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Papers of the Week

  • 1) Nature. 2015 Mar 11. doi: 10.1038/nature14319. [Epub ahead of print]

    Disruption of DNA-methylation-dependent long gene repression in Rett syndrome.

    Gabel HW(1), Kinde B(1), Stroud H(1), Gilbert CS(1), Harmin DA(1), Kastan NR(1), 
    Hemberg M(2), Ebert DH(1), Greenberg ME(1).
    
    Author information: 
    (1)Department of Neurobiology, Harvard Medical School, Boston, Massachusetts
    02115, USA. (2)Department of Ophthalmology, Children's Hospital Boston, Center
    for Brain Science and Swartz Center for Theoretical Neuroscience, Harvard
    University, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
    
    Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological 
    disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that
    has been proposed to function as a transcriptional repressor, but despite
    numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no
    clear model has emerged for how MeCP2 protein regulates transcription. Here we
    identify a genome-wide length-dependent increase in gene expression in MeCP2
    mutant mouse models and human RTT brains. We present evidence that MeCP2
    represses gene expression by binding to methylated CA sites within long genes,
    and that in neurons lacking MeCP2, decreasing the expression of long genes
    attenuates RTT-associated cellular deficits. In addition, we find that long genes
    as a population are enriched for neuronal functions and selectively expressed in 
    the brain. These findings suggest that mutations in MeCP2 may cause neurological 
    dysfunction by specifically disrupting long gene expression in the brain.
    
    PMID: 25762136  [PubMed - as supplied by publisher]
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  • 2) Neurobiol Dis. 2015 Mar 10. pii: S0969-9961(15)00042-X. doi: 10.1016/j.nbd.2015.02.015. [Epub ahead of print]

    Alterations in sociability and functional brain connectivity caused by early-life seizures are reversed by bumetanide.

    Holmes GL(1), Tian C(2), Hernan AE(2), Flynn S(2), Camp D(2), Barry J(2).
    
    Author information: 
    (1)Department of Neurological Sciences, University of Vermont College of
    Medicine, Burlington, VT 05405, USA. Electronic address: Gregory.holmes@uvm.edu. 
    (2)Department of Neurological Sciences, University of Vermont College of
    Medicine, Burlington, VT 05405, USA.
    
    There is a well-described association between infantile epilepsy and pervasive
    cognitive and behavioral deficits, including a high incidence of autism spectrum 
    disorders. Despite the robustness of the relationship between early-life seizures
    and the development of autism, the pathophysiological mechanism by which this
    occurs has not been explored. As a result of increasing evidence that autism is a
    disorder of brain connectivity we hypothesized that early-life seizures would
    interrupt normal brain connectivity during brain maturation and result in an
    autistic phenotype. Normal rat pups underwent recurrent flurothyl-induced
    seizures from postnatal (P) days 5-14 and then tested, along with controls, for
    developmental alterations of development brain oscillatory activity from P18-P25.
    Specifically we wished to understand how normal changes in rhythmicity in and
    between brain regions change as a function of age and if this rhythmicity is
    altered or interrupted by early life seizures. In rat pups with early-life
    seizures, field recordings from dorsal and ventral hippocampus and prefrontal
    cortex demonstrated marked increase in coherence as well as a decrease in voltage
    correlation at all bandwidths compared to controls while there were minimal
    differences in total power and relative power spectral densities. Rats with
    early-life seizures had resulting impairment in the sociability and social
    novelty tests but demonstrated no evidence of increased activity or generalized
    anxiety as measured in the open field. In addition, rats with early-life seizures
    had lower seizure thresholds than controls, indicating long-standing alterations 
    in the excitatory/inhibition balance. Bumetanide, a pharmacological agent that
    blocks the activity of NKCC1 and induces a significant shift of ECl toward more
    hyperpolarized values, administration at the time of the seizures precluded the
    subsequent abnormalities in coherence and voltage correlation and resulted in
    normal sociability and seizure threshold. Taken together these findings indicate 
    that early-life seizures alter the development of oscillations and result in
    autistic-like behaviors. The altered communication between these brain regions
    could reflect the physiological underpinnings underlying social cognitive
    deficits seen in autism spectrum disorders.
    
    Copyright © 2015 Elsevier Inc. All rights reserved.
    
    PMID: 25766676  [PubMed - as supplied by publisher]
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  • 3) Psychoneuroendocrinology. 2015 Feb 26;55:128-143. doi: 10.1016/j.psyneuen.2015.02.016. [Epub ahead of print]

    Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice.

