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  • Guanfacine treatment improves ADHD phenotypes of impulsivity and hyperactivity in a neurofibromatosis type 1 mouse model
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2020-01-15
    J. L. Lukkes; H. P. Drozd; S. D. Fitz; A. I. Molosh; D. W. Clapp; A. Shekhar

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a mutation in one copy of the neurofibromin gene (NF1+/−). Even though approximately 40–60% of children with NF1 meet the criteria for attention deficit hyperactivity disorder (ADHD), very few preclinical studies, if any, have investigated alterations in impulsivity and risk-taking behavior. Mice with deletion of a single NF1 gene (Nf1+/−) recapitulate many of the phenotypes of NF1 patients. We compared wild-type (WT) and Nf1+/− mouse strains to investigate differences in impulsivity and hyperactivity using the delay discounting task (DDT), cliff avoidance reaction (CAR) test, and open field. We also investigated whether treatment with the clinically effective alpha-2A adrenergic receptor agonist, guanfacine (0.3 mg/kg, i.p.), would reverse deficits observed in behavioral inhibition. Nf1+/− mice chose a higher percentage of smaller rewards when both 10- and 20-s delays were administered compared to WT mice, suggesting Nf1+/− mice are more impulsive. When treated with guanfacine (0.3 mg/kg, i.p.), Nf1+/− mice exhibited decreased impulsive choice by waiting for the larger, delayed reward. Nf1+/− mice also exhibited deficits in behavioral inhibition compared to WT mice in the CAR test by repetitively entering the outer edge of the platform where they risk falling. Treatment with guanfacine ameliorated these deficits. In addition, Nf1+/− mice exhibited hyperactivity as increased distance was traveled compared to WT controls in the open field. This hyperactivity in Nf1+/− mice was reduced with guanfacine pre-treatment. Overall, our study confirms that Nf1+/− mice exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD, and can be used as a model system to identify alterations in neural circuitry associated with symptoms of ADHD in children with NF1.

    更新日期:2020-01-15
  • Postural control processes during standing and step initiation in autism spectrum disorder
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2020-01-06
    Erin K. Bojanek; Zheng Wang; Stormi P. White; Matthew W. Mosconi

    Individuals with autism spectrum disorder (ASD) show a reduced ability to maintain postural stability, though motor control mechanisms contributing to these issues and the extent to which they are associated with other gross motor activities (e.g., stepping) are not yet known. Seventeen individuals with ASD and 20 typically developing (TD) controls (ages 6–19 years) completed three tests of postural control during standing. During the neutral stance, individuals stood with their feet shoulder width apart. During the Romberg one stance, they stood with feet close together. During the circular sway, participants stood with feet shoulder width apart and swayed in a circular motion. The standard deviation (SD) of their center of pressure (COP) in the mediolateral (ML) and anteroposterior (AP) directions and the COP trajectory length were examined for each stance. We also assessed mutual information (MI), or the shared dependencies between COP in the ML and AP directions. Participants also completed a stepping task in which they stepped forward from one force platform to an adjacent platform. The amplitude and duration of anticipatory postural adjustments (APAs) were examined, as were the maximum lateral sway, duration, and velocity of COP adjustments following the initial step. We examined stepping variables using separate one-way ANCOVAs with height as a covariate. The relationships between postural control and stepping measures and ASD symptom severity were assessed using Spearman correlations with scores on the Autism Diagnostic Observation Schedule–Second Edition (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R). Individuals with ASD showed increased COP trajectory length across stance conditions (p = 0.05) and reduced MI during circular sway relative to TD controls (p = 0.02). During stepping, groups did not differ on APA amplitude (p = 0.97) or duration (p = 0.41), but during their initial step, individuals with ASD showed reduced ML sway (p = 0.06), reduced body transfer duration (p < 0.01), and increased body transfer velocity (p = 0.02) compared to controls. Greater neutral stance COPML variability (r = 0.55, p = 0.02) and decreased lateral sway (r = − 0.55, p = 0.02) when stepping were associated with more severe restricted and repetitive behaviors in participants with ASD. We found that individuals with ASD showed reduced MI during circular sway suggesting a reduced ability to effectively coordinate joint movements during dynamic postural adjustments. Additionally, individuals with ASD showed reduced lateral sway when stepping indicating that motor rigidity may interfere with balance and gait. Postural control and stepping deficits were related to repetitive behaviors in individuals with ASD indicating that motor rigidity and key clinical issues in ASD may represent overlapping pathological processes.

    更新日期:2020-01-07
  • Initial eye gaze to faces and its functional consequence on face identification abilities in autism spectrum disorder
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-28
    Kimberly B. Schauder; Woon Ju Park; Yuliy Tsank; Miguel P. Eckstein; Duje Tadin; Loisa Bennetto

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined and diagnosed by core deficits in social communication and the presence of restricted and repetitive behaviors. Research on face processing suggests deficits in this domain in ASD but includes many mixed findings regarding the nature and extent of these differences. The first eye movement to a face has been shown to be highly informative and sufficient to achieve high performance in face identification in neurotypical adults. The current study focused on this critical moment shown to be essential in the process of face identification. We applied an established eye-tracking and face identification paradigm to comprehensively characterize the initial eye movement to a face and test its functional consequence on face identification performance in adolescents with and without ASD (n = 21 per group), and in neurotypical adults. Specifically, we presented a series of faces and measured the landing location of the first saccade to each face, while simultaneously measuring their face identification abilities. Then, individuals were guided to look at specific locations on the face, and we measured how face identification performance varied as a function of that location. Adolescent participants also completed a more traditional measure of face identification which allowed us to more fully characterize face identification abilities in ASD. Our results indicate that the location of the initial look to faces and face identification performance for briefly presented faces are intact in ASD, ruling out the possibility that deficits in face perception, at least in adolescents with ASD, begin with the initial eye movement to the face. However, individuals with ASD showed impairments on the more traditional measure of face identification. Together, the observed dissociation between initial, rapid face perception processes, and other measures of face perception offers new insights and hypotheses related to the timing and perceptual complexity of face processing and how these specific aspects of face identification may be disrupted in ASD.

    更新日期:2019-12-30
  • Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-26
    Emma K. Baker; Marta Arpone; Solange Aliaga Vera; Lesley Bretherton; Alexandra Ure; Claudine M. Kraan; Minh Bui; Ling Ling; David Francis; Matthew F. Hunter; Justine Elliott; Carolyn Rogers; Michael J. Field; Jonathan Cohen; Lorena Santa Maria; Victor Faundes; Bianca Curotto; Paulina Morales; Cesar Trigo; Isabel Salas; Angelica M. Alliende; David J. Amor; David E. Godler

    Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55–199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours. This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours. Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.

    更新日期:2019-12-27
  • Quantifying the resolution of spatial and temporal representation in children with 22q11.2 deletion syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-20
    Kathryn L. McCabe; Abbie M. Popa; Courtney Durdle; Michele Amato; Margarita H. Cabaral; Joshua Cruz; Ling M. Wong; Danielle Harvey; Nicole Tartaglia; Tony J. Simon

    Our ability to generate mental representation of magnitude from sensory information affects how we perceive and experience the world. Reduced resolution of the mental representations formed from sensory inputs may generate impairment in the proximal and distal information processes that utilize these representations. Impairment of spatial and temporal information processing likely underpins the non-verbal cognitive impairments observed in 22q11.2 deletion syndrome (22q11DS). The present study builds on prior research by seeking to quantify the resolution of spatial and temporal representation in children with 22q11DS, sex chromosome aneuploidy (SCA), and a typically developing (TD) control group. Children (22q11DS = 70, SCA = 49, TD = 46) responded to visual or auditory stimuli with varying difference ratios. The participant’s task was to identify which of two sequentially presented stimuli was of larger magnitude in terms of, size, duration, or auditory frequency. Detection threshold was calculated as the minimum difference ratio between the “standard” and the “target” stimuli required to achieve 75% accuracy in detecting that the two stimuli were different. Children with 22q11DS required larger magnitude difference between spatial stimuli for accurate identification compared with both the SCA and TD groups (% difference from standard: 22q11DS = 14; SCA = 8; TD: 7; F = 8.42, p < 0.001). Temporal detection threshold was also higher for the 22q11DS group to both visual (% difference from standard: 22q11DS = 14; SCA = 8; TD = 7; F = 8.33, p < 0.001) and auditory (% difference from standard: 22q11DS = 23; SCA = 12; TD: 8; F = 8.99, p < 0.001) stimuli compared with both the SCA and TD groups, while the SCA and TD groups displayed equivalent performance on these measures (p's > 0.05). Pitch detection threshold did not differ among the groups (p's > 0.05). The observation of higher detection thresholds to spatial and temporal stimuli indicates further evidence for reduced resolution in both spatial and temporal magnitude representation in 22q11DS, that does not extend to frequency magnitude representation (pitch detection), and which is not explained by generalized cognitive impairment alone. These findings generate further support for the hypothesis that spatiotemporal hypergranularity of mental representations contributes to the non-verbal cognitive impairment seen in 22q11DS.

    更新日期:2019-12-21
  • Refining the concept of GFAP toxicity in Alexander disease
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Albee Messing

    Alexander disease is caused by dominantly acting mutations in glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes in the central nervous system. In addition to the sequence variants that represent the origin of disease, GFAP accumulation also takes place, together leading to a gain-of-function that has sometimes been referred to as “GFAP toxicity.” Whether the nature of GFAP toxicity in patients, who have mixtures of both mutant and normal protein, is the same as that produced by simple GFAP excess, is not yet clear. The implications of these questions for the design of effective treatments are discussed.

    更新日期:2019-12-17
  • In memory of Jean de Vellis (1935–2018)
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Susan Y. Bookheimer; Harley I. Kornblum

