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Induction or augmentation of labor and autism-reply.

February 5, 2014 - 8:38am

Induction or augmentation of labor and autism-reply.

JAMA Pediatr. 2014 Feb 1;168(2):191-2

Authors: Miranda ML, Anthopolos R, Gregory SG

PMID: 24492875 [PubMed - in process]

Treating the Whole Person With Autism: The Proceedings of the Autism Speaks National Autism Conference.

February 5, 2014 - 8:38am

Treating the Whole Person With Autism: The Proceedings of the Autism Speaks National Autism Conference.

Curr Probl Pediatr Adolesc Health Care. 2014 Feb;44(2):26-47

Authors: Coury DL, Swedo SE, Thurm AE, Miller DT, Veenstra-Vanderweele JM, Carbone PS, Taylor JL

Abstract
The identification of autism spectrum disorders has increased dramatically over the past decade, with the latest estimates indicating prevalence as high as 1 in 54 boys. There is greater awareness of medical conditions that co-occur with autism and expansion of treatment options. Closer scrutiny has led to refinement of the diagnostic criteria, and there have been advances in genetics examining potential causal factors. Transition to adulthood is an area of growing concern, and professionals and families require guidance on this issue. This article summarizes the proceedings of the Autism Speaks conference on Treating the Whole Person with Autism: Care across the Lifespan. The conference was organized with the intent of providing a forum for both families and professionals to learn about the most current research in the field. Dr. Sue Swedo provides important background information regarding the changes in the diagnostic criteria for autism spectrum disorders. She particularly deals with the concerns of individuals and families that their autism diagnosis may change. Recommendations for genetic testing and its interpretation are provided by Dr. David Miller. His discussion helps make sense of the utility of genetic testing for ASD, along with demonstration of the complexity of determining which genetic factors are doing what and through which pathways. Dr. Jeremy Veenstra-VanderWeele provides useful background information on how medicines are initially identified and for what purpose and goes on to describe the present and future treatments in pharmacology. Medical issues are addressed by Dr. Paul Carbone, especially the coordination of comprehensive services through the medical home model of care. Dr. Julie Lounds Taylor concludes with guidance on preparation for adulthood, a topic of great importance to families as their child matures and for the professionals who will help guide this transition.

PMID: 24491508 [PubMed - as supplied by publisher]

Neuroligins provide molecular links between syndromic and nonsyndromic autism.

February 5, 2014 - 8:38am
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Neuroligins provide molecular links between syndromic and nonsyndromic autism.

Sci Signal. 2013 Jul 9;6(283):re4

Authors: Singh SK, Eroglu C

Abstract
Autism is a common and heritable neuropsychiatric disorder that can be categorized into two types: syndromic and nonsyndromic, the former of which are associated with other neurological disorders or syndromes. Molecular and functional links between syndromic and nonsyndromic autism genes were lacking until studies aimed at understanding the role of trans-synaptic adhesion molecule neuroligin, which is associated with nonsyndromic autism, provided important connections. Here, we integrate data from these studies into a model of how neuroligin functions to control synaptic connectivity in the central nervous system and how neuroligin dysfunction may participate in the pathophysiology of autism. Understanding the complex functional interactions between neuroligins and other autism-associated proteins at the synapse is crucial to understand the pathology of autism. This understanding might bring us closer to development of therapeutic approaches for autism.

PMID: 23838185 [PubMed - indexed for MEDLINE]

The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact.

February 4, 2014 - 8:47am
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The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact.

Int J Environ Res Public Health. 2013 Aug;10(8):3384-408

Authors: Quaak I, Brouns MR, Van de Bor M

Abstract
In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD. In the current review a literature overview with respect to neurotoxic exposure and the effects on neurotransmitter systems is presented. The aim was to identify mechanisms and related factors which together might result in ASD. The literature reported in the current review supports the hypothesis that exposure to neurotoxic compounds can lead to alterations in the GABAergic, glutamatergic, serotonergic and dopaminergic system which have been related to ASD in previous work. However, in several studies findings were reported that are not supportive of this hypothesis. Other factors also might be related, possibly altering the mechanisms at work, such as time and length of exposure as well as dose of the compound. Future research should focus on identifying the pathway through which these factors interact with exposure to neurotoxic compounds making use of human studies.

PMID: 23924882 [PubMed - indexed for MEDLINE]

Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.

February 1, 2014 - 8:14am
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Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.