    Kohl C(1), Wang XD(2), Grosse J(3), Fournier C(3), Harbich D(4), Westerholz S(4),
    Li JT(5), Bacq A(3), Sippel C(4), Hausch F(4), Sandi C(3), Schmidt MV(6).
    
    Author information: 
    (1)Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life
    Sciences, École Polytechnique Fédérale de Lausanne, EPFL, 1015 Lausanne,
    Switzerland; Max Planck Institute of Psychiatry, Department of Stress
    Neurobiology and Neurogenetics, 80804 Munich, Germany. (2)Max Planck Institute of
    Psychiatry, Department of Stress Neurobiology and Neurogenetics, 80804 Munich,
    Germany; Department of Neurobiology, Key Laboratory of Medical Neurobiology of
    Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology,
    Zhejiang University School of Medicine, 310058 Hangzhou, China. (3)Laboratory of 
    Behavioral Genetics, Brain Mind Institute, School of Life Sciences, École
    Polytechnique Fédérale de Lausanne, EPFL, 1015 Lausanne, Switzerland. (4)Max
    Planck Institute of Psychiatry, Department of Stress Neurobiology and
    Neurogenetics, 80804 Munich, Germany. (5)Institute of Mental Health, Peking
    University, No. 51 Hua Yuan Bei Road, 100191 Beijing, China. (6)Max Planck
    Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics,
    80804 Munich, Germany. Electronic address: mschmidt@mpipsykl.mpg.de.
    
    Early-life stress is a key risk factor for the development of neuropsychiatric
    disorders later in life. Neuronal cell adhesion molecules have been strongly
    implicated in the pathophysiology of psychiatric disorders and in modulating
    social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell 
    adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic
    synapses, and is involved in synaptic stabilization and maturation. Alterations
    in neuroligin-2 expression have previously been associated with changes in social
    behavior linked to psychiatric disorders, including schizophrenia and autism. In 
    this study, we show that early-life stress, induced by limited nesting and
    bedding material, leads to impaired social recognition and increased aggression
    in adult mice, accompanied by increased expression levels of hippocampal
    neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood
    mimics early-life stress-induced alterations in social behavior and social
    cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus
    attenuates the early-life stress-induced behavioral changes. Our results
    highlight the importance of neuroligin-2 in mediating early-life stress effects
    on social behavior and social cognition and its promising role as a novel
    therapeutic target for neuropsychiatric disorders.
    
    Copyright © 2015 Elsevier Ltd. All rights reserved.
    
    PMID: 25765754  [PubMed - as supplied by publisher]
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  • 4) Nucleic Acids Res. 2015 Mar 11. pii: gkv164. [Epub ahead of print]

    Genome engineering of isogenic human ES cells to model autism disorders.

    Martinez RA(1), Stein JL(2), Krostag AR(1), Nelson AM(1), Marken JS(1), Menon
    V(1), May RC(1), Yao Z(1), Kaykas A(1), Geschwind DH(3), Grimley JS(4).
    
    Author information: 
    (1)Allen Institute for Brain Science, Seattle, WA 98103, USA. (2)Neurogenetics
    Program, Department of Neurology, Center for Autism Research and Treatment, Semel
    Institute, David Geffen School of Medicine, University of California, Los
    Angeles, Los Angeles, CA 90095, USA. (3)Neurogenetics Program, Department of
    Neurology, Center for Autism Research and Treatment, Semel Institute, David
    Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
    90095, USA dhg@mednet.ucla.edu. (4)Allen Institute for Brain Science, Seattle, WA
    98103, USA joshuag@alleninstitute.org.
    
    Isogenic pluripotent stem cells are critical tools for studying human
    neurological diseases by allowing one to study the effects of a mutation in a
    fixed genetic background. Of particular interest are the spectrum of autism
    disorders, some of which are monogenic such as Timothy syndrome (TS); others are 
    multigenic such as the microdeletion and microduplication syndromes of the
    16p11.2 chromosomal locus. Here, we report engineered human embryonic stem cell
    (hESC) lines for modeling these two disorders using locus-specific endonucleases 
    to increase the efficiency of homology-directed repair (HDR). We developed a
    system to: (1) computationally identify unique transcription activator-like
    effector nuclease (TALEN) binding sites in the genome using a new software
    program, TALENSeek, (2) assemble the TALEN genes by combining golden gate cloning
    with modified constructs from the FLASH protocol, and (3) test the TALEN pairs in
    an amplification-based HDR assay that is more sensitive than the typical
    non-homologous end joining assay. We applied these methods to identify,
    construct, and test TALENs that were used with HDR donors in hESCs to generate an
    isogenic TS cell line in a scarless manner and to model the 16p11.2 copy number
    disorder without modifying genomic loci with high sequence similarity.
    
    © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic
    Acids Research.
    
    PMID: 25765640  [PubMed - as supplied by publisher]
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  • 5) Brain. 2015 Mar 12. pii: awv043. [Epub ahead of print]

    Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale.

    Khan S(1), Michmizos K(1), Tommerdahl M(2), Ganesan S(1), Kitzbichler MG(1),
    Zetino M(1), Garel KL(1), Herbert MR(1), Hämäläinen MS(3), Kenet T(4).
    
    Author information: 
    (1)1 Department of Neurology, MGH, Harvard Medical School, Boston, MA, USA 2 A.A.
    Martinos Centre for Biomedical Imaging, MGH/MIT/Harvard, Boston, MA, USA. (2)3
    Department of Biomedical Engineering, University of North Carolina at Chapel
    Hill, Chapel Hill, North Carolina, USA. (3)2 A.A. Martinos Centre for Biomedical 
    Imaging, MGH/MIT/Harvard, Boston, MA, USA 4 Department of Radiology, MGH, Harvard
    Medical School, Boston, MA, USA 5 Department of Neuroscience and Biomedical
    Engineering, Aalto University School of Science, Espoo, Finland. (4)1 Department 
    of Neurology, MGH, Harvard Medical School, Boston, MA, USA 2 A.A. Martinos Centre
    for Biomedical Imaging, MGH/MIT/Harvard, Boston, MA, USA tal@nmr.mgh.harvard.edu.
    
    Functional connectivity is abnormal in autism, but the nature of these
    abnormalities remains elusive. Different studies, mostly using functional
    magnetic resonance imaging, have found increased, decreased, or even mixed
    pattern functional connectivity abnormalities in autism, but no unifying
    framework has emerged to date. We measured functional connectivity in individuals
    with autism and in controls using magnetoencephalography, which allowed us to
    resolve both the directionality (feedforward versus feedback) and spatial scale
    (local or long-range) of functional connectivity. Specifically, we measured the
    cortical response and functional connectivity during a passive 25-Hz vibrotactile
    stimulation in the somatosensory cortex of 20 typically developing individuals
    and 15 individuals with autism, all males and right-handed, aged 8-18, and the
    mu-rhythm during resting state in a subset of these participants (12 per group,
    same age range). Two major significant group differences emerged in the response 
    to the vibrotactile stimulus. First, the 50-Hz phase locking component of the
    cortical response, generated locally in the primary (S1) and secondary (S2)
    somatosensory cortex, was reduced in the autism group (P < 0.003, corrected).
    Second, feedforward functional connectivity between S1 and S2 was increased in
    the autism group (P < 0.004, corrected). During resting state, there was no group
    difference in the mu-α rhythm. In contrast, the mu-β rhythm, which has been
    associated with feedback connectivity, was significantly reduced in the autism
    group (P < 0.04, corrected). Furthermore, the strength of the mu-β was correlated
    to the relative strength of 50 Hz component of the response to the vibrotactile
    stimulus (r = 0.78, P < 0.00005), indicating a shared aetiology for these
    seemingly unrelated abnormalities. These magnetoencephalography-derived measures 
    were correlated with two different behavioural sensory processing scores (P <
    0.01 and P < 0.02 for the autism group, P < 0.01 and P < 0.0001 for the typical
    group), with autism severity (P < 0.03), and with diagnosis (89% accuracy). A
    biophysically realistic computational model using data driven feedforward and
    feedback parameters replicated the magnetoencephalography data faithfully. The
    direct observation of both abnormally increased and abnormally decreased
    functional connectivity in autism occurring simultaneously in different
    functional connectivity streams, offers a potential unifying framework for the
    unexplained discrepancies in current findings. Given that cortical feedback,
    whether local or long-range, is intrinsically non-linear, while cortical
    feedforward is generally linear relative to the stimulus, the present results
    suggest decreased non-linearity alongside an increased veridical component of the
    cortical response in autism.
    
    © The Author (2015). Published by Oxford University Press on behalf of the
    Guarantors of Brain. All rights reserved. For Permissions, please email:
    journals.permissions@oup.com.
    
    PMID: 25765326  [PubMed - as supplied by publisher]
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  • 6) Mol Autism. 2015 Mar 11;6:15. doi: 10.1186/s13229-015-0001-8. eCollection 2015.

    Atypical development of white matter microstructure of the corpus callosum in males with autism: a longitudinal investigation.

