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Urine proteome analysis to evaluate protein biomarkers in children with autism.

April 26, 2016 - 7:09am
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Urine proteome analysis to evaluate protein biomarkers in children with autism.

Clin Chim Acta. 2015 Oct 23;450:210-9

Authors: Suganya V, Geetha A, Sujatha S

Abstract
BACKGROUND: Autism is a complex developmental disability for which no specific diagnostic markers have been identified so far. The present study aimed to evaluate whether there is any abnormal protein(s) excreted in the urine of autistic children by proteome analysis which may act as diagnostic marker.
METHODS: Urine proteome analysis was carried out in first void urine samples of autistic and normal children (n=30) in the age group of 4-12 years by 2D-PAGE followed by MALDI-TOF-MS analysis.
RESULTS: Comparison of 2D-PAGE gels revealed that many urinary proteins are expressed differentially in autistic children. Total numbers of spots observed were 250 and 159 in autism and normal samples respectively, out of which 95 matches were observed. In addition, 3 spots of abnormally expressed peptides were selected, excised and analyzed. Peptide sequence with significant match score was for kininogen-1 (KNG-1)-50 (spot-1), IgG1 heavy chain variable region-35(spot-2) and mannan-binding lectin serine protease-2 isoform-2 precursor-45(spot-3). All the autistic children showed significant increase (p<0.001) in urinary kininogen level measured quantitatively by ELISA, when compared to normal children.
CONCLUSION: Increased urinary kininogen-1 level in all the autistic children and the possibility of this protein as a diagnostic marker need further investigation.

PMID: 26296899 [PubMed - indexed for MEDLINE]

MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.

April 26, 2016 - 7:09am
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MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.

PLoS One. 2015;10(6):e0130183

Authors: Conti V, Gandaglia A, Galli F, Tirone M, Bellini E, Campana L, Kilstrup-Nielsen C, Rovere-Querini P, Brunelli S, Landsberger N

Abstract
Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions.

PMID: 26098633 [PubMed - indexed for MEDLINE]

Apitoxin protects rat pups brain from propionic acid-induced oxidative stress: The expression pattern of Bcl-2 and Caspase-3 apoptotic genes.

April 26, 2016 - 7:09am
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Apitoxin protects rat pups brain from propionic acid-induced oxidative stress: The expression pattern of Bcl-2 and Caspase-3 apoptotic genes.

Neurotoxicology. 2015 Jul;49:121-31

Authors: Khalil SR, Abd-Elhakim YM, Selim ME, Al-Ayadhi LY

Abstract
The primary aim of this study was to determine the potential modulatory role of the apitoxin (bee venom; BV) against propionic acid (PPA)-induced neurotoxicity. The biochemical responses to PPA exposure in rat pups were assayed, including changes in the antioxidant barrier systems and lipid peroxidation and protein oxidation biomarkers in the brain tissue. DNA damage was measured by single-cell gel electrophoresis and differences in Bcl-2 and Caspase-3 mRNA expression were assessed using real-time PCR. Changes in amygdala complex ultrastructure were visually assessed using electron microscopy. Sixty rat pups were assigned into six groups: a control group, a PPA-treated group, a BV-treated group, a protective co-treated group, a therapeutic co-treated group, and a protective/therapeutic co-treated group. The results indicate that PPA induced a pronounced increase (64.6%) in malondialdehyde (MDA), and in DNA damage (73.3%) with three-fold increase in protein carbonyl concentration. A significant reduction was observed in the enzyme activities of superoxide dismutase (SOD) (48.7%) and catalase (CAT) (74.8%) and reduced glutathione (GSH) level (52.6%). BV significantly neutralized the PPA-induced oxidative stress effects, especially in the BV protective/therapeutic co-treated group. In this group, GSH levels were restored to 64.5%, and MDA, protein carbonyl levels and tail moment % were diminished by 69.5, 21.1 and 18.8% relative to the control, respectively. Furthermore, while PPA induced significant apoptotic neural cell death, BV markedly inhibited apoptosis by promoting Bcl-2 expression and blocking Caspase-3 expression. BV markedly restored the normal ultrastructural morphology of the amygdala complex neurons. These results conclusively demonstrate that BV administration provides both protective and therapeutic effects in response to the PPA-induced deleterious effects, including oxidative stress, DNA damage, and neuronal death in the brains of rat pups.

PMID: 26048086 [PubMed - indexed for MEDLINE]

Rare heterozygous truncating variations and risk of autism spectrum disorder: Whole-exome sequencing of a multiplex family and follow-up study in a Japanese population.