Psychoneuroendocrinology. 2013 Aug;38(8):1370-80

Authors: Trent S, Dean R, Veit B, Cassano T, Bedse G, Ojarikre OA, Humby T, Davies W

Abstract
Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model.

PMID: 23276394 [PubMed - indexed for MEDLINE]

[Genetic bases of autism spectrum disorders].

January 31, 2014 - 1:51pm
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[Genetic bases of autism spectrum disorders].

Med Wieku Rozwoj. 2013 Jul-Sep;17(3):207-23

Authors: Wiśniowiecka-Kowalnik B, Kastory-Bronowska M, Stankiewicz P

Abstract
Autism spectrum disorders (ASDs) are an etiologically and clinically heterogeneous group of neurodevelopmental disorders affecting approximately 0.6-1% of the general population. ASDs are characterized by deficits in social communication, impaired language development, and stereotyped repetitive behaviour. The impact of genetic factors in ASDs has been confirmed in the past few years. Numerous studies have shown that among patients with ASDs, approximately 10% have DNA copy number variation and 10-20% point mutations. Most of the deficiencies identified in individuals with ASDs relate to genes encoding proteins involved mainly in the development of neurons and their synapses functioning in various signaling pathways. Due to the large heterogeneity of identified changes in the genome of individuals with ASDs, the newest techniques enabling analysis of the entire genome in one study (microarrays, next-generation sequencing) are the methods of choice in the diagnostics of this pathology.

PMID: 24296445 [PubMed - indexed for MEDLINE]

Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.

January 31, 2014 - 1:51pm
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Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.

PLoS One. 2013;8(6):e67724

Authors: Giannandrea M, Guarnieri FC, Gehring NH, Monzani E, Benfenati F, Kulozik AE, Valtorta F

Abstract
Synapsins are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles. Experimental evidence suggests a role for synapsins in synaptic vesicle clustering and recycling at the presynaptic terminal, as well as in neuronal development and synaptogenesis. Synapsin knock-out (Syn1(-/-) ) mice display an epileptic phenotype and mutations in the SYN1 gene have been identified in individuals affected by epilepsy and/or autism spectrum disorder. We investigated the impact of the c.1067G>A nonsense transition, the first mutation described in a family affected by X-linked syndromic epilepsy, on the expression and functional properties of the synapsin I protein. We found that the presence of a premature termination codon in the human SYN1 transcript renders it susceptible to nonsense-mediated mRNA decay (NMD). Given that the NMD efficiency is highly variable among individuals and cell types, we investigated also the effects of expression of the mutant protein and found that it is expressed at lower levels compared to wild-type synapsin I, forms perinuclear aggregates and is unable to reach presynaptic terminals in mature hippocampal neurons grown in culture. Taken together, these data indicate that in patients carrying the W356× mutation the function of synapsin I is markedly impaired, due to both the strongly decreased translation and the altered function of the NMD-escaped protein, and support the value of Syn1(-/-) mice as an experimental model mimicking the human pathology.

PMID: 23818987 [PubMed - indexed for MEDLINE]

Strong genetic influences on the stability of autistic traits in childhood.

January 30, 2014 - 8:56am

Strong genetic influences on the stability of autistic traits in childhood.

J Am Acad Child Adolesc Psychiatry. 2014 Feb;53(2):221-30

Authors: Holmboe K, Rijsdijk FV, Hallett V, Happé F, Plomin R, Ronald A

Abstract
OBJECTIVE: Disorders on the autism spectrum, as well as autistic traits in the general population, have been found to be both highly stable across age and highly heritable at individual ages. However, little is known about the overlap in genetic and environmental influences on autistic traits across age and the contribution of such influences to trait stability itself. The present study investigated these questions in a general population sample of twins.
METHOD: More than 6,000 twin pairs were rated on an established scale of autistic traits by their parents at 8, 9, and 12 years of age and by their teachers at 9 and 12 years of age. Data were analyzed using structural equation modeling.
RESULTS: The results indicated that, consistently across raters, not only were autistic traits stable, and moderately to highly heritable at individual ages, but there was also a high degree of overlap in genetic influences across age. Furthermore, autistic trait stability could largely be accounted for by genetic factors, with the environment unique to each twin playing a minor role. The environment shared by twins had virtually no effect on the longitudinal stability in autistic traits.
CONCLUSIONS: Autistic traits are highly stable across middle childhood. and this stability is caused primarily by genetic factors.

PMID: 24472256 [PubMed - in process]

Viewing social scenes: a visual scan-path study comparing fragile X syndrome and Williams syndrome.

