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Alpha-lipoic acid effects on brain glial functions accompanying double-stranded RNA antiviral and inflammatory signaling.

October 7, 2014 - 7:21am
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Alpha-lipoic acid effects on brain glial functions accompanying double-stranded RNA antiviral and inflammatory signaling.

Neurochem Int. 2014 Jan;64:55-63

Authors: Scumpia PO, Kelly-Scumpia K, Stevens BR

Abstract
Double-stranded RNAs (dsRNA) serve as viral ligands that trigger innate immunity in astrocytes and microglial, as mediated through Toll-like receptor 3 (TLR3) and dsRNA-dependent protein kinase (PKR). Beneficial transient TLR3 and PKR anti-viral signaling can become deleterious when events devolve into inflammation and cytotoxicity. Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson's, and autism spectrum. Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant. The objective of this study was to test our hypothesis that LA can control untoward antiviral mechanisms associated with neural dysfunction. Utilizing rat brain glial cultures (91% astrocytes:9% microglia) treated with PKR- and TLR3-ligand/viral mimetic dsRNA, polyinosinic-polycytidylic acid (polyI:C), we report in vitro glial antiviral signaling and LA reduction of the effects of this signaling. LA blunted the dsRNA-stimulated expression of IFNα/β-inducible genes Mx1, PKR, and TLR3. And in polyI:C treated cells, LA promoted gene expression of rate-limiting steps that benefit healthy neural redox status in glutamateric systems. To this end, LA decreased dsRNA-induced inflammatory signaling by downregulating IL-1β, IL-6, TNFα, iNOS, and CAT2 transcripts. In the presence of polyI:C, LA prevented cultured glial cytotoxicity which was correlated with increased expression of factors known to cooperatively control glutamate/cystine/glutathione redox cycling, namely glutamate uptake transporter GLAST/EAAT1, γ-glutamyl cysteine ligase catalytic and regulatory subunits, and IL-10. Glutamate exporting transporter subunits 4F2hc and xCT were downregulated by LA in dsRNA-stimulated glia. l-Glutamate net uptake was inhibited by dsRNA, and this was relieved by LA. Glutathione synthetase mRNA levels were unchanged by dsRNA or LA. This study demonstrates the protective effects of LA in astroglial/microglial cultures, and suggests the potential for LA efficacy in virus-induced CNS pathologies, with the caveat that antiviral benefits are concomitantly blunted. It is concluded that LA averts key aspects of TLR3- and PKR-provoked glial dysfunction, and provides rationale for exploring LA in whole animal and human clinical studies to blunt or avert neuropsychiatric disorders.

PMID: 24269587 [PubMed - indexed for MEDLINE]

PTEN knockdown alters dendritic spine/protrusion morphology, not density.

October 7, 2014 - 7:21am
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PTEN knockdown alters dendritic spine/protrusion morphology, not density.

J Comp Neurol. 2014 Apr 1;522(5):1171-90

Authors: Haws ME, Jaramillo TC, Espinosa F, Widman AJ, Stuber GD, Sparta DR, Tye KM, Russo SJ, Parada LF, Stavarache M, Kaplitt M, Bonci A, Powell CM

Abstract
Mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology by using fluorescent dye confocal imaging. Contrary to previous studies in the dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory postsynaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in the dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors.

PMID: 24264880 [PubMed - indexed for MEDLINE]

The role of β3 integrin gene variants in Autism Spectrum Disorders - Diagnosis and symptomatology.

October 5, 2014 - 6:13am

The role of β3 integrin gene variants in Autism Spectrum Disorders - Diagnosis and symptomatology.

