise to mild or severe alteration in intellectual abilities. Interestingly, pharmacological agents that are able to counteract these morphological and functional synaptic anomalies can also improve the symptoms of some of these conditions. This review is summarizing recent discoveries on the functions of some of the genes responsible for intellectual disability syndromes connected with synapse dysfunctions.

PMID: 23872408 [PubMed - indexed for MEDLINE]

Contactins in the neurobiology of autism.

July 6, 2014 - 7:37am
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Contactins in the neurobiology of autism.

Eur J Pharmacol. 2013 Nov 5;719(1-3):63-74

Authors: Zuko A, Kleijer KT, Oguro-Ando A, Kas MJ, van Daalen E, van der Zwaag B, Burbach JP

Abstract
Autism is a disease of brain plasticity. Inspiring work of Willem Hendrik Gispen on neuronal plasticity has stimulated us to investigate gene defects in autism and the consequences for brain development. The central process in the pathogenesis of autism is local dendritic mRNA translation which is dependent on axodendritic communication. Hence, most autism-related gene products (i) are part of the protein synthesis machinery itself, (ii) are components of the mTOR signal transduction pathway, or (iii) shape synaptic activity and plasticity. Accordingly, prototype drugs have been recognized that interfere with these pathways. The contactin (CNTN) family of Ig cell adhesion molecules (IgCAMs) harbours at least three members that have genetically been implicated in autism: CNTN4, CNTN5, and CNTN6. In this chapter we review the genetic and neurobiological data underpinning their role in normal and abnormal development of brain systems, and the consequences for behavior. Although data on each of these CNTNs are far from complete, we tentatively conclude that these three contactins play roles in brain development in a critical phase of establishing brain systems and their plasticity. They modulate neuronal activities, such as neurite outgrowth, synaptogenesis, survival, guidance of projections and terminal branching of axons in forming neural circuits. Current research on these CNTNs concentrate on the neurobiological mechanism of their developmental functions. A future task will be to establish if proposed pharmacological strategies to counteract ASD-related symptomes can also be applied to reversal of phenotypes caused by genetic defects in these CNTN genes.

PMID: 23872404 [PubMed - indexed for MEDLINE]

Evidence for gender-specific endophenotypes in high-functioning autism spectrum disorder during empathy.

July 6, 2014 - 7:37am
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Evidence for gender-specific endophenotypes in high-functioning autism spectrum disorder during empathy.

Autism Res. 2013 Dec;6(6):506-21

Authors: Schneider K, Regenbogen C, Pauly KD, Gossen A, Schneider DA, Mevissen L, Michel TM, Gur RC, Habel U, Schneider F

Abstract
Despite remarkable behavioral gender differences in patients with autism spectrum disorder (ASD), and growing evidence for a diminished male : female ratio for the putative "male disorder" ASD, aspects of gender are not addressed accordingly in ASD research. Our study aims at filling this gap by exploring empathy abilities in a group of 28 patients with high-functioning ASD and 28 gender-, age- and education-matched non-autistic subjects, for the first time by means of functional neuroimaging (fMRI). In an event-related fMRI paradigm, emotional ("E") and neutral ("N") video clips presented actors telling self-related short stories. After each clip, participants were asked to indicate their own emotion and its intensity as well as the emotion and intensity perceived for the actor. Behaviorally, we found significantly less empathic responses in the overall ASD group compared with non-autistic subjects, and inadequate emotion recognition for the neutral clips in the female ASD group compared with healthy women. Neurally, increased activation of the bilateral medial frontal gyrus was found in male patients compared with female patients, a pattern which was not present in the non-autistic group. Additionally, autistic women exhibited decreased activation of midbrain and limbic regions compared with non-autistic women, whereas there was no significant difference within the male group. While we did not find a fundamental empathic deficit in autistic patients, our data propose different ways of processing empathy in autistic men and women, suggesting stronger impairments in cognitive aspects of empathy/theory of mind for men, and alterations of social reciprocity for women.

PMID: 23868876 [PubMed - indexed for MEDLINE]

Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features.

July 6, 2014 - 7:37am
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Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features.