    It is fitting to dedicate the Jean de Vellis memorial issue of Journal of Neurodevelopmental Disorders to research in glial biology: Jean was an early pioneer in this field, whose work has continued to shape the careers of outstanding investigators, many of whom have contributed to this issue. It may therefore seem surprising to those who did not know him personally to learn that Jean was actually trained as a plant biochemist. His love of agriculture and especially viticulture--the cultivation of grapevines--began in his early childhood. Jean (nobody who knew him called him Dr. de Vellis) was born to a French family in Tunisia and was raised on their citrus farm. Just before he would have attended elementary school, World War II broke out and his formal studies did not start until after the war, when he attended a Jesuit boarding school next to the ancient ruins of Carthage. After receiving his baccalaureate, Jean attended the prestigious École Nationale Supérieure d’Horticulture located in Versailles. Jean then pursed his graduate studies at UCLA where he earned a PhD in plant biochemistry, studying the metabolism of bush bean roots. While earning his PhD, he met his future wife Phyllis, who introduced him to her neighbor, the future Director of the UCLA Brain Research Institute, Carmine Clemente, himself a pioneer in the neurosciences. Although Jean had no background in neuroscience, Carmine convinced Jean to join UCLA’s nascent neuroscience program, moving his studies of metabolism from beans to brains. The Atomic Energy Commission had established and funded a medical monitoring program for the Manhattan project scientists, directed by Stafford L. Warren, the founding Dean of the UCLA School of Medicine. At UCLA, Dr. Warren established the Laboratory of Nuclear Medicine and Radiation Biology at UCLA. Jean was recruited by Dr. Clemente as a faculty member in this Division, which subsequently become part of the Department of Energy Laboratory system. Jean became a glial cell biologist through his early studies of the effects of radiation on brain development. It is now well known that white matter, in particular, is highly vulnerable to radiation, but this was not clear at the time. Jean began to study the composition of irradiated brains, and developed a collaboration with Harvey Herschman, a cell biology student at the University of California, San Diego, working on a presumed brain specific protein, S100. Jean examined the expression of this protein in cultured astrocytomas from rat (cell line C-6). These first experiments involved substantial development of new technologies such as creating immunodiffusion plates and placing proteins in wells with antibodies in gels. Jean sent Harvey samples of irradiated and normal rat brains during development, and Harvey assayed the proteins. Harvey ultimately moved to UCLA and the two became lifelong friends and collaborators, sharing adjacent space in Warren Hall for many years. Jean’s research gradually moved into the study of other extrinsic regulators of brain development and then, more specifically, glial development—a move that proved to be prophetic. As his work in the field developed, he became a leading expert on the culture of brain cell lines and the factors that promoted their growth. This work led to one of the most seminal studies and critical technical advances in the basic neurosciences: the culture of highly purified primary astrocytes and oligodendrocytes from rodent brain [1] which has been cited over four thousand times. This paper, along with a subsequent one with his graduate student, Rick Morrison [2] on the culture of primary astrocytes in chemically defined medium, became the standards in the field of mammalian brain cell culture. These reports opened the door to innumerable studies on the cellular properties and functions of these major cell types of the white matter, as well as on the cellular basis of developmental myelination. Many of the techniques and even media components for these procedures became commonly used in the culture of purified neurons neural stem cells and glioma cells. One of us (HIK), in fact, learned the methods directly from Dr. Morrison in the 1980’s and is still actively using them today. The de Vellis lab continued in its pursuit of developing and refining tissue culture methodology, with a methodological paper on the generation of oligodendrocytes from induced pluripotent stem cells published as recently as 2016 [3]. Although becoming a pioneer in now standard methodology in mammalian cell culture would be enough for many investigators, Jean’s real goals were to both understand normal brain development and to find treatments for developmental and acquired central nervous system disorders. Up until his death, Jean continued to pursue research on glial biology, focusing on the cellular basis for Canavan’s disease, a rare and devastating white matter disorder; he hoped to discover how cell transplantation might alleviate progression in this otherwise fatal neurodevelopmental condition. Jean’s record of publication is vast in its breadth and includes numerous gems in the most prestigious journals. They reflect a high degree of creativity and thought, as well as technical accomplishment. Jean was a pillar of the neuroscience community at UCLA and on the national and international level. In 1970, UCLA was in the first group that was funded as an MRRC under the first director George Tarjan, a pioneer of mental retardation research. Jean was the named the Director in 1974 and held that post until 2015. Jean remained active as Associate Director until his retirement in 2018. Under Jean’s leadership, the MRRC Center grant was funded continuously from 1974 until the present. Over the course of Jean’s tenure as Director, he attracted and developed a high-level research environment bringing in leaders in basic developmental and translational neuroscience. Jean also used his position at Director to bring attention to developmental neuroscience to the leadership at UCLA. On a National Level, Jean became a major voice in the promotion of research into developmental disorders, interacting extensively with leaders from other centers as well as with the leadership at the NIH. Amazingly, given his extensive responsibilities at UCLA, Jean was active in leadership roles in many organizations, including the International Society for Neurochemistry, The Institute for Developmental Neuroscience and Aging, the NICHD Mental Retardation Research Committee and the highly influential Christopher Reeve Paralysis Research Foundation. Jean was also active in organizing the Winter Brain Conference, where he was able to show off his considerable skiing skills. Jean served on multiple editorial boards, but is most noted for his work on the Journal of Neuroscience Research, where he was Editor-in-Chief for 16 years from 1999 to 2015. This journal became a strong publisher of many important articles in developmental neuroscience at a time when there were few options for many in the field. While Jean’s intellect and scientific knowledge were enormous, the real key to much of his success was his warm personality, reflected in his mentorship style. Jean did not believe in distancing himself from his trainees. His students, postdocs, technicians and the many junior faculty for whom he was an unofficial mentor, automatically became part of his family. Jean made no distinction between his private life and his work life. Jean and Phyllis, his wife of 55 years, had three children, Phillipe and Genevieve, and daughter Gabrielle, who died tragically as a teenager. His mentees spent time with his family at their beautiful home in the Pacific Palisades, where he proudly displayed his stunning garden, reflecting his deep roots in agriculture and evoking memories of his childhood citrus farms. While Jean officially retired 2 years before his death, he was an active emeritus professor. He remained engaged and cheerful, was frequently found in his office completing his last studies on Canavan Disease up until his passing on February 12, 2018. Jean’s family, friends and nearly one hundred colleagues attended his memorial service, and a memorial scientific symposium held in his honor in March of 2019. This memorial issue of the Journal of Neurodevelopmental Disorders vividly demonstrates the broad and lasting impact of Jean de Vellis’ life and career. He will be sorely missed. Not applicable 1. McCarthy KD, de Vellis J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 1980;85(3):890–902. CAS Article Google Scholar 2. Morrison RS, de Vellis J. Growth of purified astrocytes in a chemically defined medium. Proc Natl Acad Sci U S A. 1981;78(11):7205–9. CAS Article Google Scholar 3. Espinosa-Jeffrey A, Blanchi B, Biancotti JC, Kumar S, Hirose M, Mandefro B, et al. Efficient generation of viral and integration-free human induced pluripotent stem cell-derived Oligodendrocytes. Curr Protoc Stem Cell Biol. 2016;38:2D.18.1–2D.18.27. Article Google Scholar Download references The authors thank the entire de Vellis family for their contributions and the photographs and Dr. Harvey Herschman for providing valuable historical information. Funding Not applicable Affiliations Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Los Angeles, CA, 90095, USA Susan Y. Bookheimer  & Harley I. Kornblum Authors Search for Susan Y. Bookheimer in: PubMed • Google Scholar Search for Harley I. Kornblum in: PubMed • Google Scholar Contributions SYB and HIK contributed equally to drafting the manuscript. Both authors read and approved the final manuscript. Corresponding author Correspondence to Harley I. Kornblum. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Bookheimer, S.Y., Kornblum, H.I. In memory of Jean de Vellis (1935–2018). J Neurodevelop Disord 11, 28 (2019) doi:10.1186/s11689-019-9298-5 Download citation Received 07 October 2019 Accepted 12 November 2019 Published 16 December 2019 DOI https://doi.org/10.1186/s11689-019-9298-5

    更新日期:2019-12-17
  • Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Amena Smith Fine; Christina L. Nemeth; Miriam L. Kaufman; Ali Fatemi

    The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum. The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.

    更新日期:2019-12-17
  • The role of glia in epilepsy, intellectual disability, and other neurodevelopmental disorders in tuberous sclerosis complex
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Michael Wong

    Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, different types of glial cells have been increasingly recognized to play important roles in the phenotypes of TSC. This review summarizes the literature supporting glial dysfunction from both mouse models and clinical studies of TSC. In particular, evidence for the role of astrocytes, microglia, and oligodendrocytes in the pathophysiology of epilepsy and TAND in TSC is analyzed. Therapeutic implications of targeting glia cells in developing novel treatments for the neurological manifestations of TSC are also considered. Different types of glial cells have both cell autonomous effects and interactions with neurons and other cells that are involved in the pathophysiology of the neurological phenotype of TSC. Targeting glial-mediated mechanisms may represent a novel therapeutic approach for epilepsy and TAND in TSC patients.

    更新日期:2019-12-17
  • A diffusion-weighted imaging tract-based spatial statistics study of autism spectrum disorder in preschool-aged children
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Derek Sayre Andrews; Joshua K. Lee; Marjorie Solomon; Sally J. Rogers; David G. Amaral; Christine Wu Nordahl

    The core symptoms of autism spectrum disorder (ASD) are widely theorized to result from altered brain connectivity. Diffusion-weighted magnetic resonance imaging (DWI) has been a versatile method for investigating underlying microstructural properties of white matter (WM) in ASD. Despite phenotypic and etiological heterogeneity, DWI studies in majority male samples of older children, adolescents, and adults with ASD have largely reported findings of decreased fractional anisotropy (FA) across several commissural, projection, and association fiber tracts. However, studies in preschool-aged children (i.e., < 30–40 months) suggest individuals with ASD have increased measures of WM FA earlier in development. We analyzed 127 individuals with ASD (85♂, 42♀) and 54 typically developing (TD) controls (42♂, 26♀), aged 25.1–49.6 months. Voxel-wise effects of ASD diagnosis, sex, age, and their interaction on DWI measures of FA, mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were investigated using tract-based spatial statistics (TBSS) while controlling mean absolute and relative motion. Compared to TD controls, males and females with ASD had significantly increased measures of FA in eight clusters (threshold-free cluster enhancement p < 0.05) that incorporated several WM tracts including regions of the genu, body, and splenium of the corpus callosum, inferior frontal-occipital fasciculi, inferior and superior longitudinal fasciculi, middle and superior cerebellar peduncles, and corticospinal tract. A diagnosis by sex interaction was observed in measures of AD across six significant clusters incorporating areas of the body, genu, and splenium of the corpus collosum. In these tracts, females with ASD showed increased AD compared to TD females, while males with ASD showed decreased AD compared to TD males. The current findings support growing evidence that preschool-aged children with ASD have atypical measures of WM microstructure that appear to differ in directionality from alterations observed in older individuals with the condition. To our knowledge, this study represents the largest sample of preschool-aged females with ASD to be evaluated using DWI. Microstructural differences associated with ASD largely overlapped between sexes. However, differential relationships of AD measures indicate that sex likely modulates ASD neuroanatomical phenotypes. Further longitudinal study is needed to confirm and quantify the developmental relationship of WM structure in ASD.

    更新日期:2019-12-17
  • White matter as a monitoring biomarker for neurodevelopmental disorder intervention studies
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Meghan R. Swanson; Heather C. Hazlett

    Early intervention is a valuable tool to support the development of toddlers with neurodevelopmental disorders. With recent research advances in early identification that allow for pre-symptomatic detection of autism in infancy, scientists are looking forward to intervention during infancy. These advances may be supported by the identification of biologically based treatment and outcome measures that are sensitive and dimensional. The purpose of this review is to evaluate white matter neurodevelopment as a monitoring biomarker for early treatment of neurodevelopmental disorders. Fragile X syndrome (FXS) and autism spectrum disorder (ASD) as used as exemplars. White matter has unique neurobiology, including a prolonged period of dynamic development. This developmental pattern may make white matter especially responsive to treatment. White matter develops aberrantly in children with ASD and FXS. Histologic studies in rodents have provided targets for FXS pharmacological intervention. However, pharmaceutical clinical trials in humans failed to garner positive clinical results. In this article, we argue that the use of neurobiological monitoring biomarkers may overcome some of these limitations, as they are objective, not susceptible to placebo effects, and are dimensional in nature. As the field moves towards earlier detection and early intervention for neurodevelopmental disorders, we encourage scientists to consider the advantages of using neurobiological features as monitoring biomarkers.

    更新日期:2019-12-17
  • Reducing Th2 inflammation through neutralizing IL-4 antibody rescues myelination in IUGR rat brain
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Allison E. Zanno; Micah A. Romer; Lauren Fox; Thea Golden; Lane Jaeckle-Santos; Rebecca A. Simmons; Judith B. Grinspan

    Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is associated with significant neurological deficits in infants, including white matter damage. Previous work using an animal model of IUGR has demonstrated that IUGR rats exhibit neurobehavioral deficits and developmental delays in oligodendrocyte maturation and myelination, but the mechanisms which cause this delay are unknown. Inflammation may be an important etiological factor in IUGR and has been recognized as playing a fundamental role in the pathogenesis of myelin disorders, including cerebral palsy. To create the model, the uterine arteries of pregnant rats were ligated at embryonic day 15. Rats delivered spontaneously. Cytokine and chemokine expression was evaluated at one prenatal and three postnatal time points, and myelin protein expression and oligodendrocyte cell numbers were evaluated by several methods at postnatal day 14. IL-4 was identified as a potential inhibitor of myelination, and rat pups were injected with IL-4 function blocking antibody from postnatal days 1–5 and myelination was assessed. Here, we show a novel mechanism of white matter injury. IUGR induces an exaggerated Th2 response in the developing rat brain, including upregulation of several Th2 cytokines. Of these, IL-4 is significantly increased during the period corresponding to robust developmental myelination. We show that neutralizing IL-4 antibody therapy given in the newborn period ameliorates inflammation and restores myelin protein expression and oligodendrocyte cell number in the IUGR brain to control levels, demonstrating a novel role for Th2 responses and IL-4 in IUGR and white matter injury. In addition, IL-4 directly affects oligodendrocytes in vitro decreasing differentiation. In this study, we have identified inflammation as a factor in the decrease in myelin seen in an animal model of IUGR. IL-4, an inflammatory protein often thought to be protective in the adult, is specifically increased, and treatment of these animals to prevent this increase ameliorates white matter damage. Our results suggest that the immune system plays a role in IUGR that is different in the perinatal period than in the adult and preventing this exaggerated Th2 response may be a potential therapeutic target.

    更新日期:2019-12-17
  • Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Nadine M. Aziz; Jenny A. Klein; Morgan R. Brady; Jose Luis Olmos-Serrano; Vittorio Gallo; Tarik F. Haydar

    Down syndrome (DS), caused by the triplication of chromosome 21, results in a constellation of clinical features including changes in intellectual and motor function. Although altered neural development and function have been well described in people with DS, few studies have investigated the etiology underlying the observed motor phenotypes. Here, we examine the development, patterning, and organization of the spinal cord throughout life in the Ts65Dn mouse, a model that recapitulates many of the motor changes observed in people with DS. Spinal cords from embryonic to adult animals were processed for gene and protein expression (immunofluorescence) to track the spatiotemporal development of excitatory and inhibitory neurons and oligodendroglia. Postnatal analyses were focused on the lumbar region due to the reflex and gait abnormalities found in Ts65Dn mice and locomotive alterations seen in people with DS. Between embryonic days E10.5 and E14.5, we found a larger motor neuron progenitor domain in Ts65Dn animals containing more OLIG2-expressing progenitor cells. These disturbed progenitors are delayed in motor neuron production but eventually generate a large number of ISL1+ migrating motor neurons. We found that higher numbers of PAX6+ and NKX2.2+ interneurons (INs) are also produced during this time frame. In the adult lumbar spinal cord, we found an increased level of Hb9 and a decreased level of Irx3 gene expression in trisomic animals. This was accompanied by an increase in Calretinin+ INs, but no changes in other neuronal populations. In aged Ts65Dn animals, both Calbindin+ and ChAT+ neurons were decreased compared to euploid controls. Additionally, in the dorsal corticospinal white matter tract, there were significantly fewer CC1+ mature OLs in 30- and 60-day old trisomic animals and this normalized to euploid levels at 10–11 months. In contrast, the mature OL population was increased in the lateral funiculus, an ascending white matter tract carrying sensory information. In 30-day old animals, we also found a decrease in the number of nodes of Ranvier in both tracts. This decrease normalized both in 60-day old and aged animals. We show marked changes in both spinal white matter and neuronal composition that change regionally over the life span. In the embryonic Ts65Dn spinal cord, we observe alterations in motor neuron production and migration. In the adult spinal cord, we observe changes in oligodendrocyte maturation and motor neuron loss, the latter of which has also been observed in human spinal cord tissue samples. This work uncovers multiple cellular perturbations during Ts65Dn development and aging, many of which may underlie the motor deficits found in DS.

