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Papers of the Week

  • 1) JAMA Pediatr. 2014 Dec 8. doi: 10.1001/jamapediatrics.2014.2645. [Epub ahead of print]

    Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay.

    Walker CK(1), Krakowiak P(2), Baker A(3), Hansen RL(4), Ozonoff S(5),
    Hertz-Picciotto I(2).
    
    Author information: 
    (1)Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,
    School of Medicine, University of California, Davis2Medical Investigation of
    Neurodevelopmental Disorders (MIND) Institute, University of California, Davis.
    (2)Medical Investigation of Neurodevelopmental Disorders (MIND) Institute,
    University of California, Davis3Department of Public Health Sciences, School of
    Medicine, University of California, Davis.
    (3)Department of Public Health Sciences, School of Medicine, University of
    California, Davis.
    (4)Medical Investigation of Neurodevelopmental Disorders (MIND) Institute,
    University of California, Davis4Department of Pediatrics, School of Medicine,
    University of California, Davis.
    (5)Medical Investigation of Neurodevelopmental Disorders (MIND) Institute,
    University of California, Davis5Department of Psychiatry and Behavioral Sciences,
    School of Medicine, University of California, Davis.
    
    Importance: Increasing evidence suggests that autism spectrum disorder (ASD) and 
    many forms of developmental delay (DD) originate during fetal development.
    Preeclampsia may trigger aberrant neurodevelopment through placental, maternal,
    and fetal physiologic mechanisms.
    Objective: To determine whether preeclampsia is associated with ASD and/or DD.
    Design, Setting, and Participants: The Childhood Autism Risks from Genetics and
    the Environment (CHARGE) study is a population-based, case-control investigation 
    of ASD and/or DD origins. Children from 20 California counties aged 24 to 60
    months at the time of recruitment and living in catchment areas with a biological
    parent fluent in English or Spanish were enrolled from January 29, 2003, through 
    April 7, 2011. Children with ASD (n = 517) and DD (n = 194) were recruited
    through the California Department of Developmental Services, the Medical
    Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals.
    Controls with typical development (TD) (n = 350) were randomly selected from
    birth records and frequency matched on age, sex, and broad geographic region.
    Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and
    those assessing neurodevelopmental function were masked to preeclampsia status.
    Exposures: Preeclampsia and placental insufficiency were self-reported and
    abstracted from medical records.
    Main Outcomes and Measures: The Autism Diagnostic Observation Schedule and Autism
    Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD
    and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive
    Behavior Scales and were free of autistic symptoms. Hypotheses were formulated
    before data collection.
    Results: Children with ASD were twice as likely to have been exposed in utero to 
    preeclampsia as controls with TD after adjustment for maternal educational level,
    parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); 
    risk increased with greater preeclampsia severity (test for trend, P = .02).
    Placental insufficiency appeared responsible for the increase in DD risk
    associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI,
    2.06-14.64).
    Conclusions and Relevance: Preeclampsia, particularly severe disease, is
    associated with ASD and DD. Faulty placentation manifests in the mother as
    preeclampsia with vascular damage, enhanced systemic inflammation, and insulin
    resistance; in the placenta as oxygen and nutrient transfer restriction and
    oxidative stress; and in the fetus as growth restriction and progressive
    hypoxemia. All are potential mechanisms for neurodevelopmental compromise.
    
    PMID: 25485869  [PubMed - as supplied by publisher]
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  • 2) J Neurodev Disord. 2014;6(1):41. Epub 2014 Nov 27.

    Social (pragmatic) communication disorder: a research review of this new DSM-5 diagnostic category.

    Swineford LB(1), Thurm A(1), Baird G(2), Wetherby AM(3), Swedo S(1).
    
    Author information: 
    (1)Pediatrics and Developmental Neuroscience Branch, National Institute of Mental
    Health, 10 Center Drive MSC 1255, Building 10, Room 1C250, Bethesda, MD
    20892-1255 USA.
    (2)Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Paediatric
    Neurosciences St Thomas Hospital, London, SE1 5HE UK.
    (3)Department of Clinical Science, Florida State University, 1940 North Monroe
    Street, Suite 72, Tallahassee, FL 32303 USA.
    
