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The rs251684 Variant of PLA2G4C Is Associated with Autism Spectrum Disorder in the Northeast Han Chinese Population.

September 10, 2016 - 7:23am

The rs251684 Variant of PLA2G4C Is Associated with Autism Spectrum Disorder in the Northeast Han Chinese Population.

Genet Test Mol Biomarkers. 2016 Sep 9;

Authors: Liu S, Qiu S, Lu Y, Kanu JS, Li R, Bai Y, Zhu X, Lei J, Xu N, Yu Y, Liu Y, Jiang H

Abstract
AIM: To investigate the association between autism spectrum disorder (ASD) and the phospholipase A2 group IVC (PLA2G4C) and phospholipase A2 group XIIA (PLA2G12A) polymorphisms in the Northeast Han Chinese population.
MATERIALS AND METHODS: A total of 68 family trios (children diagnosed with ASD and their unaffected parents) were enrolled. Five single-nucleotide polymorphisms (SNPs) (rs9226, rs1045376, rs251684, rs2307279, and rs156631) in PLA2G4C and four SNPs (rs6533451, rs2285714, rs2285713, and rs11728699) in PLA2G12A were selected and genotyped. The association between the SNPs and ASD was analyzed using the transmission disequilibrium test.
RESULTS: Our results showed a significant association between ASD and the rs251684 variant of PLA2G4C (transmitted/nontransmitted = 36/21, χ(2) = 3.947, p = 0.047), but no association between ASD and the other eight SNPs investigated (all p > 0.05). Moreover, we found no preference in the transmission of haplotypes constructed for either PLA2G4C or PLA2G12A.
CONCLUSION: The rs251684 polymorphism of PLA2G4C may be associated with ASD risk.

PMID: 27611910 [PubMed - as supplied by publisher]

Significant Association of HLA-B Alleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study.

September 10, 2016 - 7:23am
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Significant Association of HLA-B Alleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study.

Dis Markers. 2015;2015:724935

Authors: Puangpetch A, Suwannarat P, Chamnanphol M, Koomdee N, Ngamsamut N, Limsila P, Sukasem C

Abstract
Autism is a severe neurodevelopmental disorder. Many susceptible causative genes have been identified. Most of the previous reports showed the relationship between the Human Leukocyte Antigen (HLA) gene and etiology of autism. In order to identify HLA-B alleles associated with autism in Thai population, we compared the frequency of HLA-B allele in 364 autistic subjects with 952 normal subjects by using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP) method based on flow-cytometry technology. HLA-B (⁎) 13:02 (P = 0.019, OR = 2.229), HLA-B (⁎) 38:02 (P = 0.049, OR = 1.628), HLA-B (⁎) 44:03 (P = 0.016, OR = 1.645), and HLA-B (⁎) 56:01 (P = 1.78 × 10(-4), OR = 4.927) alleles were significantly increased in autistic subjects compared with normal subjects. Moreover, we found that the HLA-B (⁎) 18:02 (P = 0.016, OR = 0.375) and HLA-B (⁎) 46:12 (P = 0.008, OR = 0.147) alleles were negatively associated with autism when compared to normal controls. Both alleles might have a protective role in disease development. In addition, four HLA-B genotypes of autistic patients had statistically significant relationship with control groups, consisting of HLA-B (⁎) 3905/(⁎) 5801 (P = 0.032, OR = 24.697), HLA-B (⁎) 2704/(⁎) 5801 (P = 0.022, OR = 6.872), HLA-B (⁎) 3501/(⁎) 4403 (P = 0.021, OR = 30.269), and HLA-B (⁎) 1801/(⁎) 4402 (P = 0.017, OR = 13.757). This is the first report on HLA-B associated with Thai autism and may serve as a marker for genetic susceptibility to autism in Thai population.

PMID: 26819491 [PubMed - indexed for MEDLINE]

Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation.

September 10, 2016 - 7:23am
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Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation.

Int J Mol Sci. 2015;16(12):28218-29

Authors: Ibi D, Yamada K

Abstract
Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders.

PMID: 26633355 [PubMed - indexed for MEDLINE]

First glimpses of the neurobiology of autism spectrum disorder.

September 10, 2016 - 7:23am
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First glimpses of the neurobiology of autism spectrum disorder.

