|
1
|
Jin F, Wang Z. Mapping the structure of biomarkers in autism spectrum disorder: a review of the most influential studies. Front Neurosci 2024; 18:1514678. [PMID: 39734494 PMCID: PMC11671500 DOI: 10.3389/fnins.2024.1514678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/02/2024] [Indexed: 12/31/2024] Open
Abstract
BACKGROUND Autism spectrum disorder is a distinctive developmental condition which is caused by an interaction between genetic vulnerability and environmental factors. Biomarkers play a crucial role in understanding disease characteristics for diagnosis, prognosis, and treatment. This study employs bibliometric analysis to identify and review the 100 top-cited articles' characteristics, current research hotspots and future directions of autism biomarkers. METHODS A comprehensive search of autism biomarkers studies was retrieved from the Web of Science Core Collection database with a combined keyword search strategy. A comprehensive analysis of the top 100 articles was conducted with CiteSpace, VOSviewer, and Excel, including citations, countries, authors, and keywords. RESULTS The top 100 cited studies were published between 1988 and 2021, with the United States led in productivity. Core biomarkers such as genetics, children, oxidative stress, and mitochondrial dysfunction are well-established. Potential trends for future research may include brain studies, metabolomics, and associations with other psychiatric disorders. CONCLUSION This pioneering bibliometric analysis provides a comprehensive compilation of the 100 most-cited studies on autism, which not only offers a valuable resource for doctors, and researchers but shedding insights into current shortcomings and future endeavors. Future research should prioritize the application of emerging technologies for biomarkers, longitudinal study of biomarkers, and specificity of autism biomarkers to advance the precision of ASD diagnosis and treatment.
Collapse
Affiliation(s)
| | - Zhidan Wang
- School of Education Science, Jiangsu Normal University, Xuzhou, China
| |
Collapse
|
|
2
|
Gholamalizadeh H, Amiri-Shahri M, Rasouli F, Ansari A, Baradaran Rahimi V, Reza Askari V. DNA Methylation in Autism Spectrum Disorders: Biomarker or Pharmacological Target? Brain Sci 2024; 14:737. [PMID: 39199432 PMCID: PMC11352561 DOI: 10.3390/brainsci14080737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/20/2024] [Accepted: 07/21/2024] [Indexed: 09/01/2024] Open
Abstract
Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental disabilities with persistent impairments in cognition, communication, and social behavior. Although environmental factors play a role in ASD etiopathogenesis, a growing body of evidence indicates that ASD is highly inherited. In the last two decades, the dramatic rise in the prevalence of ASD has interested researchers to explore the etiologic role of epigenetic marking and incredibly abnormal DNA methylation. This review aimed to explain the current understanding of the association between changes in DNA methylation signatures and ASD in patients or animal models. We reviewed studies reporting alterations in DNA methylation at specific genes as well as epigenome-wide association studies (EWASs). Finally, we hypothesized that specific changes in DNA methylation patterns could be considered a potential biomarker for ASD diagnosis and prognosis and even a target for pharmacological intervention.
Collapse
Affiliation(s)
- Hanieh Gholamalizadeh
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad 13131-99137, Iran;
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| | - Maedeh Amiri-Shahri
- Student Research Committee, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran; (M.A.-S.); (F.R.); (A.A.)
- Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran
| | - Fatemeh Rasouli
- Student Research Committee, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran; (M.A.-S.); (F.R.); (A.A.)
- Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran
| | - Arina Ansari
- Student Research Committee, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran; (M.A.-S.); (F.R.); (A.A.)
- Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd 94149-75516, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran;
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| |
Collapse
|
|
3
|
Gámez S, Cobo J, Fernández-Lafitte M, Coronas R, Parra I, Oliva JC, Àlvarez A, Esteba-Castillo S, Giménez-Palop O, Corripio R, Palao DJ, Caixàs A. An Exploratory Analysis on the 2D:4D Digit Ratio and Its Relationship with Social Responsiveness in Adults with Prader-Willi Syndrome. J Clin Med 2023; 12:jcm12031155. [PMID: 36769803 PMCID: PMC9917981 DOI: 10.3390/jcm12031155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/22/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
Prader-Willi syndrome (PWS) is a genetic disorder produced by a lack of expression of paternally derived genes in the 15q11-13 region. Research has generally focused on its genetic and behavioral expression, but only a few studies have examined epigenetic influences. Prenatal testosterone or the maternal testosterone-to-estradiol ratio (MaTtEr) has been suggested to play an important role in the development of the 'social brain' during pregnancy. Some studies propose the 2D:4D digit ratio of the hand as an indirect MaTtEr measure. The relationship between social performance and MaTtEr has been studied in other neurodevelopmental conditions such as Autism Spectrum Disorder (ASD), but to our best knowledge, it has never been studied in PWS. Therefore, our study aims to clarify the possible existence of a relationship between social performance-as measured using the Social Responsiveness Scale (SRS)-and MaTtEr levels using the 2D:4D ratio. We found that, as a group, PWS individuals have shorter index and ring fingers than the control group, but no significant difference in the 2D:4D ratios. The 2D:4D ratio showed a correlation only with Restricted Interests and Repetitive Behavior Subscale, where a positive correlation only for male individuals with PWS was found. Considering only PWS with previous GH treatment during childhood/adolescence (PWS-GH), index and ring fingers did not show differences in length with the control group, but the 2D:4D ratio was significantly higher in the right or dominant hand compared to controls.