Gene. 2014 Sep 30;

Authors: Schuch JB, Muller D, Endres RG, Bosa CA, Longo D, Schuler-Faccini L, Ranzan J, Becker MM, Dos Santos Riesgo R, Roman T

Abstract
Autism Spectrum Disorders (ASDs) represent a group of very complex early-onset neurodevelopmental diseases. In this study, we analyzed 5 SNPs (rs2317385, rs5918, rs15908, rs12603582, rs3809865) at the β3 integrin locus (ITGB3), which has been suggested as a possible susceptibility gene, both as single markers and as part of haplotypes in 209 ASD children and their biological parents. We tested for association with the following: a) DSM-IV ASD diagnosis; b) clinical symptoms common in ASD patients (repetitive behaviors, echolalia, seizures and epilepsy, mood instability, aggression, psychomotor agitation, sleep disorders); and c) dimensional scores obtained with the Autism Screening Questionnaire and the Childhood Autism Rating Scale. These hypotheses were investigated using family-based tests, logistic regression models and analysis of covariance. The family-based tests showed an association with the H5 haplotype (composed by GTCGA alleles, the order of SNPs as above), which was transmitted less often than expected by chance (P=0.006; Pcorr=0.036). The analyses of the clinical symptoms showed a trend for an association with rs12603582 (P=0.008; Pcorr=0.064) and positive results for the haplotype composed of rs15908 and rs12603582 (Pglcorr=0.048; Pindcorr=0.015), both in symptoms of echolalia. Other nominal associations with different variants were found and involved epilepsy/seizures, aggression symptoms and higher ASQ scores. Although our positive results are not definitive, they suggest small effect associations of the ITGB3 gene with both ASD diagnosis and symptoms of echolalia. Other studies are nonetheless needed to fully understand the involvement of this locus on the etiology of ASDs and its different clinical aspects.

PMID: 25280596 [PubMed - as supplied by publisher]

Neurocognitive abilities in the general population and composite genetic risk scores for attention-deficit hyperactivity disorder.

October 4, 2014 - 6:00am

Neurocognitive abilities in the general population and composite genetic risk scores for attention-deficit hyperactivity disorder.

J Child Psychol Psychiatry. 2014 Oct 3;

Authors: Martin J, Hamshere ML, Stergiakouli E, O'Donovan MC, Thapar A

Abstract
BACKGROUND: The genetic architecture of ADHD is complex, with rare and common variants involved. Common genetic variants (as indexed by a composite risk score) associated with clinical ADHD significantly predict ADHD and autistic-like behavioural traits in children from the general population, suggesting that ADHD lies at the extreme of normal trait variation. ADHD and other neurodevelopmental disorders share neurocognitive difficulties in several domains (e.g. impaired cognitive ability and executive functions). We hypothesised that ADHD composite genetic risk scores derived from clinical ADHD cases would also contribute to variation in neurocognitive abilities in the general population.
METHODS: Children (N = 6,832) from a UK population cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), underwent neurocognitive testing. Parent-reported measures of their children's ADHD and autistic-like traits were used to construct a behavioural latent variable of 'neurodevelopmental traits'. Composite genetic risk scores for ADHD were calculated for ALSPAC children based on findings from an independent ADHD case-control genome-wide association study. Structural equation modelling was used to assess associations between ADHD composite genetic risk scores and IQ, working memory, inhibitory control and facial emotion recognition, as well as the latent 'neurodevelopmental trait' measure.
RESULTS: The results confirmed that neurocognitive and neurodevelopmental traits are correlated in children in the general population. Composite genetic risk scores for ADHD were independently associated with lower IQ (β = -.05, p < .001) and working memory performance (β = -.034, p = .013), even after accounting for the relationship with latent neurodevelopmental behavioural trait scores. No associations were found between composite genetic risk scores and inhibitory control or emotion recognition (p > .05).
CONCLUSIONS: These findings suggest that common genetic variants relevant to clinically diagnosed ADHD have pleiotropic effects on neurocognitive traits as well as behavioural dimensions in the general population. This further suggests that the well-recognised association between cognition and neurodevelopmental behavioural traits is underpinned at a biological level.

PMID: 25280069 [PubMed - as supplied by publisher]

Autism spectrum disorders and coexisting disorders in a nationwide Swedish twin study.

October 4, 2014 - 6:00am

Autism spectrum disorders and coexisting disorders in a nationwide Swedish twin study.