April 26, 2016 - 7:09am
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Rare heterozygous truncating variations and risk of autism spectrum disorder: Whole-exome sequencing of a multiplex family and follow-up study in a Japanese population.

Psychiatry Clin Neurosci. 2015 Aug;69(8):472-6

Authors: Inoue E, Watanabe Y, Egawa J, Sugimoto A, Nunokawa A, Shibuya M, Igeta H, Someya T

Abstract
AIMS: Rare heterozygous truncating variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare heterozygous truncating variations, we performed whole-exome sequencing (WES) in a multiplex ASD family with four affected individuals (two siblings and two maternal cousins), and a follow-up case-control study in a Japanese population.
METHODS: WES was performed in four individuals (a proband, his affected and unaffected siblings, and their putative carrier mother) from the multiplex ASD family. Rare heterozygous truncating variations prioritized in WES were genotyped in 243 patients and 667 controls.
RESULTS: By WES of the multiplex family, we prioritized two rare heterozygous truncating variations, RPS24 Q191X and CD300LF P261fsX266. However, we did not identify these variations in patients or controls in the follow-up study.
CONCLUSIONS: Our findings suggest that two rare heterozygous truncating variations (RPS24 Q191X and CD300LF P261fsX266) are risk candidates for ASD.

PMID: 25601189 [PubMed - indexed for MEDLINE]

Nutritional management of (some) autism: a case for gluten- and casein-free diets?

April 26, 2016 - 7:09am
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Nutritional management of (some) autism: a case for gluten- and casein-free diets?

Proc Nutr Soc. 2015 Aug;74(3):202-7

Authors: Whiteley P

Abstract
Autism spectrum disorders represent a diverse and heterogeneous array of conditions unified by the variable presence of specific behaviours impacting social and communicative functions (social affect) alongside other presentation. Common overt characteristics may come about as a consequence of several different genetic and biological processes differentially manifesting across different people or groups. The concept of plural 'autisms' is evolving, strengthened by an increasingly important evidence base detailing different developmental trajectories across the autism spectrum and the appearance of comorbidity variably interacting with core symptoms and onwards influencing quality of life. Reports that dietary intervention, specifically the removal of foods containing gluten and/or casein from the diet, may impact on the presentation of autism for some, complement this plural view of autism. Evidence suggestive of differing responses to the use of a gluten- and casein-free diet, defined as best- and non-response, has combined with some progress on determining the underlying genetic and biological correlates potentially related to such dietary elements. The preliminary suggestion of a possible diet-related autism phenotype is the result. This review will highlight several pertinent aspects onwards to an effect of food in some cases of autism including research on the pharmacological activity of food metabolites, immune response, issues with gut barrier function and some contribution from the gut microbiota. These represent promising areas in need of far greater research inspection in order to potentially define such a diet-related subgroup on the autism spectrum.

PMID: 25311313 [PubMed - indexed for MEDLINE]

Autism spectrum disorders: a qualitative study of attitudes toward prenatal genetic testing and termination decisions of affected pregnancies.

April 26, 2016 - 7:09am
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Autism spectrum disorders: a qualitative study of attitudes toward prenatal genetic testing and termination decisions of affected pregnancies.

Clin Genet. 2015 Aug;88(2):122-8

Authors: Chen LS, Xu L, Dhar SU, Li M, Talwar D, Jung E

Abstract
In the United States, prenatal genetic testing (PGT) for Autism Spectrum Disorders (ASD) is currently available via clinical genetic services. Such testing may inform parents about their unborn child's risk for ASD, prepare parents for the birth of an affected infant, and allow them to arrange for early interventions. Although PGT for autism has potential benefits, the associated ethical, legal, and social implications (ELSI) should be considered. This first qualitative study employed a hypothetical scenario to explore the attitudes toward PGT and termination decisions of 42 parents of children with ASD. Over half of the participants expressed willingness to undergo PGT for autism. Reasons included better preparation for birth, early and better treatment, termination of affected pregnancy, contribution to research, and curiosity. Of the 31 parents who were either willing or unsure about undergoing the PGT, approximately three-fourths would continue their hypothetical affected pregnancies. Explanations included preparation for birth of the child, bonding or acceptance of existing ASD-affected children, apprehensions about test limitations, and religious concerns. Parents who reported they would terminate the affected pregnancy in this hypothetical situation were primarily Asians. This study contributes to the growing understanding of the ELSI aspects of PGT in clinical practice.