Curr Opin Genet Dev. 2015 Aug;33:80-92

Authors: Sanders SJ

Abstract
Rapid progress in identifying the genes underlying autism spectrum disorder (ASD) has provided the substrate for a first wave of analyses into the underlying neurobiology. This review describes the consensus across these diverse analyses, highlighting two distinct sets of genes: 1) Genes that regulate chromatin and transcription, especially in cortical projection neurons and striatal medium spiny neurons during mid-fetal development; and 2) Genes involved in synapse development and function, especially during infancy and early childhood, and differentially expressed in the post mortem ASD brain. Both gene sets are also regulatory targets of the ASD genes CHD8 and FMRP. It remains to be seen whether these represent two independent paths to the ASD phenotype or two components of a common path.

PMID: 26547130 [PubMed - indexed for MEDLINE]

Quantitative autistic trait measurements index background genetic risk for ASD in Hispanic families.

September 9, 2016 - 7:21am

Quantitative autistic trait measurements index background genetic risk for ASD in Hispanic families.

Mol Autism. 2016;7(1):39

Authors: Page J, Constantino JN, Zambrana K, Martin E, Tunc I, Zhang Y, Abbacchi A, Messinger D

Abstract
BACKGROUND: Recent studies have indicated that quantitative autistic traits (QATs) of parents reflect inherited liabilities that may index background genetic risk for clinical autism spectrum disorder (ASD) in their offspring. Moreover, preferential mating for QATs has been observed as a potential factor in concentrating autistic liabilities in some families across generations. Heretofore, intergenerational studies of QATs have focused almost exclusively on Caucasian populations-the present study explored these phenomena in a well-characterized Hispanic population.
METHODS: The present study examined QAT scores in siblings and parents of 83 Hispanic probands meeting research diagnostic criteria for ASD, and 64 non-ASD controls, using the Social Responsiveness Scale-2 (SRS-2). Ancestry of the probands was characterized by genotype, using information from 541,929 single nucleotide polymorphic markers.
RESULTS: In families of Hispanic children with an ASD diagnosis, the pattern of quantitative trait correlations observed between ASD-affected children and their first-degree relatives (ICCs on the order of 0.20), between unaffected first-degree relatives in ASD-affected families (sibling/mother ICC = 0.36; sibling/father ICC = 0.53), and between spouses (mother/father ICC = 0.48) were in keeping with the influence of transmitted background genetic risk and strong preferential mating for variation in quantitative autistic trait burden. Results from analysis of ancestry-informative genetic markers among probands in this sample were consistent with that from other Hispanic populations.
CONCLUSIONS: Quantitative autistic traits represent measurable indices of inherited liability to ASD in Hispanic families. The accumulation of autistic traits occurs within generations, between spouses, and across generations, among Hispanic families affected by ASD. The occurrence of preferential mating for QATs-the magnitude of which may vary across cultures-constitutes a mechanism by which background genetic liability for ASD can accumulate in a given family in successive generations.

PMID: 27606047 [PubMed - in process]

Brief Report: A Preference for Biological Motion Predicts a Reduction in Symptom Severity 1 Year Later in Preschoolers with Autism Spectrum Disorders.

September 9, 2016 - 7:21am

Brief Report: A Preference for Biological Motion Predicts a Reduction in Symptom Severity 1 Year Later in Preschoolers with Autism Spectrum Disorders.

Front Psychiatry. 2016;7:143

Authors: Franchini M, Wood de Wilde H, Glaser B, Gentaz E, Eliez S, Schaer M

Abstract
Recent research has consistently demonstrated reduced orienting to social stimuli in samples of young children with autism spectrum disorders (ASD). However, social orienting greatly varies between individual children on the spectrum. Better understanding this heterogeneity in social orienting may contribute to our comprehension of the mechanisms underlying autistic symptoms thereby improving our ability to intervene. Indeed, children on the autism spectrum who show higher levels of interest in social stimuli demonstrate reduced clinical symptoms and increased adaptive functioning. However, longitudinal studies examining the influence of social orienting on subsequent outcome are critically lacking. Here, we aim to explore the relationship between social interest at the age of 3 and changes in severity of autistic symptoms over the subsequent year, in 20 children with ASD and 20 age-matched typically developing (TD) children. A visual preference for social stimuli was measured using an eye-tracking task at baseline, consisting of a previously studied visual preference paradigm presenting biological and geometric motion side-by-side. The task was altered for the current study by alternating presentation side for each type of stimuli to keep visual perseveration from influencing participants' first fixation location. Clinical data were collected both at baseline and 1 year later at follow-up. As a group, we observed reduced interest for biological motion (BIO-M) in children with ASD compared to TD children, corroborating previous findings. We also confirmed that a preference for BIO-M is associated with better adaptive functioning in preschoolers with ASD. Most importantly, our longitudinal results showed that a preference for BIO-M strongly predicted decreased severity of diagnostic symptoms. Participants who preferred social stimuli at the age of 3 showed drastic reductions in their severity level of autistic symptoms 1 year later, whereas participants who preferred geometric stimuli showed autistic symptoms that were unchanged or more severe after 1 year. As a whole, our results suggest that a preference for BIO-M may be key to understanding the behavioral phenotype of young children with ASD, and may represent a promising candidate behavior for predicting early developmental trajectories and outcome.