    Social (pragmatic) communication disorder (SCD) is a new diagnostic category in
    the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5).
    The purpose of this review is to describe and synthesize the relevant literature 
    from language and autism spectrum disorder (ASD) research relating to pragmatic
    language impairment and other previously used terms that relate to SCD. The
    long-standing debate regarding how social communication/pragmatic impairments
    overlap and/or differ from language impairments, ASD, and other
    neurodevelopmental disorders is examined. The possible impact of the addition of 
    SCD diagnostic category and directions for future research are also discussed.
    
    PMID: 25484991  [PubMed - as supplied by publisher]
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  • 3) Curr Biol. 2014 Dec 3. pii: S0960-9822(14)01419-5. doi: 10.1016/j.cub.2014.10.071. [Epub ahead of print]

    Neurobeachin Is Required Postsynaptically for Electrical and Chemical Synapse Formation.

    Miller AC(1), Voelker LH(2), Shah AN(3), Moens CB(3).
    
    Author information: 
    (1)Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview
    Avenue N, Seattle, WA 98109, USA. Electronic address: amiller@fhcrc.org.
    (2)Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview
    Avenue N, Seattle, WA 98109, USA; Molecular and Cellular Biology, University of
    Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
    (3)Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview
    Avenue N, Seattle, WA 98109, USA.
    
    BACKGROUND: Neural networks and their function are defined by synapses, which are
    adhesions specialized for intercellular communication that can be either chemical
    or electrical. At chemical synapses, transmission between neurons is mediated by 
    neurotransmitters, whereas at electrical synapses, direct ionic and metabolic
    coupling occur via gap junctions between neurons. The molecular pathways required
    for electrical synaptogenesis are not well understood, and whether they share
    mechanisms of formation with chemical synapses is not clear.
    RESULTS: Here, using a forward genetic screen in zebrafish, we find that the
    autism-associated gene neurobeachin (nbea), which encodes a
    BEACH-domain-containing protein implicated in endomembrane trafficking, is
    required for both electrical and chemical synapse formation. Additionally, we
    find that nbea is dispensable for axonal formation and early dendritic outgrowth 
    but is required to maintain dendritic complexity. These synaptic and
    morphological defects correlate with deficiencies in behavioral performance.
    Using chimeric animals in which individually identifiable neurons are either
    mutant or wild-type, we find that Nbea is necessary and sufficient autonomously
    in the postsynaptic neuron for both synapse formation and dendritic arborization.
    CONCLUSIONS: Our data identify a surprising link between electrical and chemical 
    synapse formation and show that Nbea acts as a critical regulator in the
    postsynaptic neuron for the coordination of dendritic morphology with
    synaptogenesis.
    
    Copyright © 2015 Elsevier Ltd. All rights reserved.
    
    PMID: 25484298  [PubMed - as supplied by publisher]
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  • 4) Biol Psychiatry. 2015 Jan 1;77(1):66-74. doi: 10.1016/j.biopsych.2014.11.001. Epub 2014 Nov 5.

    Genetic Epidemiology and Insights into Interactive Genetic and Environmental Effects in Autism Spectrum Disorders.

    Kim YS(1), Leventhal BL(2).
    
    Author information: 
    (1)Department of Psychiatry, University of California, San Francisco, San Francisco,
    California.. Electronic address: youngshin.kim@ucsf.edu.
    (2)Department of Psychiatry, Yonsei University College of Medicine, Seoul, South
    Korea.
    