PMID: 25251361 [PubMed - indexed for MEDLINE]

Quantifying the potential impact of measurement error in an investigation of autism spectrum disorder (ASD).

April 26, 2016 - 7:09am
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Quantifying the potential impact of measurement error in an investigation of autism spectrum disorder (ASD).

J Epidemiol Community Health. 2014 May;68(5):438-45

Authors: Heavner K, Newschaffer C, Hertz-Picciotto I, Bennett D, Burstyn I

Abstract
The Early Autism Risk Longitudinal Investigation (EARLI), an ongoing study of a risk-enriched pregnancy cohort, examines genetic and environmental risk factors for autism spectrum disorders (ASDs). We simulated the potential effects of both measurement error (ME) in exposures and misclassification of ASD-related phenotype (assessed as Autism Observation Scale for Infants (AOSI) scores) on measures of association generated under this study design. We investigated the impact on the power to detect true associations with exposure and the false positive rate (FPR) for a non-causal correlate of exposure (X2, r=0.7) for continuous AOSI score (linear model) versus dichotomised AOSI (logistic regression) when the sample size (n), degree of ME in exposure, and strength of the expected (true) OR (eOR)) between exposure and AOSI varied. Exposure was a continuous variable in all linear models and dichotomised at one SD above the mean in logistic models. Simulations reveal complex patterns and suggest that: (1) There was attenuation of associations that increased with eOR and ME; (2) The FPR was considerable under many scenarios; and (3) The FPR has a complex dependence on the eOR, ME and model choice, but was greater for logistic models. The findings will stimulate work examining cost-effective strategies to reduce the impact of ME in realistic sample sizes and affirm the importance for EARLI of investment in biological samples that help precisely quantify a wide range of environmental exposures.

PMID: 24470431 [PubMed - indexed for MEDLINE]

An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability.

April 24, 2016 - 8:42am

An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability.

Hum Genet. 2016 Apr 22;

Authors: Labonne JD, Lee KH, Iwase S, Kong IK, Diamond MP, Layman LC, Kim CH, Kim HG

Abstract
Microdeletion syndromes are frequent causes of neuropsychiatric disorders leading to intellectual disability as well as autistic features accompanied by epilepsy and craniofacial anomalies. From comparative deletion mapping of the smallest microdeletion to date at 12q24.31, found in a patient with overlapping clinical features of 12q24.31 microdeletion syndrome, we narrowed the putative critical region to 445 kb containing seven genes, one microRNA, and one non-coding RNA. Zebrafish in situ hybridization and comprehensive transcript analysis of annotated genes in the panels of human organ and brain suggest that these are all candidates for neurological phenotypes excluding the gene HPD. This is also corroborated by synteny analysis revealing the conservation of the order of these six candidate genes between humans and zebrafish. Among them, we propose histone demethylase KDM2B and histone methyltransferase SETD1B as the two most plausible candidate genes involved in intellectual disability, autism, epilepsy, and craniofacial anomalies. These two chromatin modifiers located approximately 224 kb apart were both commonly deleted in six patients, while two additional patients had either KDM2B or SETD1B deleted. The four additional candidate genes (ORAI1, MORN3, TMEM120B, RHOF), a microRNA MIR548AQ, and a non-coding RNA LINC01089 are localized between KDM2B and SETD1B. The 12q24.31 microdeletion syndrome with syndromic intellectual disability extends the growing list of microdeletion syndromes and underscores the causative roles of chromatin modifiers in cognitive and craniofacial development.

PMID: 27106595 [PubMed - as supplied by publisher]

Mouse models of autism: testing hypotheses about molecular mechanisms.

April 24, 2016 - 8:42am
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Mouse models of autism: testing hypotheses about molecular mechanisms.

Curr Top Behav Neurosci. 2011;7:187-212

Authors: Roullet FI, Crawley JN

Abstract
Autism is a neurodevelopmental disorder that is currently diagnosed by the presence of three behavioral criteria (1) qualitative impairments in reciprocal social interactions, (2) deficits in communication, including delayed language and noninteractive conversation, and (3) motor stereotypies, repetitive behaviors, insistence on sameness, and restricted interests. This chapter describes analogous behavioral assays that have been developed for mice, including tests for social approach, reciprocal social interactions, olfactory communication, ultrasonic vocalizations, repetitive and perseverative behaviors, and motor stereotypies. Examples of assay applications to genetic mouse models of autism are provided. Robust endophenotypes that are highly relevant to the core symptoms of autism are enabling the search for the genetic and environmental causes of autism, and the discovery of effective treatments.