Collapse
Affiliation(s)
- Sara Gámez
- Mental Health Department, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona—CIBERSAM, 08202 Sabadell, Spain
| | - Jesus Cobo
- Mental Health Department, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona—CIBERSAM, 08202 Sabadell, Spain
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- Institut d’Investigació i Innovació Parc Taulí (I3PT)—CERCA, 08208 Sabadell, Spain
- Correspondence: (J.C.); (A.C.)
| | - Meritxell Fernández-Lafitte
- Mental Health Department, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona—CIBERSAM, 08202 Sabadell, Spain
| | - Ramón Coronas
- Mental Health Department, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona—CIBERSAM, 08202 Sabadell, Spain
| | - Isabel Parra
- Mental Health Department, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona—CIBERSAM, 08202 Sabadell, Spain
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- Institut d’Investigació i Innovació Parc Taulí (I3PT)—CERCA, 08208 Sabadell, Spain
| | - Joan Carles Oliva
- Statistics Unit, Fundació Parc Taulí—(I3PT)—CERCA, 08208 Sabadell, Spain
| | - Aida Àlvarez
- Department of Mental Health, Mutua Terrassa University Hospital, 08221 Terrassa, Spain
| | - Susanna Esteba-Castillo
- Specialized Mental Health and Intellectual Disability Department, Institut d’Assistència Sanitària, Parc Hospitalari Martí i Julià, 17190 Girona, Spain
- Neurodevelopment Group, Girona Biomedical Research Institute IDIBGI, Institut d’Assistència Sanitària, Parc Hospitalari Martí i Julià, 17190 Girona, Spain
| | - Olga Giménez-Palop
- Endocrinology and Nutrition Department, Hospital Universitari Parc Taulí, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona, 08202 Sabadell, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Raquel Corripio
- Pediatric Endocrine Department, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònoma de Barcelona, 08202 Sabadell, Spain
| | - Diego J. Palao
- Mental Health Department, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona—CIBERSAM, 08202 Sabadell, Spain
- Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- Institut d’Investigació i Innovació Parc Taulí (I3PT)—CERCA, 08208 Sabadell, Spain
| | - Assumpta Caixàs
- Endocrinology and Nutrition Department, Hospital Universitari Parc Taulí, Corporació Sanitària Parc Taulí—Universitat Autònoma de Barcelona, 08202 Sabadell, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- Correspondence: (J.C.); (A.C.)
| |
Collapse
|
|
4
|
Social Responsiveness and Psychosocial Functioning in Adults with Prader-Willi Syndrome. J Clin Med 2022; 11:jcm11051433. [PMID: 35268524 PMCID: PMC8911114 DOI: 10.3390/jcm11051433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/20/2022] [Accepted: 03/02/2022] [Indexed: 12/04/2022] Open
Abstract
Although various studies have investigated symptoms of autism spectrum disorder (ASD) in Prader−Willi syndrome (PWS), little is known about the consequences of these symptoms, especially in psychosocial function. We aimed to explore ASD symptoms in adults with PWS with special attention to psychosocial functionality. This cross-sectional study included 26 adults (15 women) with PWS who attended a reference unit for rare diseases. Participants’ primary caregivers completed the Social Responsiveness Scale (SRS), and clinicians assessed multidimensional functioning with the Personal and Social Performance Scale (PSP). Impaired social responsiveness was identified in 20 (76.9%) participants, and manifest to marked difficulties in social functioning were identified in 13 (50%). Participants with impaired social responsiveness (SRS ≥ 60) had significantly worse scores in functionality measured with the PSP (U = 12.5; p = 0.009) and with three of the four PSP main areas. Moreover, scores for the Social Cognition domain of the SRS correlated positively with the Socially useful activities (p < 0.05) and Personal and social relationships (p < 0.01) main areas of the PSP. These results suggest that difficulties in social skills should be assessed in all psychosocial evaluations of patients with PWS.