PMID: 27605914 [PubMed]

Clinicians' experiences with the fragile X clinical and research consortium.

September 9, 2016 - 7:21am

Clinicians' experiences with the fragile X clinical and research consortium.

Am J Med Genet A. 2016 Sep 8;

Authors: Liu JA, Hagerman RJ, Miller RM, Craft LT, Finucane B, Tartaglia N, Berry-Kravis EM, Sherman SL, Kidd SA, Cohen J

Abstract
The objectives of the study were to assess the attitudes and experiences of clinicians involved in a consortium of clinics serving people with fragile X-associated disorders to gauge satisfaction with the consortium and its efforts to improve quality of life for patients and the community. An internet survey was sent to 26 fragile X (FX) clinic directors participating in the Fragile X Clinical and Research Consortium (FXCRC). Respondents were asked to complete 19 questions on consortium performance and outcomes relevant for their own clinic. The response rate was 84% (22/26), with two surveys providing incomplete data. Assistance with clinic establishment, opportunities for research collaborations, and access to colleagues and information were highly valued. Approximately 76% of clinicians reported improvements in patient care and 60% reported an increase in patient services. There was a 57% increase in participation in a FX-related clinical trial among clinics since joining the FXCRC (24% vs. 81%). Overall, respondents reported primarily positive experiences from participation in the FXCRC. Common suggestions for improvement included additional financial support and increased utilization of collected patient data for research purposes. Additionally, a Clinic Services Checklist was administered annually to examine changes in services offered over time. There were several important changes regarding the provision of services by clinics, often with multiple clinics changing with respect to a service. In conclusion, the FXCRC has led to the establishment and sustainment of fragile X clinics in the U.S., fostered cooperation among fragile X clinicians, and provided clinics with a platform to share recommendations and best practices to maximize quality of life for their patients and the overall fragile X community. The results from the survey and checklist also provide suggestions to strengthen the FXCRC and enhance future collaborations among FXCRC members. © 2016 Wiley Periodicals, Inc.

PMID: 27604509 [PubMed - as supplied by publisher]

Urine Pyrimidine Metabolite Determination by HPLC Tandem Mass Spectrometry.

September 9, 2016 - 7:21am
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Urine Pyrimidine Metabolite Determination by HPLC Tandem Mass Spectrometry.

Methods Mol Biol. 2016;1378:237-42

Authors: Sun Q

Abstract
Pyrimidine diseases result from deficiencies in pyrimidine de novo synthesis, degradation, and salvage pathways. Enzymatic deficiencies in pyrimidine catabolism lead to mitochondrial neurogastrointestinal encephalopathy (MNGIE), pyrimidinuria, dihydropyrimidinuria, ureidopropionic aciduria, and other disorders. While MNGIE presents with gastrointestinal dysmotility, cachexia, and leukoencephalopathy, pyrimidinuria and dihydropyrimidinuria may show symptoms of epilepsy, autism, mental retardation, and dysmorphic features. The application of HPLC-MS/MS facilitates rapid screening of pyrimidine metabolites. Here we describe an LCMS method for determination of uracil, thymine, thymidine, dihydrouracil, and dihydrothymine that are diagnostic biomarkers of MNGIE, pyrimidinuria, and dihydropyrimidinuria.

PMID: 26602135 [PubMed - indexed for MEDLINE]

Urine Purine Metabolite Determination by UPLC-Tandem Mass Spectrometry.

September 9, 2016 - 7:21am
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Urine Purine Metabolite Determination by UPLC-Tandem Mass Spectrometry.