PMID: 21225409 [PubMed - indexed for MEDLINE]

Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

April 23, 2016 - 7:35am

Similar white matter but opposite grey matter changes in schizophrenia and high-functioning autism.

Acta Psychiatr Scand. 2016 Apr 22;

Authors: Katz J, d'Albis MA, Boisgontier J, Poupon C, Mangin JF, Guevara P, Duclap D, Hamdani N, Petit J, Monnet D, Le Corvoisier P, Leboyer M, Delorme R, Houenou J

Abstract
OBJECTIVE: High-functioning autism (HFA) and schizophrenia (SZ) are two of the main neurodevelopmental disorders, sharing several clinical dimensions and risk factors. Their exact relationship is poorly understood, and few studies have directly compared both disorders. Our aim was thus to directly compare neuroanatomy of HFA and SZ using a multimodal MRI design.
METHODS: We scanned 79 male adult subjects with 3T MRI (23 with HFA, 24 with SZ and 32 healthy controls, with similar non-verbal IQ). We compared them using both diffusion-based whole-brain tractography and T1 voxel-based morphometry.
RESULTS: HFA and SZ groups exhibited similar white matter alterations in the left fronto-occipital inferior fasciculus with a decrease in generalized fractional anisotropy compared with controls. In grey matter, the HFA group demonstrated bilateral prefrontal and anterior cingulate increases in contrast with prefrontal and left temporal reductions in SZ.
CONCLUSION: HFA and SZ may share common white matter deficits in long-range connections involved in social functions, but opposite grey matter abnormalities in frontal regions that subserve complex cognitive functions. Our results are consistent with the fronto-occipital underconnectivity theory of HFA and the altered connectivity hypothesis of SZ and suggest the existence of both associated and diametrical liabilities to these two conditions.

PMID: 27105136 [PubMed - as supplied by publisher]

Social anxiety and autism spectrum traits among adult FMR1 premutation carriers.

April 23, 2016 - 7:35am

Social anxiety and autism spectrum traits among adult FMR1 premutation carriers.

Clin Genet. 2016 Apr 22;

Authors: López-Mourelo O, Mur E, Madrigal I, Alvarez-Mora MI, Gómez-Ansón B, Pagonabarraga J, Rodriguez-Revenga L, Milà M

Abstract
Behavioral symptoms and traits have been proposed as early markers in neurodegenerative diseases. The aim of this study was to evaluate social anxiety and autism in FMR1 premutation carriers using the Social Phobia Inventory (SPIN) and the Autism-Spectrum Quotient (AQ) questionnaires. Fifty-nine premutation carriers were compared with 50 controls. The SPIN test showed statistically significant differences between female but not male carriers. The AQ questionnaire found statistically significant differences between premutation carriers and controls in the total AQ as well as in the social skills and attention switching subdomains. A gender effect was only observed for the social skills subdomain. Spearman's correlation analysis revealed a moderately positive correlation with the total AQ scores as well as the social skills and communication subdomains. Our results show that FXTAS patients have higher AQ scores. Moreover, this is the first study to find statistically significant differences between FXTAS and no-FXTAS premutation carriers in the communication and the imagination subdomains, suggesting that FXTAS patients present a broader autistic phenotype than premutation carriers without FXTAS. Based on our results a wide range of behavioral/psychiatric traits should be included within the broader phenotypic presentation of individuals with the FMR1 premutation.

PMID: 27102723 [PubMed - as supplied by publisher]

Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish.

April 23, 2016 - 7:35am
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Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish.

Dis Model Mech. 2015 Jul 1;8(7):647-56

Authors: McCammon JM, Sive H

Abstract
The treatment of psychiatric disorders presents three major challenges to the research and clinical community: defining a genotype associated with a disorder, characterizing the molecular pathology of each disorder and developing new therapies. This Review addresses how cellular and animal systems can help to meet these challenges, with an emphasis on the role of the zebrafish. Genetic changes account for a large proportion of psychiatric disorders and, as gene variants that predispose to psychiatric disease are beginning to be identified in patients, these are tractable for study in cellular and animal systems. Defining cellular and molecular criteria associated with each disorder will help to uncover causal physiological changes in patients and will lead to more objective diagnostic criteria. These criteria should also define co-morbid pathologies within the nervous system or in other organ systems. The definition of genotypes and of any associated pathophysiology is integral to the development of new therapies. Cell culture-based approaches can address these challenges by identifying cellular pathology and by high-throughput screening of gene variants and potential therapeutics. Whole-animal systems can define the broadest function of disorder-associated gene variants and the organismal impact of candidate medications. Given its evolutionary conservation with humans and its experimental tractability, the zebrafish offers several advantages to psychiatric disorder research. These include assays ranging from molecular to behavioural, and capability for chemical screening. There is optimism that the multiple approaches discussed here will link together effectively to provide new diagnostics and treatments for psychiatric patients.