Collapse
|
|
5
|
Qian K, Koike T, Tamada K, Takumi T, Schuller BW, Yamamoto Y. Sensing the Sounds of Silence: A Pilot Study on the Detection of Model Mice of Autism Spectrum Disorder from Ultrasonic Vocalisations. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2021; 2021:68-71. [PMID: 34891241 DOI: 10.1109/embc46164.2021.9630793] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Studying the animal models of human neuropsychiatric disorders can facilitate the understanding of mechanisms of symptoms both physiologically and genetically. Previous studies have shown that ultrasonic vocalisations (USVs) of mice might be efficient markers to distinguish the wild type group and the model of autism spectrum disorder (mASD). Nevertheless, in-depth analysis of these 'silence' sounds by leveraging the power of advanced computer audition technologies (e. g., deep learning) is limited. To this end, we propose a pilot study on using a large-scale pre-trained audio neural network to extract high-level representations from the USVs of mice for the task on detection of mASD. Experiments have shown a best result reaching an unweighted average recall of 79.2 % for the binary classification task in a rigorous subject-independent scenario. To the best of our knowledge, this is the first time to analyse the sounds that cannot be heard by human beings for the detection of mASD mice. The novel findings can be significant to motivate future works with according means on studying animal models of human patients.
Collapse
|
|
6
|
Eyring KW, Geschwind DH. Three decades of ASD genetics: building a foundation for neurobiological understanding and treatment. Hum Mol Genet 2021; 30:R236-R244. [PMID: 34313757 PMCID: PMC8861370 DOI: 10.1093/hmg/ddab176] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023] Open
Abstract
Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASDs) for which microarrays, whole exome sequencing and whole genome sequencing have yielded over a hundred causal loci. Genome-wide association studies in ASD have also been fruitful, identifying 5 genome-wide significant loci thus far and demonstrating a substantial role for polygenic inherited risk. Approaches rooted in systems biology and functional genomics have increasingly placed genes implicated by risk variants into biological context. Genetic risk affects a finite group of cell-types and biological processes, converging primarily on early stages of brain development (though, the expression of many risk genes persists through childhood). Coupled with advances in stem cell-based human in vitro model systems, these findings provide a basis for developing mechanistic models of disease pathophysiology.
Collapse
Affiliation(s)
- Katherine W Eyring
- Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Daniel H Geschwind
- Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Center For Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Department of Human Genetics and Institute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| |
Collapse
|
|
7
|
Chakraborty R, Vijay Kumar MJ, Clement JP. Critical aspects of neurodevelopment. Neurobiol Learn Mem 2021; 180:107415. [PMID: 33647449 DOI: 10.1016/j.nlm.2021.107415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 12/21/2020] [Accepted: 02/16/2021] [Indexed: 12/16/2022]
Abstract
Organisms have the unique ability to adapt to their environment by making use of external inputs. In the process, the brain is shaped by experiences that go hand-in-hand with optimisation of neural circuits. As such, there exists a time window for the development of different brain regions, each unique for a particular sensory modality, wherein the propensity of forming strong, irreversible connections are high, referred to as a critical period of development. Over the years, this domain of neurodevelopmental research has garnered considerable attention from many scientists, primarily because of the intensive activity-dependent nature of development. This review discusses the cellular, molecular, and neurophysiological bases of critical periods of different sensory modalities, and the disorders associated in cases the regulators of development are dysfunctional. Eventually, the neurobiological bases of the behavioural abnormalities related to developmental pathologies are discussed. A more in-depth insight into the development of the brain during the critical period of plasticity will eventually aid in developing potential therapeutics for several neurodevelopmental disorders that are categorised under critical period disorders.
Collapse
Affiliation(s)
- Ranabir Chakraborty
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru. Karnataka. India
| | - M J Vijay Kumar
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru. Karnataka. India
| | - James P Clement
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru. Karnataka. India.
| |
Collapse
|
|
8
|
Holter MC, Hewitt LT, Nishimura KJ, Knowles SJ, Bjorklund GR, Shah S, Fry NR, Rees KP, Gupta TA, Daniels CW, Li G, Marsh S, Treiman DM, Olive MF, Anderson TR, Sanabria F, Snider WD, Newbern JM. Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition. Cereb Cortex 2021; 31:3064-3081. [PMID: 33570093 DOI: 10.1093/cercor/bhaa413] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 12/20/2022] Open
Abstract
Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.