Methods Mol Biol. 2016;1378:227-35

Authors: Sun Q

Abstract
Inborn errors of purine metabolism, either deficiencies of synthesis or catabolism pathways, lead to a wide spectrum of clinical presentations: urolithiasis (adenine phosphoribosyltransferase), primary immune deficiency (adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency), severe intellectual disability, and other neurological symptoms (Lesch-Nyhan disease, adenylosuccinase deficiency, and molybdenum cofactor deficiency). A rapid quantitative purine assay was developed using UPLC-MS/MS to determine purine nucleoside and base concentrations in urine. Taking advantages of ultra performance liquid chromatography, we achieved satisfactory analyte separation and recovery with a polar T3 column in a short run time with no requirement of time-consuming sample preparation or derivatization. This targeted assay is intended for diagnosis and management of purine diseases, newborn screening follow-up of SCID, and evaluation of autism spectrum disorders.

PMID: 26602134 [PubMed - indexed for MEDLINE]

Genetic variation in the oxytocin receptor gene is associated with a social phenotype in autism spectrum disorders.

September 9, 2016 - 7:21am
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Genetic variation in the oxytocin receptor gene is associated with a social phenotype in autism spectrum disorders.

Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):720-9

Authors: Harrison AJ, Gamsiz ED, Berkowitz IC, Nagpal S, Jerskey BA

Abstract
Oxytocin regulates social behavior in animal models. Research supports an association between genetic variation in the oxytocin receptor gene (OXTR) and autism spectrum disorders (ASD). In this study, we examine the association between the OXTR gene and a specific social phenotype within ASD. This genotype-phenotype investigation may provide insight into how OXTR conveys risk for social impairment. The current study investigated 10 SNPS in the OXTR gene that have been previously shown to be associated with ASD. We examine the association of these SNPs with both a social phenotype and a repetitive behavior phenotype comprised of behaviors commonly impaired in ASD in the Simons simplex collection (SSC). Using a large sample to examine the association between OXTR and ASD (n = range: 485-1002), we find evidence to support a relation between two OXTR SNPs and the examined social phenotype among children diagnosed with ASD. Greater impairment on the social responsiveness scale standardized total score and on several subdomains was observed among individuals with one or more copies of the minor frequency allele in both rs7632287 and rs237884. Linkage disequilibrium (LD) mapping suggests that these two SNPs are in LD within and overlapping the 3' untranslated region (3'-UTR) of the OXTR gene. These two SNPs were also associated with greater impairment on the repetitive behavior scale. Results of this study indicate that social impairment and repetitive behaviors in ASD are associated with genomic variation in the 3'UTR of the OXTR gene. These variants may be linked to an allele that alters stability of the mRNA message although further work is necessary to test this hypothesis.

PMID: 26365303 [PubMed - indexed for MEDLINE]

Relationship between ST8SIA2, polysialic acid and its binding molecules, and psychiatric disorders.

September 8, 2016 - 7:17am
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Relationship between ST8SIA2, polysialic acid and its binding molecules, and psychiatric disorders.

Biochim Biophys Acta. 2016 Aug;1860(8):1739-52

Authors: Sato C, Hane M, Kitajima K

Abstract
Polysialic acid (polySia, PSA) is a unique and functionally important glycan, particularly in vertebrate brains. It is involved in higher brain functions such as learning, memory, and social behaviors. Recently, an association between several genetic variations and single nucleotide polymorphisms (SNPs) of ST8SIA2/STX, one of two polysialyltransferase genes in vertebrates, and psychiatric disorders, such as schizophrenia (SZ), bipolar disorder (BD), and autism spectrum disorder (ASD), was reported based on candidate gene approaches and genome-wide studies among normal and mental disorder patients. It is of critical importance to determine if the reported mutations and SNPs in ST8SIA2 lead to impairments of the structure and function of polySia, which is the final product of ST8SIA2. To date, however, only a few such forward-directed studies have been conducted. In addition, the molecular mechanisms underlying polySia-involved brain functions remain unknown, although polySia was shown to have an anti-adhesive effect. In this report, we review the relationships between psychiatric disorders and polySia and/or ST8SIA2, and describe a new function of polySia as a regulator of neurologically active molecules, such as brain-derived neurotrophic factor (BDNF) and dopamine, which are deeply involved in psychiatric disorders. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.