Eur J Paediatr Neurol. 2013 Nov;17(6):589-99

Authors: Battaglia A, Doccini V, Bernardini L, Novelli A, Loddo S, Capalbo A, Filippi T, Carey JC

Abstract
BACKGROUND AND OBJECTIVES: Submicroscopic chromosomal rearrangements are the most common identifiable causes of intellectual disability and autism spectrum disorders associated with dysmorphic features. Chromosomal microarray (CMA) can detect copy number variants <1 Mb and identifies size and presence of known genes. The aim of this study was to demonstrate the usefulness of CMA, as a first-tier tool in detecting the etiology of unexplained intellectual disability/autism spectrum disorders (ID/ASDs) associated with dysmorphic features in a large cohort of pediatric patients.
PATIENTS AND METHODS: We studied 349 individuals; 223 males, 126 females, aged 5 months-19 years. Blood samples were analyzed with CMA at a resolution ranging from 1 Mb to 40 Kb. The imbalance was confirmed by FISH or qPCR. We considered copy number variants (CNVs) causative if the variant was responsible for a known syndrome, encompassed gene/s of known function, occurred de novo or, if inherited, the parent was variably affected, and/or the involved gene/s had been reported in association with ID/ASDs in dedicated databases.
RESULTS: 91 CNVs were detected in 77 (22.06%) patients: 5 (6.49%) of those presenting with borderline cognitive impairment, 54 (70.13%) with a variable degree of DD/ID, and 18/77 (23.38%) with ID of variable degree and ASDs. 16/77 (20.8%) patients had two different rearrangements. Deletions exceeded duplications (58 versus 33); 45.05% (41/91) of the detected CNVs were de novo, 45.05% (41/91) inherited, and 9.9% (9/91) unknown. The CNVs caused the phenotype in 57/77 (74%) patients; 12/57 (21.05%) had ASDs/ID, and 45/57 (78.95%) had DD/ID.
CONCLUSIONS: Our study provides further evidence of the high diagnostic yield of CMA for genetic testing in children with unexplained ID/ASDs who had dysmorphic features. We confirm the value of CMA as the first-tier tool in the assessment of those conditions in the pediatric setting.

PMID: 23711909 [PubMed - indexed for MEDLINE]

Transgenerational effects of prenatal bisphenol A on social recognition.

July 2, 2014 - 7:57am
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Transgenerational effects of prenatal bisphenol A on social recognition.

Horm Behav. 2013 Nov;64(5):833-9

Authors: Wolstenholme JT, Goldsby JA, Rissman EF

Abstract
Bisphenol A (BPA) is a man-made endocrine disrupting compound used to manufacture polycarbonate plastics. It is found in plastic bottles, canned food linings, thermal receipts and other commonly used items. Over 93% of people have detectable BPA levels in their urine. Epidemiological studies report correlations between BPA levels during pregnancy and activity, anxiety, and depression in children. We fed female mice control or BPA-containing diets that produced plasma BPA concentrations similar to concentrations in humans. Females were mated and at birth, pups were fostered to control dams to limit BPA exposure to gestation in the first generation. Sibling pairs were bred to the third generation with no further BPA exposure. First (F1) and third (F3) generation juveniles were tested for social recognition and in the open field. Adult F3 mice were tested for olfactory discrimination. In both generations, BPA exposed juvenile mice displayed higher levels of investigation than controls in a social recognition task. In F3 BPA exposed mice, dishabituation to a novel female was impaired. In the open field, no differences were noted in F1 mice, while in F3, BPA lineage mice were more active than controls. No impairments were detected in F3 mice, all were able to discriminate different male urine pools and urine from water. No sex differences were found in any task. These results demonstrate that BPA exposure during gestation has long lasting, transgenerational effects on social recognition and activity in mice. These findings show that BPA exposure has transgenerational actions on behavior and have implications for human neurodevelopmental behavioral disorders.

PMID: 24100195 [PubMed - indexed for MEDLINE]

Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder.

July 1, 2014 - 7:17am

Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder.

PLoS One. 2014;9(6):e101130

Authors: O'Dwyer L, Tanner C, van Dongen EV, Greven CU, Bralten J, Zwiers MP, Franke B, Oosterlaan J, Heslenfeld D, Hoekstra P, Hartman CA, Rommelse N, Buitelaar JK

Abstract
Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children's Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners' ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.

PMID: 24979066 [PubMed - as supplied by publisher]

Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.

July 1, 2014 - 7:17am
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Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities.

Epilepsia. 2014 Apr;55(4):e25-9

Authors: Baasch AL, Hüning I, Gilissen C, Klepper J, Veltman JA, Gillessen-Kaesbach G, Hoischen A, Lohmann K

Abstract
Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-year-old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the αII -subunit of the voltage-gated sodium channel Nav 1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A-linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

PMID: 24579881 [PubMed - indexed for MEDLINE]

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