January 30, 2014 - 8:56am
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Viewing social scenes: a visual scan-path study comparing fragile X syndrome and Williams syndrome.

J Autism Dev Disord. 2013 Aug;43(8):1880-94

Authors: Williams TA, Porter MA, Langdon R

Abstract
Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of socially salient information within scenes to investigate the visual attentional mechanisms of: capture, disengagement, and/or general engagement. Findings revealed that individuals with FXS avoid social information presented centrally, at least initially. The WS findings, on the other hand, provided some evidence that difficulties with attentional disengagement, rather than attentional capture, may play a role in the WS social phenotype. These findings are discussed in relation to the distinct social phenotypes of these two disorders.

PMID: 23224515 [PubMed - indexed for MEDLINE]

Disentangling the heterogeneity of autism spectrum disorder through genetic findings.

January 29, 2014 - 7:49am

Disentangling the heterogeneity of autism spectrum disorder through genetic findings.

Nat Rev Neurol. 2014 Jan 28;

Authors: Jeste SS, Geschwind DH

Abstract
Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes-single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities-that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment.

PMID: 24468882 [PubMed - as supplied by publisher]

Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population.

January 29, 2014 - 7:49am

Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population.

Mol Autism. 2014 Jan 27;5(1):5

Authors: Matsunami N, Hensel CH, Baird L, Stevens J, Otterud B, Leppert T, Varvil T, Hadley D, Glessner JT, Pellegrino R, Kim C, Thomas K, Wang F, Otieno FG, Ho K, Christensen GB, Li D, Prekeris R, Lambert CG, Hakonarson H, Leppert MF

Abstract
BACKGROUND: Genetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken.
METHODS: We identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population.
RESULTS: We identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci.
CONCLUSIONS: Our study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants.

PMID: 24467814 [PubMed - as supplied by publisher]

Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases.

January 29, 2014 - 7:49am
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Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases.

Eur J Med Genet. 2013 Jul;56(7):346-50

Authors: Poot M, Verrijn Stuart AA, van Daalen E, van Iperen A, van Binsbergen E, Hochstenbach R

Abstract
Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree of pre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26 we found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, attention-deficit-hyperactivity disorder, hearing loss and autism, have been found. We discuss clinical ramifications for cases with a loss of 15q26 detected by prenatal array-CGH.

PMID: 23603061 [PubMed - indexed for MEDLINE]

What do repetitive and stereotyped movements mean for infant siblings of children with autism spectrum disorders?

January 29, 2014 - 7:49am
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What do repetitive and stereotyped movements mean for infant siblings of children with autism spectrum disorders?

J Autism Dev Disord. 2013 Jun;43(6):1326-35

Authors: Damiano CR, Nahmias A, Hogan-Brown AL, Stone WL

Abstract
Repetitive and stereotyped movements (RSMs) in infancy are associated with later diagnoses of autism spectrum disorder (ASD), yet this relationship has not been fully explored in high-risk populations. The current study investigated how RSMs involving object and body use are related to diagnostic outcomes in infant siblings of children with ASD (Sibs-ASD) and typically developing children (Sibs-TD). The rate and number of different types of RSMs were measured at an average of 15 months with follow-up diagnostic evaluations approximately 18 months later. While Sibs-ASD displayed higher rates of RSMs relative to Sibs-TD, rates did not differ according to diagnostic outcome in Sibs-ASD. However preliminary evidence suggests that qualitative differences in RSM type warrant further investigation as early diagnostic markers.

PMID: 23080207 [PubMed - indexed for MEDLINE]

Patterns and predictors of anxiety among siblings of children with autism spectrum disorders.

January 29, 2014 - 7:49am
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Patterns and predictors of anxiety among siblings of children with autism spectrum disorders.

J Autism Dev Disord. 2013 Jun;43(6):1336-46

Authors: Shivers CM, Deisenroth LK, Taylor JL

Abstract
The purpose of this study was to examine patterns of anxiety among siblings of children with autism spectrum disorders (ASD), and determine the characteristics of the child with ASD and their parents that predicted anxiety. Data was collected from 1,755 siblings of children with ASD whose families participated in the Simons Simplex Collection; siblings ranged in age from 3 to 18 years (M = 9 years). Male siblings were at increased risk for sub-clinical anxiety problems during middle childhood. Parental history of anxiety disorders, higher maternal pragmatic language, and more proband behavior problems predicted higher anxiety. While siblings overall did not show elevated anxiety symptoms, higher rates of sub-clinical anxiety problems among males and siblings in middle childhood are cause for concern.