Collapse
Affiliation(s)
- Michael C Holter
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | - Lauren T Hewitt
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.,Interdepartmental Neuroscience Graduate Program, University of Texas, Austin, TX 78712, USA
| | - Kenji J Nishimura
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.,Interdepartmental Neuroscience Graduate Program, University of Texas, Austin, TX 78712, USA
| | - Sara J Knowles
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | | | - Shiv Shah
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | - Noah R Fry
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | - Katherina P Rees
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| | - Tanya A Gupta
- Department of Psychology, Arizona State University, Tempe, AZ 85287, USA
| | - Carter W Daniels
- Department of Psychology, Arizona State University, Tempe, AZ 85287, USA.,Department of Psychiatry, Columbia University, New York, NY 10032, USA
| | - Guohui Li
- College of Medicine, University of Arizona, Phoenix, AZ 85004, USA
| | - Steven Marsh
- Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | | | | | - Trent R Anderson
- College of Medicine, University of Arizona, Phoenix, AZ 85004, USA
| | - Federico Sanabria
- Department of Psychology, Arizona State University, Tempe, AZ 85287, USA
| | - William D Snider
- University of North Carolina Neuroscience Center, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Jason M Newbern
- School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
| |
Collapse
|
|
9
|
Kawamoto A, Kajiume A, Yoshida H, Toshima T, Kobayashi M. Individual Differences in Autistic Traits are Associated with Serotonin Transporter Gene Polymorphism Through Medial Prefrontal Function: A Study Using NIRS. Neuroscience 2021; 458:43-53. [PMID: 33460729 DOI: 10.1016/j.neuroscience.2021.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 01/03/2021] [Accepted: 01/05/2021] [Indexed: 11/17/2022]
Abstract
Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder that can vary considerably in severity. Autistic traits are distributed continuously across populations, even in sub-clinical individuals. Serotonin transporter-gene polymorphic region (5-HTTLPR) has been studied as a candidate genetic factor related to ASD, however results have been inconsistent. 5-HTTLPR is implicated in the function of medial prefrontal cortex (mPFC), a region associated with the social abnormalities found in ASD. Here we hypothesize that autistic traits are affected by the 5-HTTLPR genotype indirectly through mPFC mediation. Using near-infrared spectroscopy (NIRS), we first examined mPFC activation in people with ASD when they performed a facial affect-labeling task. Compared with a typical development group, the ASD group showed significantly lower mPFC activation during the task. Using the same task paradigm, we next investigated the relationship between autistic traits and 5-HTTLPR in sub-clinical participants, and whether associations were mediated by mPFC function. Correlation analyses indicated that participants with a large number of 5-HTTLPR L-alleles had high-level autistic traits related to social skills and low right mPFC activation. We also observed a significant negative correlation between autistic traits related to social skills and right mPFC activation. Structural equation analysis suggested a significant indirect effect of 5-HTTLPR on Autism-Spectrum Quotients, with right mPFC activation acting as a mediator. These results suggest that the diverse autistic traits related to social skills seen in the general population are associated with the 5-HTTLPR genotype, and that this association is mediated by right mPFC function.
Collapse
Affiliation(s)
- Akiko Kawamoto
- Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Aiko Kajiume
- Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Hiroshi Yoshida
- Faculty of Contemporary Culture, Hijiyama University, 4-1-1 Ushitashinmachi, Higashi-ku, Hiroshima 732-8509, Japan
| | - Tamotsu Toshima
- Department of Psychology, Graduate School of Education, Hiroshima University, 1-7-1 Kagamiyama, Higashi-Hiroshima 739-8521, Japan
| | - Masao Kobayashi
- Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| |
Collapse
|
|
10
|
Leader G, Forde J, Naughton K, Maher L, Arndt S, Mannion A. Relationships among gastrointestinal symptoms, sleep problems, challenging behaviour, comorbid psychopathology and autism spectrum disorder symptoms in children and adolescents with 15q duplication syndrome. JOURNAL OF INTELLECTUAL DISABILITY RESEARCH : JIDR 2021; 65:32-46. [PMID: 33073413 DOI: 10.1111/jir.12789] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 08/26/2020] [Accepted: 09/15/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Comorbidity is the presence of at least two disorders in one person at one time. This study examined the frequency of gastrointestinal (GI) symptoms, sleep problems, comorbid psychopathology, challenging behaviour and autism spectrum disorder (ASD) symptoms in children and adolescents with duplication 15q syndrome (Dup15q), aged 3-17 years. This study also examined whether challenging behaviour in Dup15q is predicted by age, gender, presence of an intellectual disability, sleep problems, GI symptoms and comorbid psychopathology. METHOD Parental measures were completed by 101 parents of children and adolescents with Dup15q. Questionnaires were composed of the Children's Sleep Habits Questionnaire, Behavior Problems Inventory - Short Form, GI Symptom Inventory, Social Communication Questionnaire and the Child Behavior Checklist. RESULTS Sleep problems (94%), GI symptoms (87%) and challenging behaviour (100%) were common comorbidities represented in the sample in this study. Significant relationships were found between challenging behaviour and the presence of co-occurring sleep problems, GI symptoms, comorbid psychopathology and ASD symptoms. Further analysis revealed that these comorbidities also predicted challenging behaviour. CONCLUSION This research demonstrated the importance of studying the relationships between GI symptoms, sleep problems, comorbid psychopathology, ASD symptoms and challenging behaviour in Dup15q and how these conditions can shape the Dup15q phenotype.