J Child Psychol Psychiatry. 2014 Oct 3;

Authors: Lundström S, Reichenberg A, Melke J, Råstam M, Kerekes N, Lichtenstein P, Gillberg C, Anckarsäter H

Abstract
BACKGROUND: Evidence from twin and molecular genetic studies is accumulating that Autism Spectrum Disorder (ASD) shares substantial etiological factors with other disorders. This is mirrored in clinical practice where ASD without coexisting disorders is rare. The present study aims to examine the range of coexisting disorders in ASD in a genetically informative cohort.
METHODS: Parents of all Swedish 9-year-old twins born between 1992 and 2001 (n = 19,130) underwent a telephone interview designed to screen for child psychiatric disorders, including ASD. To ensure full coverage of child psychiatric disorders, data were also retrieved from population-based health registers. We investigated the coexistence of eight psychiatric disorders known to coexist with ASDs in probands and their co-twins.
RESULTS: Half of the individuals with ASDs (50.3%) had four or more coexisting disorders and only 4% did not have any concomitant disorder. The 'healthy co-twin' in ASD discordant monozygotic twin pairs was very often (79% of boys and 50% of girls) affected by at least one non-ASD disorder. The corresponding figures for ASD discordant dizygotic twin pairs were significantly lower (46% of males and 30% of females).
CONCLUSIONS: Detailed phenotypic descriptions including symptoms of problems associated with a wide range of child psychiatric disorders may aid in unraveling the genetic architecture of ASD and should guide the development of intervention strategies addressing each problem type specifically.

PMID: 25279993 [PubMed - as supplied by publisher]

Evidence for ASD Recurrence Rates and Reproductive Stoppage From Large UK ASD Research Family Databases.

October 3, 2014 - 8:52am

Evidence for ASD Recurrence Rates and Reproductive Stoppage From Large UK ASD Research Family Databases.

Autism Res. 2014 Oct 1;

Authors: Wood CL, Warnell F, Johnson M, Hames A, Pearce MS, McConachie H, Parr JR

Abstract
Following a diagnosis of a developmental disorder such as autism spectrum disorder (ASD) in early childhood, parents may decide to have fewer children than previously planned. The tendency for families to halt reproduction after receiving a diagnosis for one child is known as reproductive stoppage. Stoppage may lead to an underestimate of recurrence risk estimates of parents having more than one child with ASD. Using two large UK ASD family databases, we investigated recurrence rates for ASD and evidence for reproductive stoppage for both ASD and undiagnosed ASD/broader autism phenotype in a subgroup of families. Reproductive stoppage was tested for using the Mann-Whitney U-test to disprove the null hypothesis that affected and nonaffected children were distributed randomly by birth order. Dahlberg's later-sib method was used to estimate recurrence risk and take stoppage into account. Data were available from 299 families (660 children) including 327 with ASD. Ten percent of the complete families had more than one child with an ASD. Using Dahlberg's later-sib method, the recurrence risk for ASD was 24.7% overall and 50.0% in families with two or more older siblings with ASD. Children with ASD were born significantly later in families than those without ASD in all sibship combinations. This study shows strong evidence that ASD is associated with reproductive stoppage. These data have important implications for family planning and genetic counseling. Autism Res 2014, ●●: ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 25273900 [PubMed - as supplied by publisher]

MIRA: mutual information-based reporter algorithm for metabolic networks.

October 3, 2014 - 8:52am
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MIRA: mutual information-based reporter algorithm for metabolic networks.