PMID: 26092527 [PubMed - indexed for MEDLINE]

Towards understanding the genetics of Autism.

April 22, 2016 - 9:28am
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Towards understanding the genetics of Autism.

Front Biosci (Elite Ed). 2016;8:412-426

Authors: Shailesh H, Gupta I, Sif S, Ouhtit A

Abstract
Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders that affect communication skills, social interaction and intellectual ability. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. Early studies focusing on candidate genes have shown that several genes associated with neuronal synaptic function are involved in development of ASD. Linkage studies have identified several single nucleotide polymorphisms (SNPs) associated with ASD, and genome-wide association studies have implicated several loci, but failed to recognize a single specific locus with strong significance, indicating heterogeneity in ASD genetic determinants. Detection of de novo copy number variations and single nucleotide variants in several ASD probands has confirmed the genetic heterogeneity of the disease. More interestingly, next generation sequencing approaches have recently identified novel candidate genes and several point mutations in sporadic ASDs, thus increasing our knowledge of ASD etiology. The current review summarizes the findings of recent studies using genetic and genomic approaches to understand the underlying molecular mechanisms of ASD.

PMID: 27100348 [PubMed - as supplied by publisher]

A Pooled Genome-Wide Association Study of Asperger Syndrome.

April 22, 2016 - 9:28am
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A Pooled Genome-Wide Association Study of Asperger Syndrome.

PLoS One. 2015;10(7):e0131202

Authors: Warrier V, Chakrabarti B, Murphy L, Chan A, Craig I, Mallya U, Lakatošová S, Rehnstrom K, Peltonen L, Wheelwright S, Allison C, Fisher SE, Baron-Cohen S

Abstract
Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

PMID: 26176695 [PubMed - indexed for MEDLINE]

Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.

April 22, 2016 - 9:28am
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Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.

PLoS One. 2015;10(6):e0129270

Authors: Nebel RA, Kirschen J, Cai J, Woo YJ, Cherian K, Abrahams BS

Abstract
Microcephaly and macrocephaly are overrepresented in individuals with autism and are thought to be disease-related risk factors or endophenotypes. Analysis of DNA microarray results from a family with a low functioning autistic child determined that the proband and two additional unaffected family members who carry a rare inherited 760 kb duplication of unknown clinical significance at 19p13.12 are macrocephalic. Consideration alongside overlapping deletion and duplication events in the literature provides support for a strong relationship between gene dosage at this locus and head size, with losses and gains associated with microcephaly (p=1.11x10(-11)) and macrocephaly (p=2.47x10(-11)), respectively. Data support A kinase anchor protein 8 and 8-like (AKAP8 and AKAP8L) as candidate genes involved in regulation of head growth, an interesting finding given previous work implicating the AKAP gene family in autism. Towards determination of which of AKAP8 and AKAP8L may be involved in the modulation of head size and risk for disease, we analyzed exome sequencing data for 693 autism families (2591 individuals) where head circumference data were available. No predicted loss of function variants were observed, precluding insights into relationship to head size, but highlighting strong evolutionary conservation. Taken together, findings support the idea that gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to autism risk. Exome sequencing of the family also identified a rare inherited variant predicted to disrupt splicing of TPTE / PTEN2, a PTEN homologue, which may likewise contribute to both macrocephaly and autism risk.

PMID: 26076356 [PubMed - indexed for MEDLINE]

Investigation of Gene Regulatory Networks Associated with Autism Spectrum Disorder Based on MiRNA Expression in China.

April 22, 2016 - 9:28am
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Investigation of Gene Regulatory Networks Associated with Autism Spectrum Disorder Based on MiRNA Expression in China.