Collapse
Affiliation(s)
- G Leader
- Irish Centre for Autism and Neurodevelopmental Research (ICAN), School of Psychology, National University of Ireland Galway, Galway, Ireland
| | - J Forde
- Irish Centre for Autism and Neurodevelopmental Research (ICAN), School of Psychology, National University of Ireland Galway, Galway, Ireland
| | - K Naughton
- Irish Centre for Autism and Neurodevelopmental Research (ICAN), School of Psychology, National University of Ireland Galway, Galway, Ireland
| | - L Maher
- Irish Centre for Autism and Neurodevelopmental Research (ICAN), School of Psychology, National University of Ireland Galway, Galway, Ireland
| | - S Arndt
- Irish Centre for Autism and Neurodevelopmental Research (ICAN), School of Psychology, National University of Ireland Galway, Galway, Ireland
| | - A Mannion
- Irish Centre for Autism and Neurodevelopmental Research (ICAN), School of Psychology, National University of Ireland Galway, Galway, Ireland
| |
Collapse
|
|
11
|
Folkes OM, Báldi R, Kondev V, Marcus DJ, Hartley ND, Turner BD, Ayers JK, Baechle JJ, Misra MP, Altemus M, Grueter CA, Grueter BA, Patel S. An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability. J Clin Invest 2020; 130:1728-1742. [PMID: 31874107 DOI: 10.1172/jci131752] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 12/18/2019] [Indexed: 12/24/2022] Open
Abstract
Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the basolateral amygdala-nucleus accumbens (BLA-NAc) glutamatergic circuit reduced SI and increased social avoidance in mice. Furthermore, we found that 2-arachidonoylglycerol (2-AG) endocannabinoid signaling reduced BLA-NAc glutamatergic activity and that pharmacological 2-AG augmentation via administration of JZL184, a monoacylglycerol lipase inhibitor, blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit markedly increased SI in the Shank3B-/- mouse, an ASD model with substantial SI impairment, without affecting SI in WT mice. Finally, we demonstrated that JZL184 delivered systemically or directly to the NAc also normalized SI deficits in Shank3B-/- mice, while ex vivo JZL184 application corrected aberrant NAc excitatory and inhibitory neurotransmission and reduced BLA-NAc-elicited feed-forward inhibition of NAc neurons in Shank3B-/- mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASDs and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc.
Collapse
Affiliation(s)
- Oakleigh M Folkes
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Pharmacology and
| | - Rita Báldi
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Veronika Kondev
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - David J Marcus
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Nolan D Hartley
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Brandon D Turner
- Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.,Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jade K Ayers
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jordan J Baechle
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Maya P Misra
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Megan Altemus
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Carrie A Grueter
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Brad A Grueter
- Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.,Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sachin Patel
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Pharmacology and.,Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.,Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.,Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| |
Collapse
|
|
12
|
Septyaningtrias DE, Lin CW, Ouchida R, Nakai N, Suda W, Hattori M, Morita H, Honda K, Tamada K, Takumi T. Altered microbiota composition reflects enhanced communication in 15q11-13 CNV mice. Neurosci Res 2019; 161:59-67. [PMID: 31863791 DOI: 10.1016/j.neures.2019.12.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 12/13/2019] [Accepted: 12/16/2019] [Indexed: 12/14/2022]
Abstract
Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder. In addition to the core symptoms of ASD, many patients with ASD also show comorbid gut dysbiosis, which may lead to various gastrointestinal (GI) problems. Intriguingly, there is evidence that gut microbiota communicate with the central nervous system to modulate behavioral output through the gut-brain axis. To investigate how the microbiota composition is changed in ASD and to identify which microbes are involved in autistic behaviors, we performed a 16S rRNA gene-based metagenomics analysis in an ASD mouse model. Here, we focused on a model with human 15q11-13 duplication (15q dup), the most frequent chromosomal aberration or copy number variation found in ASD. Species diversity of the microbiome was significantly decreased in 15q dup mice. A combination of antibiotics treatment and behavioral analysis showed that neomycin improved social communication in 15q dup mice. Furthermore, comparison of the microbiota composition of mice treated with different antibiotics enabled us to identify beneficial operational taxonomic units (OTUs) for ultrasonic vocalization.
Collapse
Affiliation(s)
- Dian Eurike Septyaningtrias
- RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan; Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami, Hiroshima, 734-8553, Japan
| | - Chia-Wen Lin
- RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan
| | - Rika Ouchida
- RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan
| | - Nobuhiro Nakai
- RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan
| | - Wataru Suda
- RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, 230-0045, Japan
| | - Masahira Hattori
- RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, 230-0045, Japan
| | - Hidetoshi Morita
- Graduate School of Environmental and Life Science, Okayama University, Kita, Okayama, 700-8530, Japan
| | - Kenya Honda
- RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, 230-0045, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Kota Tamada
- RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan
| | - Toru Takumi
- RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan; Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami, Hiroshima, 734-8553, Japan; RIKEN Center for Science and Technology Hub, Medical Sciences Innovation Hub Program (MIH), Japan; Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Chuo, Kobe, 650-0017, Japan.