    更新日期:2019-12-17
  • Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Anna K. Prohl; Benoit Scherrer; Xavier Tomas-Fernandez; Peter E. Davis; Rajna Filip-Dhima; Sanjay P. Prabhu; Jurriaan M. Peters; E. Martina Bebin; Darcy A. Krueger; Hope Northrup; Joyce Y. Wu; Mustafa Sahin; Simon K. Warfield

    Autism spectrum disorder (ASD) is prevalent in tuberous sclerosis complex (TSC), occurring in approximately 50% of patients, and is hypothesized to be caused by disruption of neural circuits early in life. Tubers, or benign hamartomas distributed stochastically throughout the brain, are the most conspicuous of TSC neuropathology, but have not been consistently associated with ASD. Widespread neuropathology of the white matter, including deficits in myelination, neuronal migration, and axon formation, exist and may underlie ASD in TSC. We sought to identify the neural circuits associated with ASD in TSC by identifying white matter microstructural deficits in a prospectively recruited, longitudinally studied cohort of TSC infants. TSC infants were recruited within their first year of life and longitudinally imaged at time of recruitment, 12 months of age, and at 24 months of age. Autism was diagnosed at 24 months of age with the ADOS-2. There were 108 subjects (62 TSC-ASD, 55% male; 46 TSC+ASD, 52% male) with at least one MRI and a 24-month ADOS, for a total of 187 MRI scans analyzed (109 TSC-ASD; 78 TSC+ASD). Diffusion tensor imaging properties of multiple white matter fiber bundles were sampled using a region of interest approach. Linear mixed effects modeling was performed to test the hypothesis that infants who develop ASD exhibit poor white matter microstructural integrity over the first 2 years of life compared to those who do not develop ASD. Subjects with TSC and ASD exhibited reduced fractional anisotropy in 9 of 17 white matter regions, sampled from the arcuate fasciculus, cingulum, corpus callosum, anterior limbs of the internal capsule, and the sagittal stratum, over the first 2 years of life compared to TSC subjects without ASD. Mean diffusivity trajectories did not differ between groups. Underconnectivity across multiple white matter fiber bundles develops over the first 2 years of life in subjects with TSC and ASD. Future studies examining brain-behavior relationships are needed to determine how variation in the brain structure is associated with ASD symptoms.

    更新日期:2019-12-17
  • The impact of expressive language development and the left inferior longitudinal fasciculus on listening and reading comprehension
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Stephanie N. Del Tufo; F. Sayako Earle; Laurie E. Cutting

    During the first 3-years of life, as the brain undergoes dramatic growth, children begin to develop speech and language. Hallmarks of this progression are seen when children reach developmental milestones, forming the foundation of language. Expressive language milestones, such as the production of a child’s first word, are delayed in 5–8% of children. While for some children delays in reaching these milestones are harbingers of developmental disorders, for others expressive language delays appear to resolve. Regardless of whether or not early language skills appear resolved, difficulty with later comprehension is a likely outcome. Whether this heightened risk for poor comprehension differs based on text features, individual characteristics, or receipt of intervention remains unknown. Moreover, this relationship between expressive language development and comprehension is not yet linked to neurobiology, though the inferior longitudinal fasciculus (ILF) is a potential neurobiological correlate. Therefore, we investigated the impact of, and interactions between, expressive language development, early intervention, and the ILF on comprehension. Longitudinal recurrent survival analyses predicted the risk of answering a comprehension question incorrectly. Predictors of comprehension included expressive language development, passage features, participant characteristics, fractional anisotropy, receipt of early intervention, and later diagnosis of speech or language disorders. Children with later expressive language milestones had poorer comprehension. When comprehension text features were examined, children with later milestones had poorer listening and reading comprehension, and poorer narrative and expository comprehension. The left ILF acted as a neurodevelopmental correlate, one that moderated the relationship between expressive language milestones and comprehension. Specifically, the left ILF exacerbated the relationship for those who did not receive early intervention and buffered the relationship for those who received intervention services. Early intervention decreased the risk of poor comprehension by 39% for children later diagnosed with a speech or language disorder. Early intervention should be provided for children with delayed expressive language milestones, particularly those who are at risk for speech or language disorders. The ILF plays a critical role in the relationship between expressive language development and comprehension, which may be that of a protective factor for children with the most severe early issues with speech and language.

    更新日期:2019-12-17
  • White matter and neurodevelopmental disorders: honoring Jean De Vellis through the work of the NICHD-funded intellectual and developmental disabilities research centers
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Heather Cody Hazlett; Vittorio Gallo

    Following in the footsteps of the first JND special issue in 2018, highlighting the work of the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers (IDDRCs), this year again showcases the work of the IDDRCs and honors the distinguished career of Dr. Jean de Vellis, world-renowned scientist in the study of white matter pathophysiology and long-standing director of the UCLA IDDRC. As eloquently described in the dedication [1] accompanying this special section of the Journal, Jean de Vellis devoted his life’s work to examining glia biology and the importance of these neural cells in the brain. In this issue, we present cutting-edge, clinical and pre-clinical research and reviews by IDDRC investigators as a fitting tribute to the memory of our colleague. Much of the promise in studying white matter comes from the potential this neural structure has for developing new treatments. In a review of both mouse models and clinical work [2], the novel approach of targeting glia cells to treat seizures in Tuberous Sclerosis Complex (TSC) may prove to be a successful treatment for these patients. Investigators at the Harvard-Boston Children’s IDDRC have demonstrated reduced white matter integrity in key fiber bundles may help to identify those individuals with TSC who also present with an autism spectrum disorder [3]. These investigators propose that widespread neuropathology of white matter may underlie the presence of autism in TSC. Similar findings of white matter abnormalities have been reported in autism spectrum disorder (ASD). Work at the UC Davis IDDRC suggests that white matter microstructure develops differently in young children with ASD, and in particular sex may play an important role in modulating the ASD neuroanatomical phenotype [4]. In addition to investigations of white matter morphology, a key aspect of thinking about novel treatments has come from thinking about inflammation and the negative impact this may have on neurodevelopment. Investigators at the Children’s Hospital of Philadelphia IDDRC present exciting work demonstrating that inflammation caused by Th2 cytokines during early brain development can be rescued with the application of IL-4 antibody treatment in the newborn rat [5]. This work highlights the importance of the immune system and impact on white matter development. This mechanism may play a role in injury and disorders that damage myelin, such as premature brain injury and cerebral palsy. In Alexander disease, a rare leukodystrophy resulting from demyelination, it is the accumulation of proteins that may first signify white matter abnormalities. The potential to design treatments targeting the accumulations of glial fibrillary acidic proteins (GFAP) is the focus of a review [6] by the investigators at the Waisman IDDRC, who are working to identify the toxicity of GFAP in these patients. Thinking more broadly about leukodystrophies, the team at the Kennedy Krieger IDDRC have sought to characterize a group of patients with a similar etiology [7]. Patients with mt-aaRS mutations have similar neurophenotypes, specifically observable abnormalities in white matter tracts on MRI. As may be evident by work focusing on these neurodevelopmental disorders, a key benefit of approaching treatment stems from an ability to change developmental trajectories by acting early through specific interventions. In a comprehensive study examining motor neurons in a Down syndrome mouse model (Ts65Dn), the investigators demonstrated clear changes in the spinal white matter composition across the lifespan [8]. This work highlights the fluctuations in cellular properties, depending on developmental stage, which may help inform potential treatment target windows. The prospect of using white matter properties as a biomarker is further explored in a review of literature informed by ongoing work in the field of autism and related neurogenetic disorders such as fragile X syndrome [9]. A study of language disorder suggests where the field could be headed, where white matter biomarkers could be used to help monitor treatment effectiveness. Investigators at the Vanderbilt IDDRC found an important white matter tract known to be associated with language development, the inferior longitudinal fasciculus (ILF), showed differences in language outcomes [10]. The articles included in this special issue highlight the advances made in understanding white matter in neurodevelopmental disorders that investigators across the IDDRCs strive to tackle daily. By approaching these questions from both clinical (human) and basic neuroscience perspectives, both sides gain knowledge and move forward to the goal of better interventions. We hope that the work showcased in this special issue underscores the promise for developing targeted treatments in neurodevelopmental disorders that comes from these investigations. Many of the IDDRCs contain researchers influenced and inspired by the groundbreaking work Jean de Vellis began. We hope that this special issue also serves to honor his legacy to the field. Not applicable. 1. Bookheimer SY, and Kornblum HI. In Memory of Jean de Vellis (1935-2018). J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9298-5. 2. Wong M. The role of glia in epilepsy, intellectual disability, and other neurodevelopmental disorders in tuberous sclerosis complex. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9289-6. 3. Prohl AK, Scherrer B, Tomas-Fernandez X, Davis PE, Filip-Dhima R, Prabhu SP, et al. Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9293-x. 4. Andrews DS, Lee JK, Solomon M, Rogers SJ, Amaral DG, Nordahl CW. A diffusion-weighted imaging tract-based spatial statistics study of autism spectrum disorder in preschool-aged children. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9291-z. 5. Zanno AE, Romer MA, Fox L, Golden T, Santos LJ, Simmons RA, Grinspan JB. Reducing Th2 inflammation through neutralizing IL-4 antibody rescues myelination in IUGR rat brain. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9297-6. 6. Messing A. Refining the concept of GFAP toxicity in Alexander disease. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9290-0. 7. Fine AS, Nemeth CL, Kaufman ML, Fatemi A. Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9292-y. 8. Aziz NM, Klein JA, Brady MR, Olmos-Serrano JL, Gallo V, Haydar TF. Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of Down syndrome. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9294-9. 9. Swanson MR, Hazlett HC. White matter as a monitoring biomarker for neurodevelopmental disorder intervention studies. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9295-8. 10. Del Tufo SN, Earle FS, Cutting LE. The impact of expressive language development and the left inferior longitudinal fasciculus on listening and reading comprehension. J Neurodevelop Disord. 2019. https://doi.org/10.1186/s11689-019-9296-7. Download references The authors wish to thank Drs. Susan Bookheimer and Harley Kornblum for writing the dedication to Jean de Vellis, and we thank Dr. Joseph Piven for suggesting this special issue. Funding The authors declare that they did not receive any funding for this editorial. Affiliations Department of Psychiatry, School of Medicine, UNC-Chapel Hill and Carolina Institute for Developmental Disabilities, Chapel Hill, NC, USA Heather Cody Hazlett Center for Neuroscience Research, Children’s National Research Institute, Children’s National Hospital, Washington, DC, USA Vittorio Gallo Authors Search for Heather Cody Hazlett in: PubMed • Google Scholar Search for Vittorio Gallo in: PubMed • Google Scholar Contributions Both authors contributed equally to writing the editorial and read and approved the manuscript. Corresponding author Correspondence to Heather Cody Hazlett. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Hazlett, H.C., Gallo, V. White matter and neurodevelopmental disorders: honoring Jean De Vellis through the work of the NICHD-funded intellectual and developmental disabilities research centers. J Neurodevelop Disord 11, 38 (2019) doi:10.1186/s11689-019-9299-4 Download citation Received 01 November 2019 Accepted 13 November 2019 Published 16 December 2019 DOI https://doi.org/10.1186/s11689-019-9299-4

    更新日期:2019-12-17
  • Adaptation of the Clinical Dementia Rating Scale for adults with Down syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-12-16
    Christina N. Lessov-Schlaggar; Olga L. del Rosario; John C. Morris; Beau M. Ances; Bradley L. Schlaggar; John N. Constantino

    Adults with Down syndrome (DS) are at increased risk for Alzheimer disease dementia, and there is a pressing need for the development of assessment instruments that differentiate chronic cognitive impairment, acute neuropsychiatric symptomatology, and dementia in this population of patients. We adapted a widely used instrument, the Clinical Dementia Rating (CDR) Scale, which is a component of the Uniform Data Set used by all federally funded Alzheimer Disease Centers for use in adults with DS, and tested the instrument among 34 DS patients recruited from the community. The participants were assessed using two versions of the modified CDR—a caregiver questionnaire and an in-person interview involving both the caregiver and the DS adult. Assessment also included the Dementia Scale for Down Syndrome (DSDS) and the Raven’s Progressive Matrices to estimate IQ. Both modified questionnaire and interview instruments captured a range of cognitive impairments, a majority of which were found to be chronic when accounting for premorbid function. Two individuals in the sample were strongly suspected to have early dementia, both of whom had elevated scores on the modified CDR instruments. Among individuals rated as having no dementia based on the DSDS, about half showed subthreshold impairments on the modified CDR instruments; there was substantial agreement between caregiver questionnaire screening and in-person interview of caregivers and DS adults. The modified questionnaire and interview instruments capture a range of impairment in DS adults, including subthreshold symptomatology, and the instruments provide complementary information relevant to the ascertainment of dementia in DS. Decline was seen across all cognitive domains and was generally positively related to age and negatively related to IQ. Most importantly, adjusting instrument scores for chronic, premorbid impairment drastically shifted the distribution toward lower (no impairment) scores.

    更新日期:2019-12-17
  • A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-06-11
    Marc Woodbury-Smith; Andrew D. Paterson; Irene O’Connor; Mehdi Zarrei; Ryan K. C. Yuen; Jennifer L Howe; Ann Thompson; Morgan Parlier; Bridget Fernandez; Joseph Piven; Stephen W. Scherer; Veronica Vieland; Peter Szatmari

    Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees. ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale. The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent. Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity.