    Travers BG(1), Tromp do PM(2), Adluru N(3), Lange N(4), Destiche D(3), Ennis
    C(3), Nielsen JA(5), Froehlich AL(6), Prigge MB(7), Fletcher PT(8), Anderson
    JS(9), Zielinski BA(10), Bigler ED(11), Lainhart JE(2), Alexander AL(2).
    
    Author information: 
    (1)Occupational Therapy Program, Department of Kinesiology, University of
    Wisconsin-Madison, Madison, WI USA ; Waisman Center, University of
    Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705 USA. (2)Waisman
    Center, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705 
    USA ; Department of Psychiatry, University of Wisconsin-Madison, Madison, WI USA.
    (3)Waisman Center, University of Wisconsin-Madison, 1500 Highland Avenue,
    Madison, WI 53705 USA. (4)Department of Psychiatry, Harvard School of Medicine,
    Boston, MA USA ; Neurostatistics Laboratory, McLean Hospital, Belmont, MA USA.
    (5)Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City,
    UT USA. (6)Scientific Computing and Imaging Institute, University of Utah, Salt
    Lake City, UT USA. (7)Department of Radiology, University of Utah, Salt Lake
    City, UT USA ; Department of Pediatrics, University of Utah and Primary
    Children's Medical Center, Salt Lake City, UT USA. (8)Scientific Computing and
    Imaging Institute, University of Utah, Salt Lake City, UT USA ; School of
    Computing, University of Utah, Salt Lake City, UT USA. (9)Interdepartmental
    Program in Neuroscience, University of Utah, Salt Lake City, UT USA ; Department 
    of Radiology, University of Utah, Salt Lake City, UT USA. (10)Department of
    Pediatrics, University of Utah and Primary Children's Medical Center, Salt Lake
    City, UT USA ; Department of Neurology, University of Utah, Salt Lake City, UT
    USA. (11)Department of Psychology, Brigham Young University, Provo, UT USA ;
    Neuroscience Center, Brigham Young University, Provo, UT 84602 USA.
    
    BACKGROUND: The corpus callosum is the largest white matter structure in the
    brain, and it is the most consistently reported to be atypical in diffusion
    tensor imaging studies of autism spectrum disorder. In individuals with typical
    development, the corpus callosum is known to undergo a protracted development
    from childhood through young adulthood. However, no study has longitudinally
    examined the developmental trajectory of corpus callosum in autism past early
    childhood.
    METHODS: The present study used a cohort sequential design over 9 years to
    examine age-related changes of the corpus callosum in 100 males with autism and
    56 age-matched males with typical development from early childhood (when autism
    can first be reliably diagnosed) to mid-adulthood (after development of the
    corpus callosum has been completed) (3 to 41 years of age).
    RESULTS: The group with autism demonstrated a different developmental trajectory 
    of white matter microstructure in the anterior corpus callosum's (genu and body) 
    fractional anisotropy, which suggests atypical brain maturation in these regions 
    in autism. When analyses were broken down by age group, atypical developmental
    trajectories were present only in the youngest participants (10 years of age and 
    younger). Significant main effects for group were found in terms of decreased
    fractional anisotropy across all three subregions of the corpus callosum (genu,
    body, and splenium) and increased mean diffusivity, radial diffusivity, and axial
    diffusivity in the posterior corpus callosum.
    CONCLUSIONS: These longitudinal results suggest atypical early childhood
    development of the corpus callosum microstructure in autism that transitions into
    sustained group differences in adolescence and adulthood. This pattern of results
    provides longitudinal evidence consistent with a growing number of published
    studies and hypotheses regarding abnormal brain connectivity across the life span
    in autism.
    
    PMID: 25774283  [PubMed]
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  • 7) Mol Autism. 2015 Mar 6;6:12. doi: 10.1186/s13229-015-0006-3. eCollection 2015.

    Autistic children at risk of being underestimated: school-based pilot study of a strength-informed assessment.

    Courchesne V(1), Meilleur AA(1), Poulin-Lord MP(1), Dawson M(1), Soulières I(2).
    
    Author information: 
    (1)Rivière-des-prairies Hospital, Centre d'Excellence en Troubles Envahissants du
    Développement de l'Université de Montréal (CETEDUM), 7070 boulevard Perras,
    Montréal, QC H1E 1A4 Canada. (2)Rivière-des-prairies Hospital, Centre
    d'Excellence en Troubles Envahissants du Développement de l'Université de
    Montréal (CETEDUM), 7070 boulevard Perras, Montréal, QC H1E 1A4 Canada ;
    Psychology Department, Université du Québec à Montréal, C.P. 8888 succursale
    Centre-ville, Montréal, H3C 3P8 Canada.
    