Bioinformatics. 2014 Jun 15;30(12):i175-84

Authors: Cicek AE, Roeder K, Ozsoyoglu G

Abstract
MOTIVATION: Discovering the transcriptional regulatory architecture of the metabolism has been an important topic to understand the implications of transcriptional fluctuations on metabolism. The reporter algorithm (RA) was proposed to determine the hot spots in metabolic networks, around which transcriptional regulation is focused owing to a disease or a genetic perturbation. Using a z-score-based scoring scheme, RA calculates the average statistical change in the expression levels of genes that are neighbors to a target metabolite in the metabolic network. The RA approach has been used in numerous studies to analyze cellular responses to the downstream genetic changes. In this article, we propose a mutual information-based multivariate reporter algorithm (MIRA) with the goal of eliminating the following problems in detecting reporter metabolites: (i) conventional statistical methods suffer from small sample sizes, (ii) as z-score ranges from minus to plus infinity, calculating average scores can lead to canceling out opposite effects and (iii) analyzing genes one by one, then aggregating results can lead to information loss. MIRA is a multivariate and combinatorial algorithm that calculates the aggregate transcriptional response around a metabolite using mutual information. We show that MIRA's results are biologically sound, empirically significant and more reliable than RA.
RESULTS: We apply MIRA to gene expression analysis of six knockout strains of Escherichia coli and show that MIRA captures the underlying metabolic dynamics of the switch from aerobic to anaerobic respiration. We also apply MIRA to an Autism Spectrum Disorder gene expression dataset. Results indicate that MIRA reports metabolites that highly overlap with recently found metabolic biomarkers in the autism literature. Overall, MIRA is a promising algorithm for detecting metabolic drug targets and understanding the relation between gene expression and metabolic activity.
AVAILABILITY AND IMPLEMENTATION: The code is implemented in C# language using .NET framework. Project is available upon request.

PMID: 24931981 [PubMed - indexed for MEDLINE]

Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

October 3, 2014 - 8:52am
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Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

Brain Behav Immun. 2014 Feb;36:54-60

Authors: Guerini FR, Bolognesi E, Chiappedi M, Manca S, Ghezzo A, Agliardi C, Zanette M, Littera R, Carcassi C, Sotgiu S, Clerici M

Abstract
The activity of natural killer (NK) cells is modulated by the interaction between killer-cell immune globulin-like receptor (KIR) proteins and their cognate HLA ligands; activated NK cells produce inflammatory cytokines and mediate innate immune responses. Activating KIR/HLA complexes (aKIR/HLA) were recently suggested to prevail in children with autism spectrum disorders (ASD), a neurodevelopmental syndrome characterized by brain and behavioral abnormalities and associated with a degree of inflammation. We verified whether such findings could be confirmed by analyzing two sample cohorts of Sardinian and continental Italian ASD children and their mothers. Results showed that aKIR/HLA are increased whereas inhibitory KIR/HLA complexes are reduced in ASD children; notably this skewing was even more significant in their mothers. KIR and HLA molecules are expressed by placental cells and by the trophoblast and their interactions result in immune activation and influence fetal, as well as central nervous system development and plasticity. Data herein suggest that in utero KIR/HLA immune interactions favor immune activation in ASD; this may play a role in the pathogenesis of the disease.

PMID: 24120931 [PubMed - indexed for MEDLINE]

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

October 2, 2014 - 8:42am

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

Eur J Hum Genet. 2014 Oct 1;

Authors: Mullegama SV, Pugliesi L, Burns B, Shah Z, Tahir R, Gu Y, Nelson DL, Elsea SH

Abstract
Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders.European Journal of Human Genetics advance online publication, 1 October 2014; doi:10.1038/ejhg.2014.200.

PMID: 25271084 [PubMed - as supplied by publisher]

Mass spectrometry for the study of autism and neurodevelopmental disorders.

October 2, 2014 - 8:42am
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Mass spectrometry for the study of autism and neurodevelopmental disorders.

Adv Exp Med Biol. 2014;806:525-44

Authors: Wetie AG, Dekroon RM, Mocanu M, Ryan JP, Darie CC, Woods AG

Abstract
Mass spectrometry (MS) has been increasingly used to study central nervous system disorders, including autism spectrum disorders (ASDs). The first studies of ASD using MS focused on the identification of external toxins, but current research is more directed at understanding endogenous protein changes that occur in ASD (ASD proteomics). This chapter focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using this technique, including genetic syndromes associated with autism such as fragile X syndrome and Smith-Lemli-Opitz syndrome.

PMID: 24952201 [PubMed - indexed for MEDLINE]

Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning, but normal working and spatial reference memory.

October 2, 2014 - 8:42am
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Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning, but normal working and spatial reference memory.