    更新日期:2019-11-28
  • Social skills in children with RASopathies: a comparison of Noonan syndrome and neurofibromatosis type 1
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-06-18
    Elizabeth I. Pierpont; Rebekah L. Hudock; Allison M. Foy; Margaret Semrud-Clikeman; Mary Ella Pierpont; Susan A. Berry; Ryan Shanley; Nathan Rubin; Katherine Sommer; Christopher L. Moertel

    Gene mutations within the RAS-MAPK signaling cascade result in Noonan syndrome (NS), neurofibromatosis type 1 (NF1), and related disorders. Recent research has documented an increased risk for social difficulties and features of autism spectrum disorder (ASD) among children with these conditions. Despite this emerging evidence, the neuropsychological characteristics associated with social skills deficits are not well understood, particularly for children with NS. Parents of children with NS (n = 39), NF1 (n = 39), and unaffected siblings (n = 32) between the ages of 8 and 16 years were administered well-validated caregiver questionnaires assessing their child’s social skills, language abilities, attention-deficit hyperactivity disorder (ADHD) symptoms and anxiety. With respect to overall social skills, average ratings of children in both clinical groups were similar, and indicated weaker social skills compared to unaffected siblings. Although ratings of social skills were outside of normal limits for more than four in ten children within the clinical groups, most of the deficits were mild/moderate. Fifteen percent of the children with NS and 5% of the children with NF1 were rated as having severe social skills impairment (< − 2SD). Independent of diagnosis, having fewer ADHD symptoms or better social-pragmatic language skills was predictive of stronger social skills. Amidst efforts to support social skill development among children and adolescents with RASopathies, neuropsychological correlates such as social language competence, attention, and behavioral self-regulation could be important targets of intervention.

    更新日期:2019-11-28
  • Genetic and maternal predictors of cognitive and behavioral trajectories in females with fragile X syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-06-20
    Laura del Hoyo Soriano; Angela John Thurman; Danielle Jenine Harvey; W. Ted Brown; Leonard Abbeduto

    Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene on the X chromosome, leading to decreased levels of FMR1 protein (FMRP), which causes the array of neuropsychological impairments that define FXS. Because FXS is an X-linked condition, fewer females display FXS and females with FXS are more mildly affected than males, on average. However, there is a considerable variability in terms of severity of affectedness among females with FXS. The current study was designed to investigate potential genetic (FMRP level and ratio of affected to total chromosomes) and environmental factors (maternal psychological distress and closeness in the mother–child relationship) influencing the cognitive (fluid and crystallized intelligence) and behavioral (anxiety and withdrawal) phenotype of females with FXS. We conducted a prospective 3-year longitudinal study of 16 females with FXS (with up to four assessments, each separated by a year) using an accelerated longitudinal design so that we had coverage of the age range of 10–15 years at study start and 13–18 at study end. We focused on both the level of functioning related to chronological age expectations (standard scores) and absolute change in skill (raw scores) over the 3-year period. At a cross-sectional level, fluid intelligence and crystallized intelligence were both predicted by a closer mother–child relationship and lower maternal psychological distress. However, only fluid intelligence was predicted by a lower ratio of affected to total chromosomes. Anxiety and withdrawal were predicted by a higher ratio of affected to total chromosomes. Withdrawal was also predicted by lower closeness in the mother–child relationship and higher maternal distress. In terms of longitudinal change, gains were observed in fluid and crystallized intelligence, whereas anxious and withdrawn behaviors remained stable over visits. Gains in fluid intelligence were solely predicted by FXS biomarkers (higher FMRP level and lower ratio of affected to total chromosomes), while gains in crystallized intelligence were not predicted by any of the biological and environmental variables. Our results show that FXS biomarkers and maternal variables contribute differentially to the cognitive and behavioral features of the adolescent female with FXS. These findings can help in the design of treatment studies aimed at enhancing cognitive and behavioral abilities in the FXS population.

    更新日期:2019-11-28
  • Visual subcircuit-specific dysfunction and input-specific mispatterning in the superior colliculus of fragile X mice
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-06-28
    Rachel B. Kay; Nicole A. Gabreski; Jason W. Triplett

    Sensory processing deficits are frequently co-morbid with neurodevelopmental disorders. For example, patients with fragile X syndrome (FXS), caused by a silencing of the FMR1 gene, exhibit impairments in visual function specific to the dorsal system, which processes motion information. However, the developmental and circuit mechanisms underlying this deficit remain unclear. Recently, the superior colliculus (SC), a midbrain structure regulating head and eye movements, has emerged as a model for dissecting visual circuit development and function. Previous studies have demonstrated a critical role for activity-dependent processes in the development of visual circuitry in the SC. Based on the known role of the FMR1 gene product in activity-dependent synaptic plasticity, we explored the function and organization of visual circuits in the SC of a mouse model of FXS (Fmr1−/y). We utilized in vivo extracellular electrophysiology in combination with computer-controlled visual stimuli to determine the receptive field properties of visual neurons in the SC of control and Fmr1−/y mice. In addition, we utilized anatomical tracing methods to assess the organization of visual inputs to the SC and along the retinogeniculocortical pathway. Receptive fields of visual neurons in the SC of Fmr1−/y mice were significantly larger than those found in control animals, though their shape and structure were unaffected. Further, selectivity for direction of movement was decreased, while selectivity to axis of movement was unchanged. Interestingly, axis-selective (AS) neurons exhibited a specific hyperexcitability in comparison to AS neurons in control SC and to direction-selective (DS) neurons in both control and Fmr1−/y SC. Anatomical tracings revealed that retinocollicular, retinogeniculate, and geniculocortical projections were normally organized in the absence of Fmr1. However, projections from primary visual cortex (V1) to the SC were poorly refined. Fmr1 is required for the proper development of visual circuit organization and function in the SC. We find that visual dysfunction is heterogeneously manifested in a subcircuit-specific manner in Fmr1−/y mice, consistent with previous studies in human FXS patients. Further, we show a specific alteration of inputs to the SC from V1, but not the retina. Together, these data suggest that Fmr1 may function in distinct ways during the development of different visual subcircuits.

    更新日期:2019-11-28
  • Exploring autism symptoms in an Australian cohort of patients with Prader-Willi and Angelman syndromes
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-08-06
    Emma K. Baker; David E. Godler; Minh Bui; Chriselle Hickerton; Carolyn Rogers; Mike Field; David J. Amor; Lesley Bretherton

    Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders that are caused by abnormal expression of imprinted genes in the 15q11-13 region. Dysregulation of genes located in this region has been proposed as a susceptibility factor for autism spectrum disorder (ASD) in both disorders. This study aimed to explore symptoms of ASD in 25 PWS and 19 AS individuals aged between 1 and 39 years via objective assessment. Participants completed the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) and a developmentally or age-appropriate intellectual functioning assessment. All participants had their genetic diagnosis confirmed using DNA methylation analysis and microarray testing of copy number changes within the 15q11-13 region. Participants with PWS had significantly higher overall and social affect calibrated severity scores (CSS) on the ADOS-2 compared to AS participants (p = .0055 and .0015, respectively), but the two groups did not differ significantly on CSS for the repetitive and restricted behaviour domain. PWS cases presented with greater symptoms associated with ASD compared to individuals with AS. Mental health issues associated with PWS may contribute to elevated symptoms of ASD, particularly in adolescents and adults with PWS.

    更新日期:2019-11-28
  • Improving social gaze behavior in fragile X syndrome using a behavioral skills training approach: a proof of concept study
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-08-28
    Caitlin E. Gannon; Tobias C. Britton; Ellen H. Wilkinson; Scott S. Hall

    Individuals diagnosed with fragile X syndrome (FXS), the most common known inherited form of intellectual disability, commonly exhibit significant impairments in social gaze behavior during interactions with others. Although this behavior can restrict social development and limit educational opportunities, behavioral interventions designed to improve social gaze behavior have not been developed for this population. In this proof of concept (PoC) study, we examined whether administering a behavioral skills training package—discrete trial instruction (DTI) plus relaxation training—could increase social gaze duration in males with FXS. As part of a larger clinical trial, 20 boys with FXS, aged 8 to 18 years, were randomized to receive DTI plus relaxation training administered at one of two prescribed doses over a 2-day period at our research center. Potential improvements in social gaze behavior were evaluated by direct observations conducted across trials during the training, and generalization effects were examined by administering a social challenge before and after the treatment. During the social challenge, social gaze behavior was recorded using an eye tracker and physiological arousal levels were simultaneously recorded by monitoring the child’s heart rate. Levels of social gaze behavior increased significantly across blocks of training trials for six (60%) boys who received the high-dose behavioral treatment and for three (30%) boys who received the low-dose behavioral treatment. Boys who received the high-dose treatment also showed greater improvements in social gaze behavior during the social challenge compared to boys who received the low-dose treatment. There was no effect of the treatment on physiological arousal levels recorded on the heart rate monitor at either dose. These results suggest that appropriate social gaze behavior can be successfully taught to boys with FXS using a standardized behavioral skills training approach. Future studies will need to evaluate whether younger children with FXS might benefit from this treatment, and/or whether more naturalistic forms of behavioral skills training might be beneficial, before social gaze avoidance becomes established in the child’s repertoire. ClinicalTrials.gov, NCT02616796 . Registered 30 November 2015.

    更新日期:2019-11-28
  • Face processing in 22q11.2 deletion syndrome: atypical development and visual scanning alterations
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-08-29
    Alexandra Zaharia; Maude Schneider; Bronwyn Glaser; Martina Franchini; Sarah Menghetti; Marie Schaer; Martin Debbané; Stephan Eliez

    Previous research links social difficulties to atypical face exploration in 22q11.2 deletion syndrome (22q11.2DS). Two types of face processing are distinguished: configural (CFP) and featural (FFP). CFP develops later in life and plays an important role in face and emotion recognition abilities. Recent studies reported atypical development of CFP in several neurodevelopmental disorders. Taking previous reports of atypical face exploration one step further, our study aims at characterizing face processing in children and adolescents with 22q11.2DS. First, we sought to identify biases in the first two fixation positions on faces and to detect differences between CFP and FFP in 22q11.2DS using eye-tracking technology. Second, we investigated the developmental trajectories of CFP and FFP using accuracy data from follow-up evaluation. Seventy-five individuals with 22q11.2DS and 84 typically developed (TD) individuals (aged 6–21 years) completed a discrimination task (“Jane task”) inducing CFP and FFP in an eye-tracking setting. Thirty-six individuals with 22q11DS and 30 TD from our sample completed a longitudinal follow-up evaluation. Findings revealed that individuals with 22q11.2DS demonstrate an early bias toward the mouth region during the initial fixations on the faces and reduced flexibility exploration of the faces, with a reduced number of transitions between faces and longer fixations compared to the TD group. Further, scanpaths did not differ between CFP and FFP in the 22q11.2DS group. Longitudinal analysis of accuracy data provided evidence for atypical development of CFP in 22q11.2DS. The current study brings new evidence of altered face exploration in 22q11.2DS and identifies developmental mechanisms that may contribute to difficulties impacting social interactions in the syndrome.

    更新日期:2019-11-28
  • Neurophysiological correlates of holistic face processing in adolescents with and without autism spectrum disorder
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-08-30
    Sandra Naumann; Ulrike Senftleben; Megha Santhosh; James McPartland; Sara Jane Webb

    Face processing has been found to be impaired in autism spectrum disorders (ASD). One hypothesis is that individuals with ASD engage in piecemeal compared to holistic face processing strategies. To investigate the role of possible impairments in holistic face processing in individuals with autism, the current study investigated behavioral and electroencephalography (EEG) correlates of face processing (P1/N170 and gamma-band activity) in adolescents with ASD and sex-, age-, and IQ-matched neurotypical controls. Participants were presented with upright and inverted Mooney stimuli; black and white low information faces that are only perceived as faces when processed holistically. Participants indicated behaviorally the detection of a face. EEG was collected time-locked to the presentation of the stimuli. Adolescents with ASD perceived Mooney stimuli as faces suggesting ability to use holistic processing but displayed a lower face detection rate and slower response times. ERP components suggest slowed temporal processing of Mooney stimuli in the ASD compared to control group for P1 latency but no differences between groups for P1 amplitude and at the N170. Increases in gamma-band activity was similar during the perception of the Mooney images by group, but the ASD group showed prolonged temporal elevation in activity. Overall, our results suggest that adolescents with ASD were able to utilize holistic processing to perceive a face within the Mooney stimuli. Delays in early processing, marked by the P1, and elongated elevation in gamma activity indicate that the neural systems supporting holistic processing are slightly altered suggesting a less automatic and less efficient facial processing system. Non-applicable.

    更新日期:2019-11-28
  • Emotional prosodic change detection in autism Spectrum disorder: an electrophysiological investigation in children and adults
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-09-18
    J. Charpentier; K. Kovarski; E. Houy-Durand; J. Malvy; A. Saby; F. Bonnet-Brilhault; M. Latinus; M. Gomot

    Autism spectrum disorder (ASD) is characterized by atypical behaviors in social environments and in reaction to changing events. While this dyad of symptoms is at the core of the pathology along with atypical sensory behaviors, most studies have investigated only one dimension. A focus on the sameness dimension has shown that intolerance to change is related to an atypical pre-attentional detection of irregularity. In the present study, we addressed the same process in response to emotional change in order to evaluate the interplay between alterations of change detection and socio-emotional processing in children and adults with autism. Brain responses to neutral and emotional prosodic deviancies (mismatch negativity (MMN) and P3a, reflecting change detection and orientation of attention toward change, respectively) were recorded in children and adults with autism and in controls. Comparison of neutral and emotional conditions allowed distinguishing between general deviancy and emotional deviancy effects. Moreover, brain responses to the same neutral and emotional stimuli were recorded when they were not deviants to evaluate the sensory processing of these vocal stimuli. In controls, change detection was modulated by prosody: in children, this was characterized by a lateralization of emotional MMN to the right hemisphere, and in adults, by an earlier MMN for emotional deviancy than for neutral deviancy. In ASD, an overall atypical change detection was observed with an earlier MMN and a larger P3a compared to controls suggesting an unusual pre-attentional orientation toward any changes in the auditory environment. Moreover, in children with autism, deviancy detection depicted reduced MMN amplitude. In addition in children with autism, contrary to adults with autism, no modulation of the MMN by prosody was present and sensory processing of both neutral and emotional vocal stimuli appeared atypical. Overall, change detection remains altered in people with autism. However, differences between children and adults with ASD evidence a trend toward normalization of vocal processing and of the automatic detection of emotion deviancy with age.