    BACKGROUND: An important minority of school-aged autistic children, often
    characterized as 'nonverbal' or 'minimally verbal,' displays little or no spoken 
    language. These children are at risk of being judged 'low-functioning' or
    'untestable' via conventional cognitive testing practices. One neglected avenue
    for assessing autistic children so situated is to engage current knowledge of
    autistic cognitive strengths. Our aim was thus to pilot a strength-informed
    assessment of autistic children whose poor performance on conventional
    instruments suggests their cognitive potential is very limited.
    METHODS: Thirty autistic children (6 to 12 years) with little or no spoken
    language, attending specialized schools for autistic children with the highest
    levels of impairment, were assessed using Wechsler Intelligence Scale for
    Children (WISC-IV), Raven's Colored Progressive Matrices board form (RCPM),
    Children's Embedded Figures Test (CEFT), and a visual search task. An age-matched
    control group of 27 typical children was also assessed.
    RESULTS: None of the autistic children could complete WISC-IV; only six completed
    any subtest. In contrast, 26 autistic children could complete RCPM, with 17
    scoring between the 5th and 90th percentile. Twenty-seven autistic children
    completed the visual search task, while 26 completed CEFT, on which autistic
    children were faster than RCPM-matched typical children. Autistic performance on 
    RCPM, CEFT, and visual search were correlated.
    CONCLUSION: These results indicate that 'minimally verbal' or 'nonverbal'
    school-aged autistic children may be at risk of being underestimated: they may be
    wrongly regarded as having little cognitive potential. Our findings support the
    usefulness of strength-informed approaches to autism and have important
    implications for the assessment and education of autistic children.
    
    PMID: 25774281  [PubMed]
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  • 8) Transl Psychiatry. 2015 Mar 17;5:e529. doi: 10.1038/tp.2015.23.

    Developmental white matter microstructure in autism phenotype and corresponding endophenotype during adolescence.

    Lisiecka DM(1), Holt R(2), Tait R(3), Ford M(4), Lai MC(5), Chura LR(2),
    Baron-Cohen S(6), Spencer MD(7), Suckling J(8).
    
    Author information: 
    (1)1] Brain Mapping Unit, Department of Psychiatry, University of Cambridge,
    Cambridge, UK [2] Department of Psychiatry, Behavioural and Clinical Neuroscience
    Institute, University of Cambridge, Cambridge, UK. (2)Autism Research Centre,
    Department of Psychiatry, University of Cambridge, Cambridge, UK. (3)Department
    of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of
    Cambridge, Cambridge, UK. (4)Department of Physics, University of Cambridge,
    Cambridge, UK. (5)1] Autism Research Centre, Department of Psychiatry, University
    of Cambridge, Cambridge, UK [2] Department of Psychiatry, National Taiwan
    University Hospital and College of Medicine, Taipei, Taiwan. (6)1] Department of 
    Psychiatry, Behavioural and Clinical Neuroscience Institute, University of
    Cambridge, Cambridge, UK [2] Autism Research Centre, Department of Psychiatry,
    University of Cambridge, Cambridge, UK [3] Cambridge and Peterborough NHS
    Foundation Trust, Cambridge, UK. (7)1] Autism Research Centre, Department of
    Psychiatry, University of Cambridge, Cambridge, UK [2] West Suffolk Hospital NHS 
    Trust, Bury St Edmunds, UK. (8)1] Brain Mapping Unit, Department of Psychiatry,
    University of Cambridge, Cambridge, UK [2] Department of Psychiatry, Behavioural 
    and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK [3]
    Cambridge and Peterborough NHS Foundation Trust, Cambridge, UK.
    
    During adolescence, white matter microstructure undergoes an important stage of
    development. It is hypothesized that the alterations of brain connectivity that
    have a key role in autism spectrum conditions (ASCs) may interact with the
    development of white matter microstructure. This interaction may be present
    beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to
    20 times more likely to develop certain forms of ASC. We use diffusion tensor
    imaging to examine how white matter microstructure measurements correlate with
    age in typically developing individuals, and how this correlation differs in n=43
    adolescents with ASC and their n=38 siblings. Correlations observed in n=40
    typically developing individuals match developmental changes noted in previous
    longitudinal studies. In comparison, individuals with ASC display weaker negative
    correlation between age and mean diffusivity in a broad area centred in the right
    superior longitudinal fasciculus. These differences may be caused either by
    increased heterogeneity in ASC or by temporal alterations in the group's
    developmental pattern. Siblings of individuals with ASC also show diminished
    negative correlation between age and one component of mean diffusivity-second
    diffusion eigenvalue-in the right superior longitudinal fasciculus. As the
    observed differences match for location and correlation directionality in our
    comparison of typically developing individuals to those with ASC and their
    siblings, we propose that these alterations constitute a part of the
    endophenotype of autism.
    