    Understanding the pathogenesis of neurodevelopmental disorders has proven to be
    challenging. Using autism spectrum disorder (ASD) as a paradigmatic
    neurodevelopmental disorder, this article reviews the existing literature on the 
    etiological substrates of ASD and explores how genetic epidemiology approaches
    including gene-environment interactions (G×E) can play a role in identifying
    factors associated with ASD etiology. New genetic and bioinformatics strategies
    have yielded important clues to ASD genetic substrates. The next steps for
    understanding ASD pathogenesis require significant effort to focus on how genes
    and environment interact with one another in typical development and its
    perturbations. Along with larger sample sizes, future study designs should
    include sample ascertainment that is epidemiologic and population-based to
    capture the entire ASD spectrum with both categorical and dimensional phenotypic 
    characterization; environmental measurements with accuracy, validity, and
    biomarkers; statistical methods to address population stratification, multiple
    comparisons, and G×E of rare variants; animal models to test hypotheses; and new 
    methods to broaden the capacity to search for G×E, including genome-wide and
    environment-wide association studies, precise estimation of heritability using
    dense genetic markers, and consideration of G×E both as the disease cause and a
    disease course modifier. Although examination of G×E appears to be a daunting
    task, tremendous recent progress in gene discovery has opened new horizons for
    advancing our understanding of the role of G×E in the pathogenesis of ASD and
    ultimately identifying the causes, treatments, and even preventive measures for
    ASD and other neurodevelopmental disorders.
    
    Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All
    rights reserved.
    
    PMID: 25483344  [PubMed - as supplied by publisher]
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  • 5) Biol Psychiatry. 2015 Jan 1;77(1):3-5. doi: 10.1016/j.biopsych.2014.11.003.

    Leveraging genetics and genomics to define the causes of mental illness.

    State MW(1), Geschwind DH(2).
    
    Author information: 
    (1)Department of Psychiatry and Langley Porter Psychiatric Institute, University of 
    California, San Francisco, San Francisco.
    (2)UCLA Center for Autism Research and Treatment, University of California, Los
    Angeles, Los Angeles, California.. Electronic address: dhg@mednet.ucla.edu.
    
    PMID: 25483342  [PubMed - in process]
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  • 6) Nat Commun. 2014 Dec 10;5:5748. doi: 10.1038/ncomms6748.

    Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism.

    Gupta S(1), Ellis SE(1), Ashar FN(1), Moes A(1), Bader JS(2), Zhan J(3), West
    AB(4), Arking DE(1).
    
    Author information: 
    (1)Department of Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns
    Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
    (2)1] Department of Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns 
    Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2]
    Department of Biomedical Engineering, Johns Hopkins University School of
    Medicine, Baltimore, Maryland 21205, USA.
    (3)Department of Biomedical Engineering, Johns Hopkins University School of
    Medicine, Baltimore, Maryland 21205, USA.
    (4)Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama
    35294, USA.
    
    Recent studies of genomic variation associated with autism have suggested the
    existence of extreme heterogeneity. Large-scale transcriptomics should complement
    these results to identify core molecular pathways underlying autism. Here we
    report results from a large-scale RNA sequencing effort, utilizing region-matched
    autism and control brains to identify neuronal and microglial genes robustly
    dysregulated in autism cortical brain. Remarkably, we note that a gene expression
    module corresponding to M2-activation states in microglia is negatively
    correlated with a differentially expressed neuronal module, implicating
    dysregulated microglial responses in concert with altered neuronal
    activity-dependent genes in autism brains. These observations provide pathways
    and candidate genes that highlight the interplay between innate immunity and
    neuronal activity in the aetiology of autism.
    
    PMID: 25494366  [PubMed - as supplied by publisher]
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  • 7) JAMA Psychiatry. 2014 Dec 10. doi: 10.1001/jamapsychiatry.2014.2147. [Epub ahead of print]

    The Role of Parental Cognitive, Behavioral, and Motor Profiles in Clinical Variability in Individuals With Chromosome 16p11.2 Deletions.

    Moreno-De-Luca A(1), Evans DW(2), Boomer KB(3), Hanson E(4), Bernier R(5),
    Goin-Kochel RP(6), Myers SM(7), Challman TD(7), Moreno-De-Luca D(8), Slane MM(9),
    Hare AE(9), Chung WK(10), Spiro JE(11), Faucett WA(12), Martin CL(12), Ledbetter 
    DH(13).
    