    更新日期:2019-11-28
  • Language delay aggregates in toddler siblings of children with autism spectrum disorder
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-10-22
    N Marrus; L P Hall; S J Paterson; J T Elison; J J Wolff; M R Swanson; J Parish-Morris; A T Eggebrecht; J R Pruett; H C Hazlett; L Zwaigenbaum; S Dager; A M Estes; R T Schultz; K N Botteron; J Piven; J N Constantino

    Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype. We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample. Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n = 235) versus LR-noASD group (n = 115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition. Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms.

    更新日期:2019-11-28
  • Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-10-22
    Lisa Joseph; Cristan Farmer; Colby Chlebowski; Laura Henry; Ari Fish; Catherine Mankiw; Anastasia Xenophontos; Liv Clasen; Bethany Sauls; Jakob Seidlitz; Jonathan Blumenthal; Erin Torres; Audrey Thurm; Armin Raznahan

    XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data. We evaluated a single-center cohort of 64 individuals with XYY aged 5–25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis. Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features. By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology. ClinicalTrials.gov NCT00001246 , “89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls.”

    更新日期:2019-11-28
  • An emotion recognition subtyping approach to studying the heterogeneity and comorbidity of autism spectrum disorders and attention-deficit/hyperactivity disorder
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-11-15
    Francesca Waddington; Catharina Hartman; Yvette de Bruijn; Martijn Lappenschaar; Anoek Oerlemans; Jan Buitelaar; Barbara Franke; Nanda Rommelse

    Emotion recognition dysfunction has been reported in both autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). This suggests that emotion recognition is a cross-disorder trait that may be utilised to understand the heterogeneous psychopathology of ASD and ADHD. We aimed to identify emotion recognition subtypes and to examine their relation with quantitative and diagnostic measures of ASD and ADHD to gain further insight into disorder comorbidity and heterogeneity. Factor mixture modelling was used on speed and accuracy measures of auditory and visual emotion recognition tasks. These were administered to children and adolescents with ASD (N = 89), comorbid ASD + ADHD (N = 64), their unaffected siblings (N = 122), ADHD (N = 111), their unaffected siblings (N = 69), and controls (N = 220). Identified classes were compared on diagnostic and quantitative symptom measures. A four-class solution was revealed, with the following emotion recognition abilities: (1) average visual, impulsive auditory; (2) average-strong visual and auditory; (3) impulsive/imprecise visual, average auditory; (4) weak visual and auditory. The weakest performing class (4) contained the highest percentage of patients (66.07%) and the lowest percentage controls (10.09%), scoring the highest on ASD/ADHD measures. The best performing class (2) demonstrated the opposite: 48.98% patients, 15.26% controls with relatively low scores on ASD/ADHD measures. Subgroups of youths can be identified that differ both in quantitative and qualitative aspects of emotion recognition abilities. Weak emotion recognition abilities across sensory domains are linked to an increased risk for ASD as well as ADHD, although emotion recognition impairments alone are neither necessary nor sufficient parts of these disorders.

    更新日期:2019-11-28
  • Arterial spin labeling provides a reliable neurobiological marker of autism spectrum disorder
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Benjamin E. Yerys; John D. Herrington; Gregory K. Bartley; Hua-Shan Liu; John A. Detre; Robert T. Schultz

    Research on neurobiological markers of autism spectrum disorder (ASD) has been elusive. However, radionuclide studies of cerebral blood flow (CBF) have shown decreased blood flow (hypoperfusion) in the temporal lobes of individuals with ASD across ages and intelligence. This observation fits with current neuroscientific models that implicate temporal regions in social perception and social cognition. Arterial spin labeled perfusion MRI allows noninvasive quantification of regional CBF as part of a multimodal MRI protocol. This method is almost entirely absent from ASD research to date. Our a priori hypothesis was that children with ASD would present with hypoperfusion in the temporal lobes—most notably the fusiform gyrus (given its prominent role in ASD social perception deficits). We also sought to examine the reproducibility of CBF measures, and their relationship to individual differences in facial recognition and ASD symptoms. A total of 58 males (33 with ASD) between the ages of 12 and 17 years participated in the study. All children completed two arterial spin labeling and structural (T1) scans using a 3 T Siemens Verio scanner approximately 8 weeks apart, as well as behavioral testing at time 1 that included diagnostic measures and the Benton Facial Recognition Test. CBF was the key dependent variable, as was facial recognition performance, and ASD symptoms. The two scans were used for reliability analyses. The ASD group showed hypoperfusion in the bilateral fusiform gyrus and in right inferior temporal gyrus. Intra-class correlations showed moderate to good reliability across time within both groups, and no diagnostic group × time interactions. CBF in the left fusiform gyrus was significantly positively correlated with facial recognition. No significant correlations were observed with core ASD symptoms. Arterial spin labeling revealed hypoperfusion in children with ASD in regions critical to social perception and cognition. The left fusiform gyrus plays an important role in facial recognition, and greater CBF in this region was correlated with more normative facial recognition performance in children with ASD. This study takes an important first step in establishing CBF of the temporal lobes as a reliable marker of ASD.

    更新日期:2019-11-28
  • What’s missing in autism spectrum disorder motor assessments?
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Rujuta B. Wilson; James T. McCracken; Nicole J. Rinehart; Shafali S. Jeste

    Motor delays and impairments in autism spectrum disorders (ASD) are extremely common and often herald the emergence of pervasive atypical development. Clinical accounts of ASD and standardized measures of motor function have identified deficits in multiple motor domains. However, literature describing frequently used standardized motor assessments in children with ASD, their test properties, and their limitations are sparse. We systematically reviewed the literature to identify the most frequently used standardized motor assessments used to evaluate children with ASD from infancy to early childhood. All assessments included were required to possess reference norms, evaluate more than one motor domain, and have undergone some degree of validation. We identified six frequently used standardized measures of motor function per our inclusion and exclusion criteria. We investigated and described in detail the psychometric properties of these assessments, their utility for use with children with ASD, and their individual and overall strengths and limitations. The global strengths of these assessments are the ability to identify early development delays and differences in fine and gross motor function in children with ASD. Global limitations of these studies are lack of validation in individuals with ASD and scoring systems that often miss specific and subtle abnormalities. Standardized assessments of motor function have provided valuable information on motor impairments in ASD. However, significant limitations remain in the use of these measures in children with ASD. Moving forward, it is imperative that standardized measures of motor function receive greater validation testing in children with ASD to assess their potential application given the clinical heterogeneity of this condition. In addition, utilizing quantitative measures of motor function should allow for evaluation and comparison of individuals with ASD across the lifespan with varying cognitive and behavioral abilities.

    更新日期:2019-11-28
  • ADHD-related sex differences in fronto-subcortical intrinsic functional connectivity and associations with delay discounting
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Keri S. Rosch; Stewart H. Mostofsky; Mary Beth Nebel

    Attention-deficit/hyperactivity disorder (ADHD) is associated with atypical fronto-subcortical neural circuitry and heightened delay discounting, or a stronger preference for smaller, immediate rewards over larger, delayed rewards. Recent evidence of ADHD-related sex differences in brain structure and function suggests anomalies in fronto-subcortical circuitry may differ among girls and boys with ADHD. The current study examined whether the functional connectivity (FC) within fronto-subcortical neural circuitry differs among girls and boys with ADHD compared to same-sex typically developing (TD) controls and relates to delay discounting. Participants include 8–12-year-old children with ADHD (n = 72, 20 girls) and TD controls (n = 75, 21 girls). Fronto-subcortical regions of interest were functionally defined by applying independent component analysis to resting-state fMRI data. Intrinsic FC between subcortical components, including the striatum and amygdala, and prefrontal components, including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and anterior dorsolateral prefrontal cortex (dlPFC), was compared across diagnostic groups overall and within sex. Correlations between intrinsic FC of the six fronto-subcortical pairs and delay discounting were also examined. Both girls and boys with ADHD show atypical FC between vmPFC and subcortical regions including the striatum (stronger positive FC in ADHD) and amygdala (weaker negative FC in ADHD), with the greatest diagnostic effects among girls. In addition, girls with ADHD show atypical intrinsic FC between the striatum and dlPFC components, including stronger positive FC with ACC and stronger negative FC with dlPFC. Further, girls but not boys, with ADHD, show heightened real-time delay discounting. Brain–behavior correlations suggest (1) stronger negative FC between the striatal and dlPFC components correlated with greater money delay discounting across all participants and (2) stronger FC between the amygdala with both the dlPFC and ACC components was differentially related to heightened real-time discounting among girls and boys with and without ADHD. Our findings suggest fronto-subcortical functional networks are affected in children with ADHD, particularly girls, and relate to delay discounting. These results also provide preliminary evidence of greater disruptions in fronto-subcortical FC among girls with ADHD that is not due to elevated inattention symptom severity, intellectual reasoning ability, age, or head motion.

    更新日期:2019-11-28
  • Statistical learning as a window into developmental disabilities
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Jenny R. Saffran

    Until recently, most behavioral studies of children with intellectual and developmental disabilities (IDD) have used standardized assessments as a means to probe etiology and to characterize phenotypes. Over the past decade, however, tasks originally developed to investigate learning processes in typical development have been brought to bear on developmental processes in children with IDD. This brief review will focus on one learning process in particular—statistical learning—and will provide an overview of what has been learned thus far from studies using statistical learning tasks with different groups of children with IDD conditions. While a full picture is not yet available, results to date suggest that studies of learning are both feasible and informative about learning processes that may differ across diagnostic groups, particularly as they relate to language acquisition. More generally, studies focused on learning processes may be highly informative about different developmental trajectories both across groups and within groups of children.

    更新日期:2019-11-28
  • 更新日期:2019-11-28
  • Applying a network framework to the neurobiology of reading and dyslexia
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Stephen K. Bailey; Katherine S. Aboud; Tin Q. Nguyen; Laurie E. Cutting

    There is a substantial literature on the neurobiology of reading and dyslexia. Differences are often described in terms of individual regions or individual cognitive processes. However, there is a growing appreciation that the brain areas subserving reading are nested within larger functional systems, and new network analysis methods may provide greater insight into how reading difficulty arises. Yet, relatively few studies have adopted a principled network-based approach (e.g., connectomics) to studying reading. In this study, we combine data from previous reading literature, connectomics studies, and original data to investigate the relationship between network architecture and reading. First, we detailed the distribution of reading-related areas across many resting-state networks using meta-analytic data from NeuroSynth. Then, we tested whether individual differences in modularity, the brain’s tendency to segregate into resting-state networks, are related to reading skill. Finally, we determined whether brain areas that function atypically in dyslexia, as identified by previous meta-analyses, tend to be concentrated in hub regions. We found that most resting-state networks contributed to the reading network, including those subserving domain-general cognitive skills such as attention and executive function. There was also a positive relationship between the global modularity of an individual’s brain network and reading skill, with the visual, default mode and cingulo-opercular networks showing the highest correlations. Brain areas implicated in dyslexia were also significantly more likely to have a higher participation coefficient (connect to multiple resting-state networks) than other areas. These results contribute to the growing literature on the relationship between reading and brain network architecture. They suggest that an efficient network organization, i.e., one in which brain areas form cohesive resting-state networks, is important for skilled reading, and that dyslexia can be characterized by abnormal functioning of hub regions that map information between multiple systems. Overall, use of a connectomics framework opens up new possibilities for investigating reading difficulty, especially its commonalities across other neurodevelopmental disorders.

    更新日期:2019-11-28
  • Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Cynthia E. Rogers; Rachel E. Lean; Muriah D. Wheelock; Christopher D. Smyser

    Despite advances in antenatal and neonatal care, preterm birth remains a leading cause of neurological disabilities in children. Infants born prematurely, particularly those delivered at the earliest gestational ages, commonly demonstrate increased rates of impairment across multiple neurodevelopmental domains. Indeed, the current literature establishes that preterm birth is a leading risk factor for cerebral palsy, is associated with executive function deficits, increases risk for impaired receptive and expressive language skills, and is linked with higher rates of co-occurring attention deficit hyperactivity disorder, anxiety, and autism spectrum disorders. These same infants also demonstrate elevated rates of aberrant cerebral structural and functional connectivity, with persistent changes evident across advanced magnetic resonance imaging modalities as early as the neonatal period. Emerging findings from cross-sectional and longitudinal investigations increasingly suggest that aberrant connectivity within key functional networks and white matter tracts may underlie the neurodevelopmental impairments common in this population. This review begins by highlighting the elevated rates of neurodevelopmental disorders across domains in this clinical population, describes the patterns of aberrant structural and functional connectivity common in prematurely-born infants and children, and then reviews the increasingly established body of literature delineating the relationship between these brain abnormalities and adverse neurodevelopmental outcomes. We also detail important, typically understudied, clinical, and social variables that may influence these relationships among preterm children, including heritability and psychosocial risks. Future work in this domain should continue to leverage longitudinal evaluations of preterm infants which include both neuroimaging and detailed serial neurodevelopmental assessments to further characterize relationships between imaging measures and impairment, information necessary for advancing our understanding of modifiable risk factors underlying these disorders and best practices for improving neurodevelopmental trajectories in this high-risk clinical population.