    PMID: 25781228  [PubMed - as supplied by publisher]
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  • 9) J Autism Dev Disord. 2015 Mar 17. [Epub ahead of print]

    A Review of Level 2 Parent-Report Instruments Used to Screen Children Aged 1.5-5 for Autism: A Meta-Analytic Update.

    Hampton J(1), Strand PS.
    
    Author information: 
    (1)Department of Psychology, Washington State University, Pullman, WA,
    99164-4820, USA, justin.hampton@email.wsu.edu.
    
    The present study utilized meta-analytic procedures to estimate the diagnostic
    validity of instruments used to screen young children, ages 1.5-5 years, for
    autism. Five scales met inclusion criteria, and data from 18 studies contributed 
    the meta-analysis. Results revealed that 4 of 5 scales met criteria for "good"
    validity, including two broad band scales (instruments not restricted to
    screening for autism). The current results suggest that validity differences
    might be a function of how instruments sample across the DSM content domains.
    Specifically, high validity instruments included a higher proportion of items
    assessing social interaction skills. The availability of valid broad- and
    narrow-band instruments, as well as implications for constructing future
    screening instruments, is discussed.
    
    PMID: 25778838  [PubMed - as supplied by publisher]
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  • 10) J Abnorm Child Psychol. 2015 Mar 17. [Epub ahead of print]

    Predicting Outcome of Community-Based Early Intensive Behavioral Intervention for Children with Autism.

    Smith T(1), Klorman R, Mruzek DW.
    
    Author information: 
    (1)Division of Neurodevelopmental and Behavioral Pediatrics, Department of
    Pediatrics, Saunders Research Building, University of Rochester Medical Center,
    265 Crittenden Blvd., Rochester, NY, 14620, USA,
    tristram_smith@urmc.rochester.edu.
    
    We examined predictors of outcome (IQ, adaptive behavior, and ASD severity) after
    12 and 24 months of early intensive behavioral intervention (EIBI) in 71,
    20-59 months old children with autism spectrum disorder (ASD) who were enrolled
    in publicly-funded, community-based agencies. Predictors included social
    engagement (combining variables loading onto a single factor: social approach,
    joint attention, and imitation) and sensorimotor rituals. Younger age and higher 
    IQ at intake predicted favorable outcomes at both 12 and 24 months. Adjusting for
    age, IQ, baseline predictor scores, EIBI hours, treatment site, and sensorimotor 
    rituals, social engagement predicted superior later IQ and adaptive behavior. In 
    contrast, sensorimotor rituals did not predict outcome. Although limited by the
    absence of a control group, the study indicates social engagement predicts some
    EIBI outcomes.
    
    PMID: 25778537  [PubMed - as supplied by publisher]
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  • 11) Mol Psychiatry. 2015 Mar 17. doi: 10.1038/mp.2015.20. [Epub ahead of print]

    Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.

    Chanda S(1), Aoto J(2), Lee SJ(2), Wernig M(3), Südhof TC(2).
    
    Author information: 
    (1)1] Department of Molecular and Cellular Physiology and Howard Hughes Medical
    Institute, Stanford University School of Medicine, Stanford, CA, USA [2]
    Institute for Stem Cell Biology and Regenerative Medicine and Department of
    Pathology, Stanford University School of Medicine, Stanford, CA, USA.
    (2)Department of Molecular and Cellular Physiology and Howard Hughes Medical
    Institute, Stanford University School of Medicine, Stanford, CA, USA.
    (3)Institute for Stem Cell Biology and Regenerative Medicine and Department of
    Pathology, Stanford University School of Medicine, Stanford, CA, USA.
    
    Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic
    neurexins. Although the general synaptic role of neuroligins is undisputed, their
    specific functions at a synapse remain unclear, even controversial. Moreover,
    many neuroligin gene mutations were associated with autism, but the
    pathophysiological relevance of these mutations is often unknown, and their
    mechanisms of action uninvestigated. Here, we examine the synaptic effects of an 
    autism-associated neuroligin-4 substitution (called R704C), which mutates a
    cytoplasmic arginine residue that is conserved in all neuroligins. We show that
    the R704C mutation, when introduced into neuroligin-3, enhances the interaction
    between neuroligin-3 and AMPA receptors, increases AMPA-receptor internalization 
    and decreases postsynaptic AMPA-receptor levels. When introduced into
    neuroligin-4, conversely, the R704C mutation unexpectedly elevated
    AMPA-receptor-mediated synaptic responses. These results suggest a general
    functional link between neuroligins and AMPA receptors, indicate that both
    neuroligin-3 and -4 act at excitatory synapses but perform surprisingly distinct 
    functions, and demonstrate that the R704C mutation significantly impairs the
    normal function of neuroligin-4, thereby validating its pathogenicity.Molecular
    Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.20.
    
    PMID: 25778475  [PubMed - as supplied by publisher]
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  • 12) Matern Child Health J. 2015 Mar 17. [Epub ahead of print]

    Parental Age and Autism Spectrum Disorders Among New York City Children 0-36 Months of Age.

    Quinlan CA(1), McVeigh KH, Driver CR, Govind P, Karpati A.
    
    Author information: 
    (1)Division of Mental Hygiene, New York City Department of Health and Mental
    Hygiene, 42-09 28th Street, Queens, NY, 11101, USA, carol.quinlan@nyumc.org.
    
    We examined trends in autism spectrum disorders (ASD) and the association of ASD 
    with parental age among young New York City (NYC) children. Children born in NYC 
    to resident mothers from 1994-2001 were identified through vital statistics
    records (N = 927,003). Records were linked to data from NYC Early Intervention
    (EI) Program through 2004. The independent parental age-specific odds of having
    an ASD before 36 months of age were estimated using multiple logistic regression 
    controlling for risk factors. The increase in ASD attributable to changes in
    parental age at birth was examined. Births to mothers and fathers 35 years or
    older increased 14.9 and 11.5 %, respectively, between 1994 and 2001. ASD
    prevalence in EI increased significantly from 1 in 3,300 children born in 1994 to
    1 in 233 children born in 2001. Children born to mothers ages 25-29, 30-34 and 35
    or older had significantly greater odds of being diagnosed with ASD than children
    of mothers younger than 25 years (OR 1.5, 1.6, and 1.9, respectively). Children
    born to fathers ages 35 or older (OR 1.4) had greater odds of ASD than children
    of fathers younger than 25. The change in parental age accounted for only 2.7 %
    of the increase in ASD prevalence. Older paternal age and maternal age were
    independently associated with increased risk of ASD. However, while parental age 
    at birth increased between the 1994 and 2001 birth cohorts in NYC, it did not
    explain the increase in number of ASD cases.
    
    PMID: 25776271  [PubMed - as supplied by publisher]
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  • 13) BMC Med Genomics. 2015;8 Suppl 1:S7. doi: 10.1186/1755-8794-8-S1-S7. Epub 2015 Jan 15.

    Performance of case-control rare copy number variation annotation in classification of autism.

    Engchuan W, Dhindsa K, Lionel AC, Scherer SW, Chan JH, Merico D.
    
    BACKGROUND: A substantial proportion of Autism Spectrum Disorder (ASD) risk
    resides in de novo germline and rare inherited genetic variation. In particular, 
    rare copy number variation (CNV) contributes to ASD risk in up to 10% of ASD
    subjects. Despite the striking degree of genetic heterogeneity, case-control
    studies have detected specific burden of rare disruptive CNV for neuronal and
    neurodevelopmental pathways. Here, we used machine learning methods to classify
    ASD subjects and controls, based on rare CNV data and comprehensive gene
    annotations. We investigated performance of different methods and estimated the
    percentage of ASD subjects that could be reliably classified based on presumed
    etiologic CNV they carry.
    RESULTS: We analyzed 1,892 Caucasian ASD subjects and 2,342 matched controls.
    Rare CNVs (frequency 1% or less) were detected using Illumina 1M and 1M-Duo
    BeadChips. Conditional Inference Forest (CF) typically performed as well as or
    better than other classification methods. We found a maximum AUC (area under the 
    ROC curve) of 0.533 when considering all ASD subjects with rare genic CNVs,
    corresponding to 7.9% correctly classified ASD subjects and less than 3%
    incorrectly classified controls; performance was significantly higher when
    considering only subjects harboring de novo or pathogenic CNVs. We also found
    rare losses to be more predictive than gains and that curated neurally-relevant
    annotations (brain expression, synaptic components and neurodevelopmental
    phenotypes) outperform Gene Ontology and pathway-based annotations.
    CONCLUSIONS: CF is an optimal classification approach for case-control rare CNV
    data and it can be used to prioritize subjects with variants potentially
    contributing to ASD risk not yet recognized. The neurally-relevant annotations
    used in this study could be successfully applied to rare CNV case-control
    data-sets for other neuropsychiatric disorders.
    