PLoS One. 2013;8(11):e81270

Authors: Typlt M, Mirkowski M, Azzopardi E, Ruettiger L, Ruth P, Schmid S

Abstract
Genetic variations in the large-conductance, voltage- and calcium activated potassium channels (BK channels) have been recently implicated in mental retardation, autism and schizophrenia which all come along with severe cognitive impairments. In the present study we investigate the effects of functional BK channel deletion on cognition using a genetic mouse model with a knock-out of the gene for the pore forming α-subunit of the channel. We tested the F1 generation of a hybrid SV129/C57BL6 mouse line in which the slo1 gene was deleted in both parent strains. We first evaluated hearing and motor function to establish the suitability of this model for cognitive testing. Auditory brain stem responses to click stimuli showed no threshold differences between knockout mice and their wild-type littermates. Despite of muscular tremor, reduced grip force, and impaired gait, knockout mice exhibited normal locomotion. These findings allowed for testing of sensorimotor gating using the acoustic startle reflex, as well as of working memory, spatial learning and memory in the Y-maze and the Morris water maze, respectively. Prepulse inhibition on the first day of testing was normal, but the knockout mice did not improve over the days of testing as their wild-type littermates did. Spontaneous alternation in the y-maze was normal as well, suggesting that the BK channel knock-out does not impair working memory. In the Morris water maze knock-out mice showed significantly slower acquisition of the task, but normal memory once the task was learned. Thus, we propose a crucial role of the BK channels in learning, but not in memory storage or recollection.

PMID: 24303038 [PubMed - indexed for MEDLINE]

Neural mechanisms underlying stress resilience in Ahi1 knockout mice: relevance to neuropsychiatric disorders.

October 2, 2014 - 8:42am
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Neural mechanisms underlying stress resilience in Ahi1 knockout mice: relevance to neuropsychiatric disorders.

Mol Psychiatry. 2014 Feb;19(2):243-52

Authors: Lotan A, Lifschytz T, Slonimsky A, Broner EC, Greenbaum L, Abedat S, Fellig Y, Cohen H, Lory O, Goelman G, Lerer B

Abstract
The Abelson helper integration site 1 (AHI1) gene has a pivotal role in brain development. Studies by our group and others have demonstrated association of AHI1 with schizophrenia and autism. To elucidate the mechanism whereby alteration in AHI1 expression may be implicated in the pathogenesis of neuropsychiatric disorders, we studied Ahi1 heterozygous knockout (Ahi1(+/-)) mice. Although their performance was not different from wild-type mice on tests that model classical schizophrenia-related endophenotypes, Ahi1(+/-) mice displayed an anxiolytic-like phenotype across different converging modalities. Using behavioral paradigms that involve exposure to environmental and social stress, significantly decreased anxiety was evident in the open field, elevated plus maze and dark-light box, as well as during social interaction in pairs. Assessment of core temperature and corticosterone secretion revealed a significantly blunted response of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis in Ahi1(+/-) mice exposed to environmental and visceral stress. However, response to centrally acting anxiogenic compounds was intact. On resting-state functional MRI, connectivity of the amygdala with other brain regions involved in processing of anxiogenic stimuli and inhibitory avoidance learning, such as the lateral entorhinal cortex, ventral hippocampus and ventral tegmental area, was significantly reduced in the mutant mice. Taken together, our data link Ahi1 under-expression with a defect in the process of threat detection. Alternatively, the results could be interpreted as representing an anxiety-related endophenotype, possibly granting the Ahi1(+/-) mouse relative resilience to various types of stress. The current knockout model highlights the contribution of translational approaches to understanding the genetic basis of emotional regulation and its associated neurocircuitry, with possible relevance to neuropsychiatric disorders.

PMID: 24042478 [PubMed - indexed for MEDLINE]

Autism Spectrum Disorders: Perceptions of Genetic Etiology and Recurrence Risk among Taiwanese Parents of Affected Children.

October 1, 2014 - 8:14am
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Autism Spectrum Disorders: Perceptions of Genetic Etiology and Recurrence Risk among Taiwanese Parents of Affected Children.