    更新日期:2019-11-28
  • Cerebrospinal fluid and the early brain development of autism
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Mark D. Shen

    There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory proteins involved in neurodegenerative diseases, such as amyloid-β. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system. This article will review the importance of CSF in regulating normal brain development and function, from the prenatal period throughout the lifespan, and highlight recent research that CSF abnormalities in autism spectrum disorder (ASD) are present in infancy, are detectable by conventional structural MRI, and could serve as an early indicator of altered neurodevelopment. The identification of early CSF abnormalities in children with ASD, along with emerging knowledge of the underlying pathogenic mechanisms, has the potential to serve as early stratification biomarkers that separate children with ASD into biological subtypes that share a common pathophysiology. Such subtypes could help parse the phenotypic heterogeneity of ASD and map on to targeted, biologically based treatments.

    更新日期:2019-11-28
  • Imaging episodic memory during development and childhood epilepsy
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-13
    Leigh N. Sepeta; Madison M. Berl; William Davis Gaillard

    Epilepsy affects 2.2 million adults in the USA, with 1 in 26 people developing epilepsy at some point in their lives. Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy as medial structures, and the hippocampus in particular, are prone to generating seizures. Selective anterior temporal resection (which removes the hippocampus) is the most effective intractable TLE treatment, but given the critical role of the mesial temporal lobe in memory functioning, resection can have negative effects on this crucial cognitive skill. To minimize the adverse impact of temporal lobe surgery on memory functioning, reliable pre-surgical guides are needed. Clinical functional magnetic resonance imaging (fMRI) provides reliable, noninvasive guidance of language functioning and plays a growing role in the pre-surgical evaluation for epilepsy patients; however, localization of memory function in children with epilepsy using fMRI has not been established. Aside from the lack of neuroimaging memory studies in children with TLE, studies of typical development are limited. This review will focus on the functional anatomy of memory systems throughout development, with a focus on TLE. TLE provides the ideal model from which to understand memory function and the limits of plasticity and compensation/reorganization throughout development.

    更新日期:2019-11-28
  • The reach-to-grasp movement in infants later diagnosed with autism spectrum disorder: a high-risk sibling cohort study
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-27
    Lori-Ann R. Sacrey; Lonnie Zwaigenbaum; Susan Bryson; Jessica Brian; Isabel M. Smith

    Although autism spectrum disorder (ASD) is characterized by impairments in social communication and the presence of repetitive behavior and/or restricted interests, there is evidence that motor impairments may be a contributing factor to the ASD phenotype. The purpose of this study was to examine the motor act of reaching-to-grasp in children at high risk (HR; with an older sibling diagnosed with ASD) and low-risk (LR; no family history of ASD) for ASD. Children were compared for differences in reaching-to-grasp based on sibling status and diagnostic outcome. Children were enrolled between 6 and 12 months of age and the reach-to-grasp movement was scored at 6, 9, (where available) 12, 15, 18, 24, and 36 months of age using the qualitative Skilled Reaching Rating Scale to determine the presence of any group-, age-, or sex-related differences in the mechanics of the reach-to-grasp movement using a Mixed Models analysis. At 36 months, all children underwent a gold-standard diagnostic assessment, which resulted in three outcome groups: HR children diagnosed with ASD (HR-ASD; n = 10), HR children not diagnosed with ASD (HR-N; n = 10), and low-risk children not diagnosed with ASD (LR; n = 10). The group of children who were later diagnosed with ASD (HR-ASD group) showed higher (worse) total scores on the reach-to-grasp movement, as well as higher scores on the components of Orient, Lift, and Pronate compared to children in the LR and HR-N groups. Our results support the growing literature indicating that children who are later diagnosed with ASD show impaired early motor performance. These results highlight the importance of early surveillance of children who are at elevated risk for ASD, and early initiatives should focus on early signs of the phenotype, including both movement and sensory differences (prodromal signs) prior to the emergence of diagnostic characteristics.

    更新日期:2019-11-28
  • Substance use and nicotine dependence in persistent, remittent, and late-onset ADHD: a 10-year longitudinal study from childhood to young adulthood
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2018-12-27
    Shahrzad Ilbegi; Annabeth P. Groenman; Arnt Schellekens; Catharina A. Hartman; Pieter J. Hoekstra; Barbara Franke; Stephen V. Faraone; Nanda N. J. Rommelse; Jan K. Buitelaar

    Attention-deficit/hyperactivity disorder (ADHD) is associated with substance use disorders (SUD; alcohol and/or drug dependence) and nicotine dependence. This study aims to advance our knowledge about the association between SUD, nicotine dependence, and the course of ADHD (persistent versus remittent ADHD and late-onset ADHD). ADHD, SUD, and nicotine dependence were longitudinally assessed (mean age at study entry 11.3 years, mean age at follow-up 21.1 years) using structured psychiatric interviews and multi-informant questionnaires in a subsample of the Dutch part of the International Multicenter ADHD Genetics study. Individuals with persistent ADHD (n = 62), remittent ADHD (n = 12), late-onset ADHD (n = 18; age of onset after 12 years), unaffected siblings (n = 50), and healthy controls (n = 47) were assessed. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated by Cox regression and adjusted for clustered family data, gender, follow-up length, and current age. Individuals with persistent ADHD were at significantly higher risk of development of SUD relative to healthy controls (HR = 4.56, CI 1.17–17.81). In contrast, levels of SUD in those with remittent ADHD were not different from healthy controls (HR = 1.00, CI .07–13.02). ADHD persisters had also higher prevalence rates of nicotine dependence (24.2%) than ADHD remitters (16.7%) and healthy controls (4.3%). A similar pattern was found in initially unaffected siblings who met ADHD criteria at follow-up (“late-onset” ADHD); they had also a higher prevalence of SUD (33%) compared to stable unaffected siblings (20%) and were at significantly increased risk of development of nicotine dependence compared to healthy controls (HR = 13.04, CI 2.08–81.83). SUD and nicotine dependence are associated with a negative ADHD outcome. Results further emphasize the need for clinicians to comprehensively assess substance use when diagnosing ADHD in adolescents and adults.

    更新日期:2019-11-28
  • Differentiating social preference and social anxiety phenotypes in fragile X syndrome using an eye gaze analysis: a pilot study
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-01-21
    Michael P. Hong; Eleanor M. Eckert; Ernest V. Pedapati; Rebecca C. Shaffer; Kelli C. Dominick; Logan K. Wink; John A. Sweeney; Craig A. Erickson

    Fragile X syndrome (FXS) is the leading inherited cause of autism spectrum disorder, but there remains debate regarding the clinical presentation of social deficits in FXS. The aim of this study was to compare individuals with FXS to typically developing controls (TDC) and individuals with idiopathic autism spectrum disorder (ASD) across two social eye tracking paradigms. Individuals with FXS and age- and gender-matched TDC and individuals with idiopathic ASD completed emotional face and social preference eye tracking tasks to evaluate gaze aversion and social interest, respectively. Participants completed a battery of cognitive testing and caregiver-reported measures for neurobehavioral characterization. Individuals with FXS exhibited reduced eye and increased mouth gaze to emotional faces compared to TDC. Gaze aversive findings were found to correlate with measures of anxiety, social communication deficits, and behavioral problems. In the social interest task, while individuals with idiopathic ASD showed significantly less social preference, individuals with FXS displayed social preference similar to TDC. These findings suggest fragile X syndrome social deficits center on social anxiety without the prominent reduction in social interest associated with autism spectrum disorder. Specifically designed eye tracking techniques clarify the nature of social deficits in fragile X syndrome and may have applications to improve phenotyping and evaluate interventions targeting social functioning impairments.

    更新日期:2019-11-28
  • Static and dynamic postural control deficits in aging fragile X mental retardation 1 (FMR1) gene premutation carriers
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-01-21
    Zheng Wang; Pravin Khemani; Lauren M. Schmitt; Su Lui; Matthew W. Mosconi

    Individuals with premutation alleles of the fragile X mental retardation 1 (FMR1) gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. Characterization of motor issues associated with aging in FMR1 premutation carriers is needed to determine neurodegenerative processes and establish new biobehavioral indicators to help identify individuals at greatest risk of developing FXTAS. We examined postural stability in 18 premutation carriers ages 46–77 years and 14 age-matched healthy controls. Participants completed a test of static stance and two tests of dynamic postural sway on a force platform to quantify postural variability and complexity. CGG repeat length was measured for each premutation carrier, and MRI and neurological evaluations were conducted to identify carriers who currently met criteria for FXTAS. Of the 18 premutation carriers, seven met criteria for definite/probable FXTAS (FXTAS+), seven showed no MRI or neurological signs of FXTAS (FXTAS−), and four were inconclusive due to insufficient data. Compared to controls, premutation carriers showed increased center of pressure (COP) variability in the mediolateral (COPML) direction during static stance and reduced COP variability in the anterior-posterior (COPAP) direction during dynamic AP sway. They also showed reductions in COPML complexity during each postural condition. FXTAS+ individuals showed reduced COPAP variability compared to FXTAS− carriers and healthy controls during dynamic AP sway. Across all carriers, increased sway variability during static stance and decreased sway variability in target directions during dynamic sways were associated with greater CGG repeat length and more severe neurologically rated posture and gait abnormalities. Our findings indicate that aging FMR1 premutation carriers show static and dynamic postural control deficits relative to healthy controls implicating degenerative processes of spinocerebellar and cerebellar-brainstem circuits that may be independent of or precede the onset of FXTAS. Our finding that FXTAS+ and FXTAS− premutation carriers differed on their level of intentional AP sway suggests that neural mechanisms of dynamic postural control may be differentially impacted in patients with FXTAS, and its measurement may be useful for rapidly and precisely identifying disease presence and onset.

    更新日期:2019-11-28
  • Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-02-07
    Gregory Costain; Susan Walker; Bob Argiropoulos; Danielle A. Baribeau; Anne S. Bassett; Erik Boot; Koen Devriendt; Barbara Kellam; Christian R. Marshall; Aparna Prasad; Moises A. Serrano; D. James Stavropoulos; Hope Twede; Joris R. Vermeesch; Jacob A. S. Vorstman; Stephen W. Scherer

    Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.

    更新日期:2019-11-28
  • Adaptation to different communicative contexts: an eye tracking study of autistic adults
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-04-13
    Julia Parish-Morris; Ashley A. Pallathra; Emily Ferguson; Brenna B. Maddox; Alison Pomykacz; Leat S. Perez; Leila Bateman; Juhi Pandey; Robert T. Schultz; Edward S. Brodkin

    Learning through social observation (i.e., watching other people interact) lays the foundation for later social skills and social cognition. However, social situations are often complex, and humans are only capable of attending to one aspect of a scene at a time. How do people choose where to allocate their visual resources when viewing complex social scenarios? For typically developing (TD) individuals, faces are often given priority. Depending upon context, however, it may be more useful to attend to other aspects of the environment, such as hands, tools, or background objects. Previous studies reported reduced face looking in individuals with autism spectrum disorder (ASD), but modulation of visual attention in response to contextual differences (e.g., according to social richness, or the presence/absence of communicative behaviors between two people) has only briefly been explored. In this study, we used eye-tracking technology to test the extent to which ASD adults and TD adults use social context to guide their gaze behavior. Fifty-five adults participated (28 with ASD). The location and duration of participants’ gaze were recorded while they watched a series of naturalistic social videos. Half of the videos depicted two people engaging in non-verbal communication (rich social scenes) while playing with toys. The other half depicted two people playing with toys separately, not interacting with each other (lean social scenes). ASD and TD adults both increased their attention to faces in communicative contexts (rich social scenes) as compared to non-communicative contexts (lean social scenes). However, TD adults increased their attention to faces significantly more when watching two people communicate than did ASD adults, who increased their attention to a lesser degree. Further analysis revealed that ASD adults persisted in looking at hands and toys, even when observing two people communicate in a rich social scene. Diminished gaze to faces when observing two people communicating may lead to fewer opportunities for social learning and subsequent reductions in social knowledge. Naturalistic measures of contextual modulation could help identify areas of need for individuals learning about the social world and could become treatment targets to improve everyday social learning.