    PMID: 25783485  [PubMed - in process]
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  • 14) Eur J Hum Genet. 2015 Mar 18. doi: 10.1038/ejhg.2015.37. [Epub ahead of print]

    Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.

    Torrico B(1), Fernàndez-Castillo N(1), Hervás A(2), Milà M(3), Salgado M(2),
    Rueda I(4), Buitelaar JK(5), Rommelse N(6), Oerlemans AM(5), Bralten J(7),
    Freitag CM(8), Reif A(9), Battaglia A(10), Mazzone L(11), Maestrini E(12),
    Cormand B(1), Toma C(1).
    
    Author information: 
    (1)1] Departament de Genètica, Universitat de Barcelona, Barcelona, Spain [2]
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER),
    Barcelona, Spain [3] Institut de Biomedicina de la Universitat de Barcelona,
    Barcelona, Spain. (2)1] Child and Adolescent Mental Health Unit, Hospital
    Universitari Mútua de Terrassa, Terrassa, Spain [2] Developmental Disorders Unit 
    (UETD), Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain. (3)1] Centro de
    Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain 
    [2] Biochemistry and Molecular Genetics Department, Hospital Clinic, IDIBAPS,
    Barcelona, Spain. (4)Developmental Disorders Unit (UETD), Hospital Sant Joan de
    Déu, Esplugues de Llobregat, Spain. (5)1] Radboud University Medical Center,
    Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive
    Neuroscience, Nijmegen, The Netherlands [2] Karakter Child and Adolescent
    Psychiatry University Center, Nijmegen, The Netherlands. (6)1] Karakter Child and
    Adolescent Psychiatry University Center, Nijmegen, The Netherlands [2] Radboud
    University Medical Center, Donders Institute for Brain, Cognition and Behaviour, 
    Department of Psychiatry, Nijmegen, The Netherlands. (7)1] Radboud University
    Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department 
    of Cognitive Neuroscience, Nijmegen, The Netherlands [2] Radboud University
    Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department 
    of Human Genetics, Nijmegen, The Netherlands. (8)Department of Child and
    Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe-University
    Frankfurt am Main, Frankfurt, Germany. (9)Department of Psychiatry,
    Psychosomatics and Psychotherapy, JW Goethe-University Frankfurt am Main,
    Frankfurt, Germany. (10)Stella Maris Clinical Research Institute for Child and
    Adolescent Neuropsychiatry, Calambrone, Pisa, Italy. (11)Child Neuropsychiatry
    Unit, Department of Neuroscience, I.R.C.C.S. Children's Hospital Bambino Gesù,
    Rome, Italy. (12)Department of Pharmacy and Biotechnology, University of Bologna,
    Bologna, Italy.
    
    Recent findings revealed rare copy number variants and missense changes in the
    X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual
    disability (ID). Here, we aim to explore the contribution of common PTCHD1
    variants in ASD and gain additional evidence for the role of rare variants of
    this gene in ASD and ID. A two-stage case-control association study investigated 
    28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls 
    from four European populations. Mutation screening was performed in 673
    individuals who included 240 ASD cases, 183 ID patients and 250 controls. The
    case-control association study showed a significant association with rs7052177
    (P=6.13E-4) in the ASD discovery sample that was replicated in an independent
    sample (P=0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the
    four European populations showed an odds ratio of 0.58 (P=7E-05). This SNP is
    predicted to be located in a transcription factor binding site. No rare missense 
    PTCHD1 variants were found in our ASD cohort and only one was identified in the
    ID sample. A duplication (27 bp) in the promoter region, absent from 590
    controls, was found in three ASD patients (Fisher exact test, P=0.024). A gene
    reporter assay showed a significant decrease in the transcriptional activity
    (26%) driven by this variant. Moreover, we found that the longest allele of a
    trinucleotide repeat located upstream from PTCHD1 was associated with ASD
    (P=0.003, permP=0.0186). Our results further support the involvement of PTCHD1 in
    ASD, suggesting that both common and rare variants contribute to the
    disorder.European Journal of Human Genetics advance online publication, 18 March 
    2015; doi:10.1038/ejhg.2015.37.
    
    PMID: 25782667  [PubMed - as supplied by publisher]
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