PMID: 27105834 [PubMed - indexed for MEDLINE]

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

September 8, 2016 - 7:17am
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Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

Sci Rep. 2015;5:16239

Authors: Maekawa M, Iwayama Y, Ohnishi T, Toyoshima M, Shimamoto C, Hisano Y, Toyota T, Balan S, Matsuzaki H, Iwata Y, Takagai S, Yamada K, Ota M, Fukuchi S, Okada Y, Akamatsu W, Tsujii M, Kojima N, Owada Y, Okano H, Mori N, Yoshikawa T

Abstract
The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.

PMID: 26548558 [PubMed - indexed for MEDLINE]

Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study.

September 7, 2016 - 7:13am
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Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study.

PLoS One. 2016;11(4):e0153667

Authors: Firouzabadi N, Ghazanfari N, Alavi Shoushtari A, Erfani N, Fathi F, Bazrafkan M, Bahramali E

Abstract
BACKGROUND: Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism.
METHODS: Considering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods.
RESULTS: There were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64-5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37-3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26-2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008).
CONCLUSION: Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism.

PMID: 27082637 [PubMed - indexed for MEDLINE]

Subthreshold traits of the broad autistic spectrum are distributed across different subgroups in parents, but not siblings, of probands with autism.

September 7, 2016 - 7:13am
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Subthreshold traits of the broad autistic spectrum are distributed across different subgroups in parents, but not siblings, of probands with autism.

Eur Child Adolesc Psychiatry. 2014 Apr;23(4):225-33

Authors: Robel L, Rousselot-Pailley B, Fortin C, Levy-Rueff M, Golse B, Falissard B

Abstract
Autism is a categorical developmental disorder characterized by impairment in socialization, communication, and by restricted and circumscribed interests. Several authors have described the presence of subthreshold autistic traits in the general population, pervasive developmental disorders representing the extreme end of their distribution. In this study, we explored the presence of autistic traits in siblings and parents of a proband with autism, and in siblings and parents of a normally developing child, using the previously validated self-report French Autism Quotient, an adaptation of the AQ developed by S. Baron-Cohen. Scores were distributed between two main factors, F1 corresponding to socialization and communication, F2 to imagination and rigidity. Here, we show that both parents and siblings of a child with autism have more symptomatic scores in the domains of communication and socialization. In addition, we show that in these families the parents, but not the siblings, are distributed across different subcategories, according to their scores for the F1 and F2 domains. We hypothesize that these different subgroups may correspond to different underlying genetic mechanisms.

PMID: 23864543 [PubMed - indexed for MEDLINE]

Novel mechanisms and treatment approaches in autism spectrum disorder.

September 2, 2016 - 7:02am

Novel mechanisms and treatment approaches in autism spectrum disorder.

Discov Med. 2016 Aug;22(119):47-54

Authors: Brian J, Doyle-Thomas K, Baribeau D, Anagnostou E

Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by marked heterogeneity in biology, expression, and response to treatment. The past decade has yielded considerable progress in understanding the underlying biological mechanisms, in characterizing the earliest behavioral phenotype(s), and in developing and evaluating effective treatments for ASD. This review highlights recent research advances in genetics and neuroimaging, as well as in novel behavioral and psychopharmacological treatment approaches, arguing for the value of trans-disciplinary initiatives to move the field forward exponentially. Despite considerable complexity, patterns are beginning to emerge that can inform the identification of novel treatment targets and approaches. The next generation of major innovations in ASD research will involve collaborations across genetics/genomics, neuroimaging, and intervention science. Such efforts, currently under way, hold tremendous promise for exponentially increasing our capacity to understand the mechanisms that contribute to the emergence of ASD and to develop and evaluate personalized interventions that yield maximal impact in a meaningful way.

PMID: 27585230 [PubMed - as supplied by publisher]

Severity of ASD symptoms and their correlation with the presence of copy number variations and exposure to first trimester ultrasound.

September 2, 2016 - 7:02am

Severity of ASD symptoms and their correlation with the presence of copy number variations and exposure to first trimester ultrasound.