    更新日期:2019-11-28
  • Cognitive training for children and adolescents with fragile X syndrome: a randomized controlled trial of Cogmed
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-04-15
    David Hessl; Julie B. Schweitzer; Danh V. Nguyen; Yingratana A. McLennan; Cindy Johnston; Ryan Shickman; Yanjun Chen

    Individuals with fragile X syndrome (FXS) typically demonstrate profound executive function (EF) deficits that interfere with learning, socialization, and emotion regulation. We completed the first large, non-pharmacological controlled trial for FXS, designed to evaluate the efficacy of Cogmed, a computer/tablet-based working memory (WM) training program. The study was a randomized, blinded, parallel two-arm controlled trial in 100 children and adolescents with FXS (63 male, 37 female; 15.28 ± 3.36 yrs.). Participants were randomized equally to adaptive (difficulty level adjusted to performance) or non-adaptive (control) Cogmed training. Participants were assessed at home using objective measures of WM (primary outcome) and EF at baseline, following 20–25 caregiver-supported sessions over 5–6 weeks, and at follow-up 3 months after cessation of training. Parents and teachers provided ratings of WM, attention, and EF. The WM composite and selective domains of EF (distractibility, cognitive flexibility), as well as parent- and teacher-reported attention and EF, significantly improved across the full study sample, with many changes maintained at follow-up. However, comparisons of improvement between adaptive and non-adaptive control conditions did not differ, showing that progressively challenging the WM system by expanding span length did not provide added benefit overall. Further experimental comparisons are needed before Cogmed working memory training can be considered empirically validated for children with FXS, forming the basis of treatment recommendation. However, given that prior studies show no significant changes on these measures in FXS without treatment, that improvements were maintained for 3 months, and that blinded teachers reported improvements in the classroom, the modest benefits seen in both adaptive and non-adaptive groups overall are unlikely to be attributable to placebo or practice effects alone. Future analyses examining inter-individual differences (e.g., baseline capacity, training efficiency, co-morbidity, training environment, characteristics of training aide) may help to link this intervention to outcomes and potential transfer effects. US National Institutes of Health (ClinicalTrials.gov), NCT02747394 .

    更新日期:2019-11-28
  • Lifespan trajectory of affect in Cornelia de Lange syndrome: towards a neurobiological hypothesis
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-06-07
    Laura Groves; Joanna Moss; Hayley Crawford; Lisa Nelson; Chris Stinton; Gursharan Singla; Chris Oliver

    Depressive symptomology and low affect are comparatively common in individuals with genetic disorders such as Cornelia de Lange syndrome. However, lifespan trajectories and associated person characteristics have not been examined. In this study, the trajectories for affect and associated behavioural characteristics were investigated in individuals with Cornelia de Lange syndrome with individuals with fragile X syndrome (FXS) comparable for chronological age and total number of behavioural indicators of ASD included for the purpose of contrast. A 7-year longitudinal study of affect (mood, interest and pleasure) was conducted in individuals with CdLS (n = 44) and FXS (n = 95). The trajectories of low affect were explored, as well as associations between Time 1 behavioural characteristics and affect at Time 1 and Time 3 (7 years later). The CdLS group were lower in mood than the FXS group overall (p < .001). Interest and pleasure scores showed a significant decline over the lifespan for individuals with CdLS (p < .001) but not the FXS group. Lower level of ability at Time 1 was associated with lower mood at Time 1 and Time 3 in the FXS group only. Higher levels of ASD symptomology at Time 1 were associated with low mood and interest and pleasure in both syndrome groups at Time 1 and Time 3. Greater insistence on sameness at Time 1 was associated with lower mood at Time 1 in the FXS group and lower interest and pleasure at Time 1 and Time 3 in the CdLS group. Low affect in specific genetic syndromes may be associated with differing lifespan trajectories and behavioural profiles. Specifically, individuals with CdLS appear at risk for experiencing declines in levels of interest and pleasure whereas individuals with FXS show no significant change in the level of affect with age.

    更新日期:2019-11-28
  • In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-06-07
    Zahra Motahari; Sally Ann Moody; Thomas Michael Maynard; Anthony-Samuel LaMantia

    22q11.2 deletion syndrome (22q11DS), a copy number variation (CNV) disorder, occurs in approximately 1:4000 live births due to a heterozygous microdeletion at position 11.2 (proximal) on the q arm of human chromosome 22 (hChr22) (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011). This disorder was known as DiGeorge syndrome, Velo-cardio-facial syndrome (VCFS) or conotruncal anomaly face syndrome (CTAF) based upon diagnostic cardiovascular, pharyngeal, and craniofacial anomalies (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011; Burn et al., J Med Genet 30:822-4, 1993) before this phenotypic spectrum was associated with 22q11.2 CNVs. Subsequently, 22q11.2 deletion emerged as a major genomic lesion associated with vulnerability for several clinically defined behavioral deficits common to a number of neurodevelopmental disorders (Fernandez et al., Principles of Developmental Genetics, 2015; Robin and Shprintzen, J Pediatr 147:90-6, 2005; Schneider et al., Am J Psychiatry 171:627-39, 2014). The mechanistic relationships between heterozygously deleted 22q11.2 genes and 22q11DS phenotypes are still unknown. We assembled a comprehensive “line-up” of the 36 protein coding loci in the 1.5 Mb minimal critical deleted region on hChr22q11.2, plus 20 protein coding loci in the distal 1.5 Mb that defines the 3 Mb typical 22q11DS deletion. We categorized candidates based upon apparent primary cell biological functions. We analyzed 41 of these genes that encode known proteins to determine whether haploinsufficiency of any single 22q11.2 gene—a one gene to one phenotype correspondence due to heterozygous deletion restricted to that locus—versus complex multigenic interactions can account for single or multiple 22q11DS phenotypes. Our 22q11.2 functional genomic assessment does not support current theories of single gene haploinsufficiency for one or all 22q11DS phenotypes. Shared molecular functions, convergence on fundamental cell biological processes, and related consequences of individual 22q11.2 genes point to a matrix of multigenic interactions due to diminished 22q11.2 gene dosage. These interactions target fundamental cellular mechanisms essential for development, maturation, or homeostasis at subsets of 22q11DS phenotypic sites.

    更新日期:2019-11-28
  • Using kinematic analyses to explore sensorimotor control impairments in children with 22q11.2 deletion syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-06-10
    Adam C. Cunningham; Liam Hill; Mark Mon-Williams; Kathryn J. Peall; David E. J. Linden; Jeremy Hall; Michael J. Owen; Marianne B. M. van den Bree

    The 22q11.2 deletion is associated with psychiatric and behavioural disorders, intellectual disability and multiple physical abnormalities. Recent research also indicates impaired coordination skills may be part of the clinical phenotype. This study aimed to characterise sensorimotor control abilities in children with 22q11.2 deletion syndrome (22q11.2DS) and investigate their relationships with co-occurring IQ impairments and psychopathology. Fifty-four children with 22q11.2DS and 24 unaffected sibling controls, comparable in age and gender, underwent kinematic analysis of their hand movements, whilst performing a battery of three visuo-manual coordination tasks that measured their tracking, aiming and steering abilities. Additionally, standardised assessments of full-scale IQ (FSIQ), attention deficit hyperactivity disorder, indicative autism spectrum disorder (ASD) and anxiety disorder symptomatology were conducted. Children with 22q11.2DS showed deficits on seven of eight kinematic descriptors of movement quality across the three coordination tasks, compared to controls. Within 22q11.2DS cases, the extent of impairment on only three kinematic descriptors was significantly related to FSIQ after correction for multiple testing. Moreover, only error whilst visuo-manually tracking was nominally associated with ADHD symptom counts. Impairments in sensorimotor control are seen on a range of visuo-manual tasks in children with 22q11.2DS but the extent of these impairments are largely unrelated to the severity of other psychopathological and intellectual impairments commonly found in children with 22q11.2DS.

    更新日期:2019-11-28
  • Lesser suppression of response to bright visual stimuli and visual abnormality in children with autism spectrum disorder: a magnetoencephalographic study
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-06-14
    Sho Aoki; Kuriko Kagitani-Shimono; Junko Matsuzaki; Ryuzo Hanaie; Mariko Nakanishi; Koji Tominaga; Yukie Nagai; Ikuko Mohri; Masako Taniike

    Visual abnormality is a common sensory impairment in autism spectrum disorder (ASD), which may cause behavioral problems. However, only a few studies exist on the neural features corresponding to the visual symptoms in ASD. The purpose of this study was to investigate the relationship between cortical responses to visual stimuli and visual abnormality to examine the neurophysiological mechanisms of the visual abnormality in ASD. Twenty-two high-functioning children with ASD (10.95 ± 2.01 years old) and 23 age-matched typically developing (TD) children (10.13 ± 2.80 years old) participated in this study. We measured the cortical responses (i.e., activated intensity and attenuation ratio) elicited by the Original visual image and other two types of bright images (the Dot noise or Blind image, which includes overlapped particles onto the Original image or the enhanced-brightness version of the Original image, respectively) using magnetoencephalography. The severity of visual abnormalities was significantly associated with behavioral problems in children with ASD. In addition, we found the increased cortical activation in response to the Original image in the left supramarginal gyrus (SMG) and middle temporal gyrus in children with ASD. However, there were no inter-group differences in the primary visual and medial orbitofrontal cortices. Furthermore, when we compared cortical responses according to the type of images, children with ASD showed lesser attenuation of the activated intensities than children with TD in response to the bright images compared with the Original image in the right SMG. These attenuation ratios (Dot noise/Original and Blind/Original) were also associated with the severity of visual abnormalities. Our results show that dysfunction of stimulus-driven neural suppression plays a crucial role in the neural mechanism of visual abnormality in children with ASD. To the best of our knowledge, this is the first magnetoencephalography study to demonstrate the association between the severity of visual abnormality and lower attenuation ratios in children with ASD. Our results contribute to the knowledge of the mechanisms underlying visual abnormality in children with ASD, and may therefore lead to more effective diagnosis and earlier intervention.

    更新日期:2019-11-28
  • Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-06-15
    Santosh Kumar; Kurt Reynolds; Yu Ji; Ran Gu; Sunil Rai; Chengji J. Zhou

    The development of an autistic brain is a highly complex process as evident from the involvement of various genetic and non-genetic factors in the etiology of the autism spectrum disorder (ASD). Despite being a multifactorial neurodevelopmental disorder, autistic patients display a few key characteristics, such as the impaired social interactions and elevated repetitive behaviors, suggesting the perturbation of specific neuronal circuits resulted from abnormal signaling pathways during brain development in ASD. A comprehensive review for autistic signaling mechanisms and interactions may provide a better understanding of ASD etiology and treatment. Recent studies on genetic models and ASD patients with several different mutated genes revealed the dysregulation of several key signaling pathways, such as WNT, BMP, SHH, and retinoic acid (RA) signaling. Although no direct evidence of dysfunctional FGF or TGF-β signaling in ASD has been reported so far, a few examples of indirect evidence can be found. This review article summarizes how various genetic and non-genetic factors which have been reported contributing to ASD interact with WNT, BMP/TGF-β, SHH, FGF, and RA signaling pathways. The autism-associated gene ubiquitin-protein ligase E3A (UBE3A) has been reported to influence WNT, BMP, and RA signaling pathways, suggesting crosstalk between various signaling pathways during autistic brain development. Finally, the article comments on what further studies could be performed to gain deeper insights into the understanding of perturbed signaling pathways in the etiology of ASD. The understanding of mechanisms behind various signaling pathways in the etiology of ASD may help to facilitate the identification of potential therapeutic targets and design of new treatment methods.

    更新日期:2019-11-28
  • Novel pathogenic variants and multiple molecular diagnoses in neurodevelopmental disorders
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-06-25
    Joanne Trinh; Krishna Kumar Kandaswamy; Martin Werber; Maximilian E. R. Weiss; Gabriela Oprea; Shivendra Kishore; Katja Lohmann; Arndt Rolfs

    Rare denovo variants represent a significant cause of neurodevelopmental delay and intellectual disability (ID). Exome sequencing was performed on 4351 patients with global developmental delay, seizures, microcephaly, macrocephaly, motor delay, delayed speech and language development, or ID according to Human Phenotype Ontology (HPO) terms. All patients had previously undergone whole exome sequencing as part of diagnostic genetic testing with a focus on variants in genes implicated in neurodevelopmental disorders up to January 2017. This resulted in a genetic diagnosis in 1336 of the patients. In this study, we specifically searched for variants in 14 recently implicated novel neurodevelopmental disorder (NDD) genes. We identified 65 rare, protein-changing variants in 11 of these 14 novel candidate genes. Fourteen variants in CDK13, CHD4, KCNQ3, KMT5B, TCF20, and ZBTB18 were scored pathogenic or likely pathogenic. Of note, two of these patients had a previously identified cause of their disease, and thus, multiple molecular diagnoses were made including pathogenic/likely pathogenic variants in FOXG1 and CDK13 or in TMEM237 and KMT5B. Looking for pathogenic variants in newly identified NDD genes enabled us to provide a molecular diagnosis to 14 patients and their close relatives and caregivers. This underlines the relevance of re-evaluation of existing exome data on a regular basis to improve the diagnostic yield and serve the needs of our patients.

    更新日期:2019-11-28
  • Children with facial paralysis due to Moebius syndrome exhibit reduced autonomic modulation during emotion processing
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-07-10
    Elisa De Stefani; Martina Ardizzi; Ylenia Nicolini; Mauro Belluardo; Anna Barbot; Chiara Bertolini; Gioacchino Garofalo; Bernardo Bianchi; Gino Coudé; Lynne Murray; Pier Francesco Ferrari

    Facial mimicry is crucial in the recognition of others’ emotional state. Thus, the observation of others’ facial expressions activates the same neural representation of that affective state in the observer, along with related autonomic and somatic responses. What happens, therefore, when someone cannot mimic others’ facial expressions? We investigated whether psychophysiological emotional responses to others’ facial expressions were impaired in 13 children (9 years) with Moebius syndrome (MBS), an extremely rare neurological disorder (1/250,000 live births) characterized by congenital facial paralysis. We inspected autonomic responses and vagal regulation through facial cutaneous thermal variations and by the computation of respiratory sinus arrhythmia (RSA). These parameters provide measures of emotional arousal and show the autonomic adaptation to others’ social cues. Physiological responses in children with MBS were recorded during dynamic facial expression observation and were compared to those of a control group (16 non-affected children, 9 years). There were significant group effects on thermal patterns and RSA, with lower values in children with MBS. We also observed a mild deficit in emotion recognition in these patients. Results support “embodied” theory, whereby the congenital inability to produce facial expressions induces alterations in the processing of facial expression of emotions. Such alterations may constitute a risk for emotion dysregulation.