PLoS One. 2015;10(6):e0129052

Authors: Huang F, Long Z, Chen Z, Li J, Hu Z, Qiu R, Zhuang W, Tang B, Xia K, Jiang H

Abstract
Autism spectrum disorder (ASD) comprise a group of neurodevelopmental disorders characterized by deficits in social and communication capacities and repetitive behaviors. Increasing neuroscientific evidence indicates that the neuropathology of ASD is widespread and involves epigenetic regulation in the brain. Differentially expressed miRNAs in the peripheral blood from autism patients were identified by high-throughput miRNA microarray analyses. Five of these miRNAs were confirmed through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. A search for candidate target genes of the five confirmed miRNAs was performed through a Kyoto encyclopedia of genes and genomes (KEGG) biological pathways and Gene Ontology enrichment analysis of gene function to identify gene regulatory networks. To the best of our knowledge, this study provides the first global miRNA expression profile of ASD in China. The differentially expressed miR-34b may potentially explain the higher percentage of male ASD patients, and the aberrantly expressed miR-103a-3p may contribute to the abnormal ubiquitin-mediated proteolysis observed in ASD.

PMID: 26061495 [PubMed - indexed for MEDLINE]

Bipolar disorder and its relation to major psychiatric disorders: a family-based study in the Swedish population.

April 22, 2016 - 9:28am
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Bipolar disorder and its relation to major psychiatric disorders: a family-based study in the Swedish population.

Bipolar Disord. 2015 Mar;17(2):184-93

Authors: Song J, Bergen SE, Kuja-Halkola R, Larsson H, Landén M, Lichtenstein P

Abstract
OBJECTIVES: Bipolar disorder (BPD) shares genetic components with other psychiatric disorders; however, uncertainty remains about where in the psychiatric spectra BPD falls. To understand the etiology of BPD, we studied the familial aggregation of BPD and co-aggregation between BPD and schizophrenia, depression, anxiety disorders, attention-deficit hyperactivity disorder, drug abuse, personality disorders, and autism spectrum disorders.
METHODS: A population-based cohort was created by linking several Swedish national registers. A total of 54,723 individuals with BPD were identified among 8,141,033 offspring from 4,149,748 nuclear families. The relative risk of BPD in relatives and the co-occurrence of other psychiatric disorders in patients with BPD and their relatives were compared to those of matched-population controls. Structural equation modeling was used to estimate the heritability and tetrachoric correlation.
RESULTS: The familial risks for relatives of BPD probands were 5.8-7.9 in first-degree relatives, and decreased with genetic distance. Co-occurrence risks for other psychiatric disorders were 9.7-22.9 in individuals with BPD and 1.7-2.8 in full siblings of BPD probands. Heritability for BPD was estimated at 58%. The correlations between BPD and other psychiatric disorders were considerable (0.37-0.62) and primarily due to genetic effects. The correlation with depression was the highest (0.62), and was 0.44 for schizophrenia.
CONCLUSIONS: The high familial risks provide evidence that genetic factors play an important role in the etiology of BPD, and the shared genetic determinants suggest pleiotropic effects across different psychiatric disorders. Results also indicate that BPD is in both the mood and psychotic spectra, but possibly more closely related to mood disorders.

PMID: 25118125 [PubMed - indexed for MEDLINE]

Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

April 21, 2016 - 8:48am

Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.

J Dev Behav Pediatr. 2016 Apr 18;

Authors: Thurm A, Himelstein D, DʼSouza P, Rennert O, Jiang S, Olatunji D, Longo N, Pasquali M, Swedo S, Salomons GS, Carrillo N

Abstract
OBJECTIVE: Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders.
METHOD: Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability.
RESULTS: We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD.
CONCLUSION: Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.

PMID: 27096572 [PubMed - as supplied by publisher]

Neurobiology of rodent self-grooming and its value for translational neuroscience.

April 21, 2016 - 8:48am
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Neurobiology of rodent self-grooming and its value for translational neuroscience.

Nat Rev Neurosci. 2016 Jan;17(1):45-59

Authors: Kalueff AV, Stewart AM, Song C, Berridge KC, Graybiel AM, Fentress JC

Abstract
Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders--including models of autism spectrum disorder and obsessive compulsive disorder--that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.

PMID: 26675822 [PubMed - indexed for MEDLINE]

Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.

April 21, 2016 - 8:48am
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Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.

J Neurosci. 2015 Dec 9;35(49):16282-94

Authors: Kogan JH, Gross AK, Featherstone RE, Shin R, Chen Q, Heusner CL, Adachi M, Lin A, Walton NM, Miyoshi S, Miyake S, Tajinda K, Ito H, Siegel SJ, Matsumoto M

Abstract
UNLABELLED: The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia.
SIGNIFICANCE STATEMENT: Recently discovered pathologic copy number variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV.

PMID: 26658876 [PubMed - indexed for MEDLINE]

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