PMID: 23076507 [PubMed - indexed for MEDLINE]

Brief report: altered social behavior in isolation-reared Fmr1 knockout mice.

January 29, 2014 - 7:49am
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Brief report: altered social behavior in isolation-reared Fmr1 knockout mice.

J Autism Dev Disord. 2013 Jun;43(6):1452-8

Authors: Heitzer AM, Roth AK, Nawrocki L, Wrenn CC, Valdovinos MG

Abstract
Social behavior abnormalities in Fragile X syndrome (FXS) are characterized by social withdrawal, anxiety, and deficits in social cognition. To assess these deficits, a model of FXS, the Fmr1 knockout mouse (Fmr1 KO), has been utilized. This mouse model has a null mutation in the fragile X mental retardation 1 gene (Fmr1) and displays physical and behavioral characteristics similar to humans with FXS. Several studies have investigated the social behavior of this model, but the results on the behavioral phenotype have not been consistent. In order to further characterize the social behavior in the knockout, isolation-reared Fmr1 KO were evaluated to determine if they differ in their social behavior compared to wild-type littermate controls. Differences by genotype were not observed in social approach behavior; however, the knockout mice showed a significantly reduced preference for social novelty and decreased sniff time in the sociability phase. These findings add to the growing body of knowledge on the subtle differences in social behavior shown by the Fmr1 knockout mice, and that differences occur when the subjects are isolation-reared. Validity of the model and possible changes to methodology are discussed.

PMID: 23015112 [PubMed - indexed for MEDLINE]

Strong genetic influences on measures of behavioral-regulation among inbred rat strains.

January 28, 2014 - 6:46am
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Strong genetic influences on measures of behavioral-regulation among inbred rat strains.

Genes Brain Behav. 2013 Jul;12(5):490-502

Authors: Richards JB, Lloyd DR, Kuehlewind B, Militello L, Paredez M, Solberg Woods L, Palmer AA

Abstract
A fundamental challenge for any complex nervous system is to regulate behavior in response to environmental challenges. Three measures of behavioral-regulation were tested in a panel of eight inbred rat strains. These measures were: (1) sensation seeking as assessed by locomotor response to novelty and the sensory reinforcing effects of light onset, (2) attention and impulsivity, as measured by a choice reaction time task and (3) impulsivity as measured by a delay discounting task. Deficient behavioral-regulation has been linked to a number of psychopathologies, including ADHD, Schizophrenia, Autism, drug abuse and eating disorders. Eight inbred rat strains (August Copenhagen Irish, Brown Norway, Buffalo, Fischer 344, Wistar Kyoto, Spontaneous Hypertensive Rat, Lewis, Dahl Salt Sensitive) were tested. With n = 9 for each strain, we observed robust strain differences for all tasks; heritability was estimated between 0.43 and 0.66. Performance of the eight inbred rat strains on the choice reaction time task was compared to the performance of outbred Sprague Dawley (n = 28) and Heterogeneous strain rats (n = 48). The results indicate a strong genetic influence on complex tasks related to behavioral-regulation and indicate that some of the measures tap common genetically driven processes. Furthermore, our results establish the potential for future studies aimed at identifying specific alleles that influence variability for these traits. Identification of such alleles could contribute to our understanding of the molecular genetic basis of behavioral-regulation, which is of fundamental importance and likely contributes to multiple psychiatric disorders.

PMID: 23710681 [PubMed - indexed for MEDLINE]

Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.

January 25, 2014 - 8:57am

Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.

Environ Health. 2014 Jan 23;13(1):3

Authors: Keil AP, Daniels JL, Hertz-Picciotto I

Abstract
BACKGROUND: The environmental contribution to autism spectrum disorders (ASD) is largely unknown, but household pesticides are receiving increased attention. We examined associations between ASD and maternally-reported use of imidacloprid, a common flea and tick treatment for pets.
METHODS: Bayesian logistic models were used to estimate the association between ASD and imidacloprid and to correct for potential differential exposure misclassification due to recall in a case control study of ASD.
RESULTS: Our analytic dataset included complete information for 262 typically developing controls and 407 children with ASD. Compared with exposure among controls, the odds of prenatal imidacloprid exposure among children with ASD were slightly higher, with an odds ratio (OR) of 1.3 (95% Credible Interval [CrI] 0.78, 2.2). A susceptibility window analysis yielded higher ORs for exposures during pregnancy than for early life exposures, whereas limiting to frequent users of imidacloprid, the OR increased to 2.0 (95% CI 1.0, 3.9).
CONCLUSIONS: Within plausible estimates of sensitivity and specificity, the association could result from exposure misclassification alone. The association between imidacloprid exposure and ASD warrants further investigation, and this work highlights the need for validation studies regarding prenatal exposures in ASD.