    更新日期:2019-11-28
  • A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-07-18
    Claudia Ismania Samogy-Costa; Elisa Varella-Branco; Frederico Monfardini; Helen Ferraz; Rodrigo Ambrósio Fock; Ricardo Henrique Almeida Barbosa; André Luiz Santos Pessoa; Ana Beatriz Alvarez Perez; Naila Lourenço; Maria Vibranovski; Ana Krepischi; Carla Rosenberg; Maria Rita Passos-Bueno

    Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the clinical variability seen among individuals. Our goals were to characterize a Brazilian cohort of PMS individuals, explore the genotype-phenotype correlation underlying this syndrome, and describe an atypical individual with mild phenotype. A total of 34 PMS individuals were clinically and genetically evaluated. Data were obtained by a questionnaire answered by parents, and dysmorphic features were assessed via photographic evaluation. We analyzed 22q13.3 deletions and other potentially pathogenic copy number variants (CNVs) and also performed genotype-phenotype correlation analysis to determine whether comorbidities, speech status, and ASD correlate to deletion size. Finally, a Brazilian cohort of 829 ASD individuals and another independent cohort of 2297 ID individuals was used to determine the frequency of PMS in these disorders. Our data showed that 21% (6/29) of the PMS individuals presented an additional rare CNV, which may contribute to clinical variability in PMS. Increased pain tolerance (80%), hypotonia (85%), and sparse eyebrows (80%) were prominent clinical features. An atypical case diagnosed with PMS at 18 years old and IQ within the normal range is here described. Among Brazilian ASD or ID individuals referred to CNV analyses, the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.61% (15/2297), respectively. Finally, renal abnormalities, lymphedema, and language impairment were found to be positively associated with deletion sizes, and the minimum deletion to cause these abnormalities is here suggested. This is the first work describing a cohort of Brazilian individuals with PMS. Our results confirm the impact of 22q13 deletions on ASD and several comorbidities, such as hypotonia. The estimation of a minimal deletion size for developing lymphedema and renal problem can assist prediction of prognosis in PMS individuals, particularly those diagnosed in early infancy. We also identified one atypical individual carrying SHANK3 deletion, suggesting that resilience to such mutations occurs. This case expands the clinical spectrum of variability in PMS and opens perspectives to identify protective mechanisms that can minimize the severity of this condition.

    更新日期:2019-11-28
  • Infant regulatory function acts as a protective factor for later traits of autism spectrum disorder and attention deficit/hyperactivity disorder but not callous unemotional traits
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-07-18
    Rachael Bedford; Teodora Gliga; Alexandra Hendry; Emily J. H. Jones; Greg Pasco; Tony Charman; Mark H. Johnson; Andrew Pickles

    Reduced executive functions (EF) are commonly associated with developmental conditions (e.g., autism spectrum disorder, ASD; attention deficit/hyperactivity disorder, ADHD), although EF seems to be typical in children with callous unemotional (CU) traits. Regulatory function (RF) is a proposed infant precursor that maps on onto factors driving later EF. Here, we first test whether RF is specifically and negatively associated with ASD and ADHD traits, but not CU traits. Second, we test whether RF can act as a protective factor, by moderating the association between infant markers and subsequent ASD and ADHD traits. Participants were 79 infants at high (N = 42) and low (N = 37) familial risk for ASD. Data come from the 14-month infant visit (Autism Observational Scale for Infants; AOSI; activity level and RF from the Infant Behavior Questionnaire; IBQ) and the 7-year visit (ASD traits: Social Responsiveness Scale, SRS; ADHD traits: Conners 3, CU traits: Inventory of Callous Unemotional Traits). Infant RF was negatively associated with later traits of ASD (B = − 0.5, p = 0.01) and ADHD inattention (B = − 0.24, p = 0.02) but not hyperactivity (B = − 0.25, p = 0.10) or CU traits (B = 0.02, p = 0.86). RF moderated the association between infant AOSI score and ASD traits, with a significant effect in those with low RF (B = 0.10, p = 0.006), not high RF (B = 0.01, p = 0.78). Similarly, for ADHD, infant activity level was associated with later ADHD inattention in those with low (B = 0.17, p = 0.04) but not high RF (B = 0.07, p = 0.48). For ADHD hyperactivity symptoms, activity level was predictive at both high and low levels of RF. Strong RF may allow children to compensate for other atypicalities, thus attenuating the association between infant markers and later disorder traits. Whilst infant RF was associated with both ASD and ADHD inattention traits, there was no association with ADHD hyperactivity or CU traits. This suggests that any protective effect may not be universal and emphasises the need for a better understanding of the underlying moderating mechanisms.

    更新日期:2019-11-28
  • Electroencephalographic spectral power as a marker of cortical function and disease severity in girls with Rett syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-07-31
    Katherine J. Roche; Jocelyn J. LeBlanc; April R. Levin; Heather M. O’Leary; Lauren M. Baczewski; Charles A. Nelson

    Rett syndrome is a neurodevelopmental disorder caused by a mutation in the X-linked MECP2 gene. Individuals with Rett syndrome typically develop normally until around 18 months of age before undergoing a developmental regression, and the disorder can lead to cognitive, motor, sensory, and autonomic dysfunction. Understanding the mechanism of developmental regression represents a unique challenge when viewed through a neuroscience lens. Are circuits that were previously established erased, and are new ones built to supplant old ones? One way to examine circuit-level changes is with the use of electroencephalography (EEG). Previous studies of the EEG in individuals with Rett syndrome have focused on morphological characteristics, but few have explored spectral power, including power as an index of brain function or disease severity. This study sought to determine if EEG power differs in girls with Rett syndrome and typically developing girls and among girls with Rett syndrome based on various clinical characteristics in order to better understand neural connectivity and cortical organization in individuals with this disorder. Resting state EEG data were acquired from girls with Rett syndrome (n = 57) and typically developing children without Rett syndrome (n = 37). Clinical data were also collected for girls with Rett syndrome. EEG power across several brain regions in numerous frequency bands was then compared between girls with Rett syndrome and typically developing children and power in girls with Rett syndrome was compared based on these clinical measures. 1/ƒ slope was also compared between groups. Girls with Rett syndrome demonstrate significantly lower power in the middle frequency bands across multiple brain regions. Additionally, girls with Rett syndrome that are postregression demonstrate significantly higher power in the lower frequency delta and theta bands and a significantly more negative slope of the power spectrum. Increased power in these bands, as well as a more negative 1/ƒ slope, trended with lower cognitive assessment scores. Increased power in lower frequency bands is consistent with previous studies demonstrating a “slowing” of the background EEG in Rett syndrome. This increase, particularly in the delta band, could represent abnormal cortical inhibition due to dysfunctional GABAergic signaling and could potentially be used as a marker of severity due to associations with more severe Rett syndrome phenotypes.

    更新日期:2019-11-28
  • A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-08-02
    Helen Heussler; Jonathan Cohen; Natalie Silove; Nancy Tich; Marcel O. Bonn-Miller; Wei Du; Carol O’Neill; Terri Sebree

    Fragile X syndrome (FXS) is characterized by a range of developmental, neuropsychiatric, and behavioral symptoms that cause significant impairment in those with the disorder. Cannabidiol (CBD) holds promise as a potential treatment for FXS symptoms due to its safety profile and positive effects on a number of emotional and behavioral symptoms associated with FXS. The aim of the current study was to evaluate the safety, tolerability, and initial efficacy of ZYN002, a transdermal CBD gel, in a pediatric population with FXS. Twenty children and adolescents (aged 6–17 years) with a diagnosis of FXS (confirmed through molecular documentation of FMR1 full mutation) were enrolled in an open-label, multi-site, trial of ZYN002. Transdermal CBD gel was administered twice daily for 12 weeks, titrated from 50 mg to a maximum daily dose of 250 mg. The primary efficacy endpoint was change from screening to week 12 on the Anxiety, Depression, and Mood Scale (ADAMS). Secondary endpoint measures included the Aberrant Behavior Checklist—Community for FXS (ABC-CFXS), Pediatric Anxiety Rating Scale (PARS-R), Pediatric Quality of Life Inventory (PedsQL™), three Visual Analogue Scales (VAS), and the Clinical Global Impression Scale—Severity (CGI-S) and Improvement (CGI-I). The majority of treatment-emergent AEs (reported by 85% of participants) were mild in severity (70%), and no serious adverse events were reported. There was a statistically significant reduction in ADAMS total score from screening to week 12 and significant reductions on nearly all other secondary endpoints, including all ADAMS subscales (except depressed mood), all ABC-CFXS subscale scores (e.g., social avoidance, irritability), PARS-R total severity score, and PedsQL total score. ZYN002 was well tolerated and produced clinically meaningful reductions in anxiety and behavioral symptoms in children and adolescents with FXS. These findings support further study of ZYN002 in a randomized, well-controlled trial for the treatment of behavioral symptoms of FXS. ANZCTR, ACTRN12617000150347 Registered 27 January 2017

    更新日期:2019-11-28
  • STXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-08-06
    Sinéad O’Brien; Elise Ng-Cordell; Duncan E. Astle; Gaia Scerif; Kate Baker

    De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families.

    更新日期:2019-11-28
  • Phenotypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and developmental progression
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-08-08
    Andres Jimenez-Gomez; Sizhe Niu; Fabiola Andujar-Perez; Elizabeth A. McQuade; Alfred Balasa; David Huss; Rohini Coorg; Michael Quach; Sherry Vinson; Sarah Risen; J. Lloyd Holder

    The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28–174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker.

    更新日期:2019-11-28
  • Magnetoencephalographic (MEG) brain activity during a mental flexibility task suggests some shared neurobiology in children with neurodevelopmental disorders
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-08-19
    Alexandra Mogadam; Anne E. Keller; Paul D. Arnold; Russell Schachar; Jason P. Lerch; Evdokia Anagnostou; Elizabeth W. Pang

    Children with neurodevelopmental disorders (NDDs) exhibit a shared phenotype that involves executive dysfunctions including impairments in mental flexibility (MF). It is of interest to understand if this phenotype stems from some shared neurobiology. To investigate this possibility, we used magnetoencephalography (MEG) neuroimaging to compare brain activity in children (n = 88; 8–15 years) with autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), as they completed a set-shifting/mental flexibility task. Neuroimaging results revealed a similar parietal activation profile across the NDD, groups suggesting a link to their shared phenotype. Differences in frontal activity differentiated the three clinical groups. Brain-behaviour analyses showed a link with repetitive behaviours suggesting shared dysfunction in the associative loop of the corticostriatal system. Our study supports the notion that NDDs may exist along a complex phenotypic/biological continuum. All NDD groups showed a sustained parietal activity profile suggesting that they share a strong reliance on the posterior parietal cortices to complete the mental flexibility task; future studies could elucidate whether this is due to delayed brain development or compensatory functioning. The differences in frontal activity may play a role in differentiating the NDDs. The OCD group showed sustained prefrontal activity that may be reflective of hyperfrontality. The ASD group showed reduced frontal activation suggestive of frontal dysfunction and the ADHD group showed an extensive hypoactivity that included frontal and parietal regions. Brain-behaviour analyses showed a significant correlation with repetitive behaviours which may reflect dysfunction in the associative loop of the corticostriatal system, linked to inflexible behaviours.

    更新日期:2019-11-28
  • Assessing general cognitive and adaptive abilities in adults with Down syndrome: a systematic review
    J. Neurodev. Disord. (IF 3.59) Pub Date : 2019-08-30
    Sarah Hamburg; Bryony Lowe; Carla Marie Startin; Concepcion Padilla; Antonia Coppus; Wayne Silverman; Juan Fortea; Shahid Zaman; Elizabeth Head; Benjamin L. Handen; Ira Lott; Weihong Song; André Strydom

    Measures of general cognitive and adaptive ability in adults with Down syndrome (DS) used by previous studies vary substantially. This review summarises the different ability measures used previously, focusing on tests of intelligence quotient (IQ) and adaptive behaviour (AB), and where possible examines floor effects and differences between DS subpopulations. We aimed to use information regarding existing measures to provide recommendations for individual researchers and the DS research community. Nineteen studies reporting IQ test data met inclusion for this review, with 17 different IQ tests used. Twelve of these IQ tests were used in only one study while five were used in two different studies. Eleven studies reporting AB test data met inclusion for this review, with seven different AB tests used. The only AB scales to be used by more than one study were the Vineland Adaptive Behaviour Scale (VABS; used by three studies) and the Vineland Adaptive Behavior Scale 2nd Edition (VABS-II; used by two studies). A variety of additional factors were identified which make comparison of test scores between studies problematic, including different score types provided between studies (e.g. raw scores compared to age-equivalent scores) and different participant inclusion criteria (e.g. whether individuals with cognitive decline were excluded). Floor effects were common for IQ tests (particularly for standardised test scores). Data exists to suggest that floor effects may be minimised by the use of raw test scores rather than standardised test scores. Raw scores may, therefore, be particularly useful in longitudinal studies to track change in cognitive ability over time. Studies assessing general ability in adults with DS are likely to benefit from the use of both IQ and AB scales. The DS research community may benefit from the development of reporting standards for IQ and AB data, and from the sharing of raw study data enabling further in-depth investigation of issues highlighted by this review.

    更新日期:2019-11-28
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