| |
Collapse
|
|
13
|
High-resolution chromosomal microarray analysis for copy-number variations in high-functioning autism reveals large aberration typical for intellectual disability. J Neural Transm (Vienna) 2019; 127:81-94. [PMID: 31838600 DOI: 10.1007/s00702-019-02114-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 12/03/2019] [Indexed: 10/25/2022]
Abstract
Copy-number variants (CNVs), in particular rare, small and large ones (< 1% frequency) and those encompassing brain-related genes, have been shown to be associated with neurodevelopmental disorders like autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID). However, the vast majority of CNV findings lack specificity with respect to autistic or developmental-delay phenotypes. Therefore, the aim of the study was to investigate the size and frequency of CNVs in high-functioning ASD (HFA) without ID compared with a random population sample and with published findings in ASD and ID. To investigate the role of CNVs for the "core symptoms" of high-functioning autism, we included in the present exploratory study only patients with HFA without ID. The aim was to test whether HFA have similar large rare (> 1 Mb) CNVs as reported in ASD and ID. We performed high-resolution chromosomal microarray analysis in 108 children and adolescents with HFA without ID. There was no significant difference in the overall number of rare CNVs compared to 124 random population samples. However, patients with HFA carried significantly more frequently CNVs containing brain-related genes. Surprisingly, six HFA patients carried very large CNVs known to be typically present in ID. Our findings provide new evidence that not only small, but also large CNVs affecting several key genes contribute to the genetic etiology/risk of HFA without affecting their intellectual ability.
Collapse
|
|
14
|
Attia SM, Al-Hamamah MA, Ahmad SF, Nadeem A, Attia MSM, Ansari MA, Bakheet SA, Al-Ayadhi LY. Evaluation of DNA repair efficiency in autistic children by molecular cytogenetic analysis and transcriptome profiling. DNA Repair (Amst) 2019; 85:102750. [PMID: 31765876 DOI: 10.1016/j.dnarep.2019.102750] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 09/02/2019] [Accepted: 11/12/2019] [Indexed: 12/13/2022]
Abstract
Data regarding DNA repair perturbations in autism, which might increase the risk of malignancy, are scarce. To evaluate whether DNA repair may be disrupted in autistic children, we assessed the incidence of endogenous basal DNA strand breaks as well as the efficiency of repairing DNA damage caused by γ-ray in lymphocytes isolated from autistic and healthy children. The incidence of DNA damage and the kinetics of DNA repair were determined by comet assay, while the incidence of residual DNA damage was evaluated by structural chromosomal aberration analysis. Transcriptome profiling of 84 genes associated with DNA damage and repair-signaling pathways was performed by RT² Profiler PCR Array. The array data were confirmed by RT-PCR and western blot studies. Our data indicate that the incidence of basal oxidative DNA strand breaks in autistic children was greater than that in nonautistic controls. Lymphocytes from autistic children displayed higher susceptibility to damage by γ-irradiation and slower repair rate than those from nonautistic children. Although the total unstable chromosomal aberrations were unaffected, lymphocytes from autistic children were more susceptible to chromosomal damage caused by γ-ray than those from nonautistic children. Transcriptomic analysis revealed that several genes associated with repair were downregulated in lymphocytes from autistic individuals and in those exposed to γ-irradiation. This may explain the increased oxidative DNA damage and reduced repair rate in lymphocytes from autistic individuals. These features may be related to the possible correlation between autism and the elevated risk of cancer and may explain the role of the disruption of the DNA repair process in the pathogenesis of autism.
Collapse
Affiliation(s)
- Sabry M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
| | - Mohammed A Al-Hamamah
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sheikh F Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | | | - Mushtaq A Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Laila Y Al-Ayadhi
- Autism Research and Treatment Center, AL-Amodi Autism Research Chair, Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
15
|
Guinovart M, Coronas R, Caixàs A. Psychopathological disorders in Prader-Willi syndrome. ACTA ACUST UNITED AC 2019; 66:579-587. [PMID: 31006652 DOI: 10.1016/j.endinu.2019.03.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 02/27/2019] [Accepted: 03/02/2019] [Indexed: 01/07/2023]
Abstract
Prader-Willi syndrome is a genetic disorder caused by chromosomal changes in segment 15q11-q13 including cognitive, mental, and behavioral symptoms, as well as a specific physical phenotype. Both the most common psychopathological changes (intellectual disability, obsessions, impulsivity, autism spectrum disorders, self-injuries) and the main psychiatric comorbidities (affective disorders, psychosis, obsessive-compulsive disorder, autism spectrum disorder) are characterized by a great heterogeneity, which warrants the need for better identification of their frequency and clinical signs. In addition to its effects on body compositionand hypotony, growth hormone has been shown to be useful for regulating patient behavior, and psychoactive drugs are also an option. Other alternatives have shown promising results in experimental trials. Adequate understanding of the psychopathology associated to Prader-Willi syndrome would allow for improving clinical approach, symptom identification, detection of comorbidities, and administration of more effective treatments, leading to better clinical outcomes.