Clin Genet. 2014 Sep 30;

Authors: Chen LS, Li C, Wang CH, Amuta A, Li M, Huang TY, Dhar SU, Talwar D, Jang E

Abstract
In Taiwan, Autism Spectrum Disorders (ASD) are an emerging public health concern. The ongoing scientific progress for understanding the genetic etiology of ASD makes it increasingly important to examine how parents of children with ASD perceive the causes and recurrence risk of having another child with ASD. These perceptions may influence their family planning, attitudes toward genetic services, and willingness to take their children for ASD genetic testing. However, previous studies addressing this issue were conducted primarily in western countries. As culture might shape an individual's views of genetic/genomic disorders, this first-of-its-kind study examined the perceptions of the genetic etiology for ASD and the recurrence risk among Taiwanese parents of children affected with ASD. In-depth, semi-structured interviews were conducted among 39 parents having at least one child with ASD. Although the majority of participants believed that ASD has a genetic link, less than half perceived genetic factors as the cause of their own child's ASD. Moreover, all participants articulated their recurrence risk incorrectly. Some parents were concerned about their doctors' limited genomic competencies. In order to provide parents with better education, counseling, and support for making reproductive decisions, ASD-related genomic education among Taiwanese physicians is needed.

PMID: 25267333 [PubMed - as supplied by publisher]

Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

October 1, 2014 - 8:14am
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Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

Mol Psychiatry. 2014 Sep 30;

Authors: Bacon C, Schneider M, Le Magueresse C, Froehlich H, Sticht C, Gluch C, Monyer H, Rappold GA

Abstract
Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.Molecular Psychiatry advance online publication, 30 September 2014; doi:10.1038/mp.2014.116.

PMID: 25266127 [PubMed - as supplied by publisher]

Mode of genetic inheritance modifies the association of head circumference and autism-related symptoms: a cross-sectional study.

October 1, 2014 - 8:14am
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Mode of genetic inheritance modifies the association of head circumference and autism-related symptoms: a cross-sectional study.

PLoS One. 2013;8(9):e74940

Authors: Davis JM, Keeney JG, Sikela JM, Hepburn S

Abstract
BACKGROUND: Frequently individuals with autism spectrum disorder (ASD) have been noted with a larger head circumference (HC) than their typical developing peers. Biologic hypotheses suggest that an overly rapid brain growth leads to the core symptoms of ASD by impairing connectivity. Literature is divided however where deleterious, protective and null associations of HC with ASD symptoms in individuals with ASD have been found.
METHOD: Individuals (n = 1,416) from the Autism Genetic Resource Exchange with ASD were examined for associations of HC with ASD like symptoms. Mixed models controlling for sex, age, race/ethnicity, simplex/multiplex status and accounting for correlations between siblings were used. Interactions by simplex/multiplex were explored. Adjustments for height in a sub-population with available data were explored as well.
RESULTS: A Significant interaction term (p = 0.03) suggested that the effect of HC was dependent on whether the individual was simplex or multiplex. In simplex individuals at mean age (8.9 years) 1 cm increase in head circumference was associated with a 24% increase in the odds of a high social diagnostic score from the Autism Diagnostic Interview-Revised (odds ratio  = 1.24, p = 0.01). There was no association in multiplex individuals. Additionally, individuals classified with a non-verbal IQ <70 were 90% simplex and had a significantly increased head circumference (0.7 cm p = 0.03) relative to a mid-range non-verbal IQ group. Interestingly, children classified with a >110 non-verbal IQ also had an increased HC (0.4 cm p = 0.04), relative to a mid-range non-verbal IQ group, and were 90% multiplex. HC effects do not appear to be confounded by height, however, larger samples with height information are needed.
CONCLUSION: The potential link between brain growth and autism like symptoms is complex and could depend on specific etiologies. Further investigations accounting for a likely mode of inheritance will help identify an ASD subtype related to HC.

PMID: 24058641 [PubMed - indexed for MEDLINE]

Zylka et al. reply.

September 30, 2014 - 7:56am
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Zylka et al. reply.

Nature. 2014 Aug 7;512(7512):E2

Authors: Zylka MJ, Philpot BD, King IF

PMID: 25100485 [PubMed - indexed for MEDLINE]

Epilepsy and outcome in FOXG1-related disorders.

September 30, 2014 - 7:56am
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Epilepsy and outcome in FOXG1-related disorders.