    Author information: 
    (1)Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, 
    Pennsylvania2Genomic Medicine Institute, Geisinger Health System, Danville,
    Pennsylvania3Department of Radiology, Geisinger Health System, Danville,
    Pennsylvania4Program in N.
    (2)Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, 
    Pennsylvania4Program in Neuroscience, Bucknell University, Lewisburg,
    Pennsylvania5Department of Psychology, Bucknell University, Lewisburg,
    Pennsylvania.
    (3)Department of Mathematics, Bucknell University, Lewisburg, Pennsylvania.
    (4)Division of Developmental Medicine, Children's Hospital Boston, Boston,
    Massachusetts8Department of Psychiatry, Harvard Medical School, Boston,
    Massachusetts.
    (5)Department of Psychiatry and Behavioral Sciences, University of Washington,
    Seattle.
    (6)Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
    (7)Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, 
    Pennsylvania4Program in Neuroscience, Bucknell University, Lewisburg,
    Pennsylvania11Department of Pediatrics, Geisinger Health System, Danville,
    Pennsylvania.
    (8)Department of Psychiatry, Yale University, New Haven, Connecticut.
    (9)Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, 
    Pennsylvania.
    (10)Simons Foundation, New York, New York14Department of Pediatrics, Columbia
    University, New York, New York15Department of Medicine, Columbia University, New 
    York, New York.
    (11)Simons Foundation, New York, New York.
    (12)Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, 
    Pennsylvania2Genomic Medicine Institute, Geisinger Health System, Danville,
    Pennsylvania.
    (13)Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, 
    Pennsylvania2Genomic Medicine Institute, Geisinger Health System, Danville,
    Pennsylvania4Program in Neuroscience, Bucknell University, Lewisburg,
    Pennsylvania.
    
    Importance: Most disorders caused by copy number variants (CNVs) display
    significant clinical variability, often referred to as incomplete penetrance and 
    variable expressivity. Genetic and environmental sources of this variability are 
    not well understood.
    Objectives: To investigate the contributors to phenotypic variability in probands
    with CNVs involving the same genomic region; to measure the effect size for de
    novo mutation events; and to explore the contribution of familial background to
    resulting cognitive, behavioral, and motor performance outcomes in probands with 
    de novo CNVs.
    Design, Setting, and Participants: Family-based study design with a volunteer
    sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier
    parents and siblings from the Simons Variation in Individuals Project.
    Main Outcomes and Measures: We used linear mixed-model analysis to measure effect
    size and intraclass correlation to determine the influence of family background
    for a de novo CNV on quantitative traits representing the following 3
    neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior
    (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test).
    We included an anthropometric trait, body mass index, for comparison.
    Results: A significant deleterious effect of the 16p11.2 deletion was
    demonstrated across all domains. Relative to the biparental mean, the effect
    sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD
    for neuromotor performance (P < .001). Despite large deleterious effects,
    significant positive correlations between parents and probands were preserved for
    the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the
    Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD
    increase in the body mass index of probands compared with siblings, with an
    intraclass correlation of 0.40 (P = .07).
    Conclusions and Relevance: Analysis of families with de novo CNVs provides the
    least confounded estimate of the effect size of the 16p11.2 deletion on
    heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all
    neurodevelopmental dimensions. Significant parent-proband correlations indicate
    that family background contributes to the phenotypic variability seen in this and
    perhaps other CNV disorders and may have implications for counseling families
    regarding their children's developmental and psychiatric prognoses. Use of
    biparental mean scores rather than general population mean scores may be more
    relevant to examine the effect of a mutation or any other cause of trait
    variation on a neurodevelopmental outcome and possibly on systems of diagnosis
    and trait ascertainment for developmental disorders.
    
    PMID: 25493922  [PubMed - as supplied by publisher]
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