Collapse
Affiliation(s)
- Martí Guinovart
- Servicio de Salud Mental, Hospital Universitari Parc Taulí, Universidad Autónoma de Barcelona, Sabadell (Barcelona), España
| | - Ramón Coronas
- Servicio de Salud Mental, Hospital Universitari Parc Taulí, Universidad Autónoma de Barcelona, Sabadell (Barcelona), España; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, España
| | - Assumpta Caixàs
- Servicio de Endocrinología y Nutrición, Hospital Universitari Parc Taulí, Universidad Autónoma de Barcelona, Sabadell (Barcelona), España.
| |
Collapse
|
|
16
|
|
|
17
|
Almandil NB, Alkuroud DN, AbdulAzeez S, AlSulaiman A, Elaissari A, Borgio JF. Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16040658. [PMID: 30813406 PMCID: PMC6406800 DOI: 10.3390/ijerph16040658] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 12/28/2022]
Abstract
One of the most common neurodevelopmental disorders worldwide is autism spectrum disorder (ASD), which is characterized by language delay, impaired communication interactions, and repetitive patterns of behavior caused by environmental and genetic factors. This review aims to provide a comprehensive survey of recently published literature on ASD and especially novel insights into excitatory synaptic transmission. Even though numerous genes have been discovered that play roles in ASD, a good understanding of the pathophysiologic process of ASD is still lacking. The protein⁻protein interactions between the products of NLGN, SHANK, and NRXN synaptic genes indicate that the dysfunction in synaptic plasticity could be one reason for the development of ASD. Designing more accurate diagnostic tests for the early diagnosis of ASD would improve treatment strategies and could enhance the appropriate monitoring of prognosis. This comprehensive review describes the psychotropic and antiepileptic drugs that are currently available as effective pharmacological treatments and provides in-depth knowledge on the concepts related to clinical, diagnostic, therapeutic, and genetic perspectives of ASD. An increase in the prevalence of ASD in Gulf Cooperation Council countries is also addressed in the review. Further, the review emphasizes the need for international networking and multidimensional studies to design novel and effective treatment strategies.
Collapse
Affiliation(s)
- Noor B Almandil
- Department of Clinical Pharmacy Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
| | - Deem N Alkuroud
- Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
| | - Sayed AbdulAzeez
- Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
| | - Abdulla AlSulaiman
- Department of Neurology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
| | - Abdelhamid Elaissari
- Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEP-UMR 5007, F-69622 Lyon, France.
| | - J Francis Borgio
- Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
| |
Collapse
|
|
18
|
Wiśniowiecka-Kowalnik B, Nowakowska BA. Genetics and epigenetics of autism spectrum disorder-current evidence in the field. J Appl Genet 2019; 60:37-47. [PMID: 30627967 PMCID: PMC6373410 DOI: 10.1007/s13353-018-00480-w] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/14/2018] [Accepted: 12/18/2018] [Indexed: 12/26/2022]
Abstract
Autism spectrum disorders (ASD) is a heterogenous group of neurodevelopmental disorders characterized by problems in social interaction and communication as well as the presence of repetitive and stereotyped behavior. It is estimated that the prevalence of ASD is 1–2% in the general population with the average male to female ratio 4–5:1. Although the causes of ASD remain largely unknown, the studies have shown that both genetic and environmental factors play an important role in the etiology of these disorders. Array comparative genomic hybridization and whole exome/genome sequencing studies identified common and rare copy number or single nucleotide variants in genes encoding proteins involved in brain development, which play an important role in neuron and synapse formation and function. The genetic etiology is recognized in ~ 25–35% of patients with ASD. In this article, we review the current state of knowledge about the genetic etiology of ASD and also propose a diagnostic algorithm for patients.