PMID: 24456651 [PubMed - as supplied by publisher]

Identifying phenotypic signatures of neuropsychiatric disorders from electronic medical records.

January 25, 2014 - 8:57am
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Identifying phenotypic signatures of neuropsychiatric disorders from electronic medical records.

J Am Med Inform Assoc. 2013 Dec;20(e2):e297-305

Authors: Lyalina S, Percha B, LePendu P, Iyer SV, Altman RB, Shah NH

Abstract
OBJECTIVE: Mental illness is the leading cause of disability in the USA, but boundaries between different mental illnesses are notoriously difficult to define. Electronic medical records (EMRs) have recently emerged as a powerful new source of information for defining the phenotypic signatures of specific diseases. We investigated how EMR-based text mining and statistical analysis could elucidate the phenotypic boundaries of three important neuropsychiatric illnesses-autism, bipolar disorder, and schizophrenia.
METHODS: We analyzed the medical records of over 7000 patients at two facilities using an automated text-processing pipeline to annotate the clinical notes with Unified Medical Language System codes and then searching for enriched codes, and associations among codes, that were representative of the three disorders. We used dimensionality-reduction techniques on individual patient records to understand individual-level phenotypic variation within each disorder, as well as the degree of overlap among disorders.
RESULTS: We demonstrate that automated EMR mining can be used to extract relevant drugs and phenotypes associated with neuropsychiatric disorders and characteristic patterns of associations among them. Patient-level analyses suggest a clear separation between autism and the other disorders, while revealing significant overlap between schizophrenia and bipolar disorder. They also enable localization of individual patients within the phenotypic 'landscape' of each disorder.
CONCLUSIONS: Because EMRs reflect the realities of patient care rather than idealized conceptualizations of disease states, we argue that automated EMR mining can help define the boundaries between different mental illnesses, facilitate cohort building for clinical and genomic studies, and reveal how clear expert-defined disease boundaries are in practice.

PMID: 23956017 [PubMed - indexed for MEDLINE]

Genetic Variants of Neurotransmitter-Related Genes and miRNAs in Egyptian Autistic Patients.

January 24, 2014 - 8:37am

Genetic Variants of Neurotransmitter-Related Genes and miRNAs in Egyptian Autistic Patients.

ScientificWorldJournal. 2013 Dec 23;2013:670621

Authors: Salem AM, Ismail S, Zarouk WA, Abdul Baky O, Sayed AA, Abd El-Hamid S, Salem S

Abstract
Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

PMID: 24453887 [PubMed - in process]

Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders.

January 24, 2014 - 8:37am

Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders.

J Neurosci. 2014 Jan 22;34(4):1420-31

Authors: Xu X, Wells AB, O'Brien DR, Nehorai A, Dougherty JD

Abstract
Recent advances have substantially increased the number of genes that are statistically associated with complex genetic disorders of the CNS such as autism and schizophrenia. It is now clear that there will likely be hundreds of distinct loci contributing to these disorders, underscoring a remarkable genetic heterogeneity. It is unclear whether this genetic heterogeneity indicates an equal heterogeneity of cellular mechanisms for these diseases. The commonality of symptoms across patients suggests there could be a functional convergence downstream of these loci upon a limited number of cell types or circuits that mediate the affected behaviors. One possible mechanism for this convergence would be the selective expression of at least a subset of these genes in the cell types that comprise these circuits. Using profiling data from mice and humans, we have developed and validated an approach, cell type-specific expression analysis, for identifying candidate cell populations likely to be disrupted across sets of patients with distinct genetic lesions. Using human genetics data and postmortem gene expression data, our approach can correctly identify the cell types for disorders of known cellular etiology, including narcolepsy and retinopathies. Applying this approach to autism, a disease where the cellular mechanism is unclear, indicates there may be multiple cellular routes to this disorder. Our approach may be useful for identifying common cellular mechanisms arising from distinct genetic lesions.

PMID: 24453331 [PubMed - in process]

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