Epilepsia. 2014 Aug;55(8):1292-300

Authors: Seltzer LE, Ma M, Ahmed S, Bertrand M, Dobyns WB, Wheless J, Paciorkowski AR

Abstract
OBJECTIVE: FOXG1-related disorders are associated with severe intellectual disability, absent speech with autistic features, and epilepsy. Children with deletions or intragenic mutations of FOXG1 also have postnatal microcephaly, morphologic abnormalities of the corpus callosum, and choreiform movements. Duplications of 14q12 often present with infantile spasms, and have subsequent intellectual disability with autistic features. Long-term epilepsy outcome and response to treatment have not been studied systematically in a well-described cohort of subjects with FOXG1-related disorders. We report on the epilepsy features and developmental outcome of 23 new subjects with deletions or intragenic mutations of FOXG1, and 7 subjects with duplications.
METHODS: Subjects had either chromosomal microarray or FOXG1 gene sequencing performed as part of routine clinical care. Development and epilepsy follow-up data were collected from medical records from treating neurologists and through telephone parental interviews using standardized questionnaires.
RESULTS: Epilepsy was diagnosed in 87% of the subjects with FOXG1-related disorders. The mean age of epilepsy diagnosis in FOXG1 duplications was significantly younger than those with deletions/intragenic mutations (p = 0.0002). All of the duplication FOXG1 children with infantile spasms responded to hormonal therapy, and only one required long-term antiepileptic therapy. In contrast, more children with deletions/intragenic mutations required antiepileptic drugs on follow-up (p < 0.0005). All subjects with FOXG1-related disorders had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or intractability of seizures. All had impaired verbal language and social contact, and three duplication subjects were formally diagnosed with autism. Subjects with deletion/intragenic mutations, however, had significantly worse ambulation (p = 0.04) and functional hand use (p < 0.0005).
SIGNIFICANCE: Epilepsy and developmental outcome characteristics allow clinicians to distinguish among the FOXG1-related disorders. Further genotype-phenotype studies of FOXG1 may help to elucidate why children develop different forms of developmental epilepsy.

PMID: 24836831 [PubMed - indexed for MEDLINE]

Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK.

September 30, 2014 - 7:56am
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Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK.

PLoS One. 2014;9(2):e88276

Authors: LaConte LE, Chavan V, Mukherjee K

Abstract
The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future.

PMID: 24505460 [PubMed - indexed for MEDLINE]

Neural measures of social attention across the first years of life: characterizing typical development and markers of autism risk.

September 30, 2014 - 7:56am
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Neural measures of social attention across the first years of life: characterizing typical development and markers of autism risk.

Dev Cogn Neurosci. 2014 Apr;8:131-43

Authors: Luyster RJ, Powell C, Tager-Flusberg H, Nelson CA

Abstract
Few studies employing event-related potentials (ERPs) to examine infant perception/cognition have systematically characterized age-related changes over the first few years of life. Establishing a 'normative' template of development is important in its own right, and doing so may also better highlight points of divergence for high-risk populations of infants, such as those at elevated genetic risk for autism spectrum disorder (ASD). The present investigation explores the developmental progression of the P1, N290, P400 and Nc components for a large sample of young children between 6 and 36 months of age, addressing age-related changes in amplitude, sensitivity to familiar and unfamiliar stimuli and hemispheric lateralization. Two samples of infants are included: those at low- and high-risk for ASD. The four components of interest show differential patterns of change over time and hemispheric lateralization; however, infants at low- and high-risk for ASD do not show significant differences in patterns of neural response to faces. These results will provide a useful point of reference for future developmental cognitive neuroscience research targeting both typical development and vulnerable populations.

PMID: 24183618 [PubMed - indexed for MEDLINE]

MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons.

September 30, 2014 - 7:56am
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MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons.

PLoS One. 2013;8(6):e65069

Authors: Larimore J, Ryder PV, Kim KY, Ambrose LA, Chapleau C, Calfa G, Gross C, Bassell GJ, Pozzo-Miller L, Smith Y, Talbot K, Park IH, Faundez V

Abstract
Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.

PMID: 23750231 [PubMed - indexed for MEDLINE]

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