Autism Res. 2016 Sep 1;

Authors: Jane Webb S, Garrison MM, Bernier R, McClintic AM, King BH, Mourad PD

Abstract
Current research suggests that incidence and heterogeneity of autism spectrum disorder (ASD) symptoms may arise through a variety of exogenous and/or endogenous factors. While subject to routine clinical practice and generally considered safe, there exists speculation, though no human data, that diagnostic ultrasound may also contribute to ASD severity, supported by experimental evidence that exposure to ultrasound early in gestation could perturb brain development and alter behavior. Here we explored a modified triple hit hypothesis [Williams & Casanova, ] to assay for a possible relationship between the severity of ASD symptoms and (1) ultrasound exposure (2) during the first trimester of pregnancy in fetuses with a (3) genetic predisposition to ASD. We did so using retrospective analysis of data from the SSC (Simon's Simplex Collection) autism genetic repository funded by the Simons Foundation Autism Research Initiative. We found that male children with ASD, copy number variations (CNVs), and exposure to first trimester ultrasound had significantly decreased non-verbal IQ and increased repetitive behaviors relative to male children with ASD, with CNVs, and no ultrasound. These data suggest that heterogeneity in ASD symptoms may result, at least in part, from exposure to diagnostic ultrasound during early prenatal development of children with specific genetic vulnerabilities. These results also add weight to on-going concerns expressed by the FDA about non-medical use of diagnostic ultrasound during pregnancy. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 27582229 [PubMed - as supplied by publisher]

Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.

September 2, 2016 - 7:02am

Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.

J Neurosci. 2016 Aug 31;36(35):9124-34

Authors: Arons MH, Lee K, Thynne CJ, Kim SA, Schob C, Kindler S, Montgomery JM, Garner CC

Abstract
UNLABELLED: Shank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines. In support of this hypothesis, we find that zinc is a potent regulator of Shank3 activation and dynamics in rat hippocampal neurons. Moreover, we show that zinc modulation of synaptic transmission is Shank3 dependent. Interestingly, an autism spectrum disorder (ASD)-associated variant of Shank3 (Shank3(R87C)) retains its zinc sensitivity and supports zinc-dependent activation of AMPAR-mediated synaptic transmission. However, elevated zinc was unable to rescue defects in trans-synaptic signaling caused by the R87C mutation, implying that trans-synaptic increases in neurotransmitter release are not necessary for the postsynaptic effects of zinc. Together, these data suggest that Shank3 is a key component of a zinc-sensitive signaling system, regulating synaptic strength that may be impaired in ASD.
SIGNIFICANCE STATEMENT: Shank3 is a postsynaptic protein associated with neurodevelopmental disorders such as autism and schizophrenia. In this study, we show that Shank3 is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic transmission. Intriguingly, an autism-associated mutation in Shank3 partially impairs this signaling system. Therefore, perturbation of zinc homeostasis may impair, not only synaptic functionality and plasticity, but also may lead to cognitive and behavioral abnormalities seen in patients with psychiatric disorders.

PMID: 27581454 [PubMed - in process]

Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling.

September 2, 2016 - 7:02am
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Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling.

PLoS One. 2016;11(4):e0153329

Authors: Wen Y, Alshikho MJ, Herbert MR

Abstract
We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases. ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities.

PMID: 27055244 [PubMed - indexed for MEDLINE]

Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia.

September 2, 2016 - 7:02am
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Heterozygous deletion of α-neurexin I or α-neurexin II results in behaviors relevant to autism and schizophrenia.

Behav Neurosci. 2015 Dec;129(6):765-76

Authors: Dachtler J, Ivorra JL, Rowland TE, Lever C, Rodgers RJ, Clapcote SJ

Abstract
The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding α-neurexin I (Nrxn1α) and α-neurexin II (Nrxn2α), in individuals with autism spectrum disorders and schizophrenia. However, the link between α-neurexin deficiency and the manifestation of psychiatric disorders remain unclear. To assess whether the heterozygous loss of neurexins results in behaviors relevant to autism or schizophrenia, we used mice with heterozygous (HET) deletion of Nrxn1α or Nrxn2α. We found that in a test of social approach, Nrxn1α HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1α HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2α HET mice. Nrxn2α HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1α and Nrxn2α genotypic effects were specific, as neither HET deletion had effects on a wide range of other behavioral measures, including several measures of anxiety. Our findings demonstrate that the heterozygous loss of α-neurexin I and α-neurexin II in mice leads to phenotypes relevant to autism and schizophrenia.

PMID: 26595880 [PubMed - indexed for MEDLINE]

Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice.

September 2, 2016 - 7:02am
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Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice.

Behav Neurosci. 2015 Dec;129(6):731-43

Authors: Truong DT, Rendall AR, Castelluccio BC, Eigsti IM, Fitch RH

Abstract
Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder.

PMID: 26501174 [PubMed - indexed for MEDLINE]

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