Collapse
|
|
19
|
Salehi P, Herzig L, Capone G, Lu A, Oron AP, Kim SJ. Comparison of Aberrant Behavior Checklist profiles across Prader-Willi syndrome, Down syndrome, and autism spectrum disorder. Am J Med Genet A 2018; 176:2751-2759. [DOI: 10.1002/ajmg.a.40665] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 03/12/2018] [Accepted: 09/04/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Parisa Salehi
- Seattle Children's Hospital, Division of Endocrine; University of Washington; Seattle Washington
| | - Lisa Herzig
- Seattle Children's Hospital, Division of Developmental Medicine; University of Washington; Seattle Washington
| | - George Capone
- Kennedy Krieger Institute, Johns Hopkins University School of Medicine; Baltimore Maryland
| | - Amanda Lu
- Seattle Children's Hospital; University of Washington; Seattle Washington
| | - Assaf P. Oron
- Epidemiology Section; Institute for Disease Modeling; Bellevue Washington
| | - Soo-Jeong Kim
- Seattle Children's Hospital, Division of Psychiatry; University of Washington; Seattle Washington
| |
Collapse
|
|
20
|
Abstract
UBE3A is a dual function protein consisting of ubiquitin ligase as well as transcriptional co-activator function. UBE3A gene is imprinted in the brain with preferential maternal-specific expression particularly in the neuron and loss of activity of the maternally inherited UBE3A causes Angelman syndrome (AS), characterized by severe mental retardation, lack of speech, seizures and autistic features. Interestingly, duplication, triplication, or gain-of-function mutations in the UBE3A gene are also linked with autism clinically distinguished by social impairments and stereotyped behaviors. These findings indicate that the expression and activity of UBE3A must be tightly regulated during brain development and UBE3A might be playing a crucial role in controlling synaptic function and plasticity through proteasome-mediated degradation as well as transcriptional regulation of its target proteins. In fact, several recent reports demonstrated the role of UBE3A in the modulation of synaptic function and plasticity. This review focuses on the critical role of UBE3A in regulating the synaptic function and how its altered activity is associated with autism.
Collapse
Affiliation(s)
- Naman Vatsa
- Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Gurugram, India
| | - Nihar Ranjan Jana
- School of Bioscience, Indian Institute of Technology, Kharagpur, India
| |
Collapse
|
|
21
|
Baker EK, Godler DE, Bui M, Hickerton C, Rogers C, Field M, Amor DJ, Bretherton L. Exploring autism symptoms in an Australian cohort of patients with Prader-Willi and Angelman syndromes. J Neurodev Disord 2018; 10:24. [PMID: 30081815 PMCID: PMC6091196 DOI: 10.1186/s11689-018-9242-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 07/23/2018] [Indexed: 11/24/2022] Open
Abstract
Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s11689-018-9242-0) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Emma K Baker
- Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.
| | - David E Godler
- Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.,Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Minh Bui
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia
| | - Chriselle Hickerton
- Genetics Education and Health Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia
| | - Carolyn Rogers
- Genetics of Learning Disability Service (GOLD Service), Hunter Genetics, Newcastle, NSW, Australia
| | - Mike Field
- Genetics of Learning Disability Service (GOLD Service), Hunter Genetics, Newcastle, NSW, Australia
| | - David J Amor
- Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.,Neurodisability and Rehabilitation, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia
| | - Lesley Bretherton
- Child Neuropsychology, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.,Melbourne School of Psychological Sciences, University of Melbourne, Parkville, VIC, Australia
| |
Collapse
|
|
22
|
A case of Nablus mask-like facial syndrome with autism spectrum disorders. Psychiatr Genet 2018; 28:75. [PMID: 29957742 DOI: 10.1097/ypg.0000000000000198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
23
|
Copy number variants in people with autism spectrum disorders and co-morbid psychosis. Eur J Med Genet 2018; 61:230-234. [DOI: 10.1016/j.ejmg.2017.12.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/27/2017] [Accepted: 12/04/2017] [Indexed: 12/11/2022]
|
|
24
|
Cataldo I, Azhari A, Esposito G. A Review of Oxytocin and Arginine-Vasopressin Receptors and Their Modulation of Autism Spectrum Disorder. Front Mol Neurosci 2018; 11:27. [PMID: 29487501 PMCID: PMC5816822 DOI: 10.3389/fnmol.2018.00027] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 01/18/2018] [Indexed: 12/24/2022] Open
Abstract
Oxytocin (OXT) and arginine-vasopressin (AVP) play a key regulatory part in social and affiliative behaviors; two aspects highly compromised in Autism Spectrum Disorder (ASD). Furthermore, variants in the adjacent oxytocin-vasopressin gene regions have been found to be associated with ASD diagnosis and endophenotypes. This review focuses mainly on common OXTr single nucleotide polymorphisms (SNPs), AVPR1a microsatellites and AVPR1b polymorphisms in relation to the development of autism. Although these genes did not surface in genome-wide association studies, evidence supports the hypothesis that these receptors and their polymorphisms are widely involved in the regulation of social behavior, and in modulating neural and physiological pathways contributing to the etiology of ASD. With a specific focus on variants considered to be among the most prevalent in the development of ASD, these issues will be discussed in-depth and suggestions to approach inconsistencies in the present literature will be provided. Translational implications and future directions are deliberated from a short-term and a forward-looking perspective. While the scientific community has made significant progress in enhancing our understanding of ASD, more research is required for the ontology of this disorder to be fully elucidated. By supplementing information related to genetics, highlighting the differences across male and female sexes, this review provides a wider view of the current state of knowledge of OXTr and AVPr mechanisms of functioning, eventually addressing future research in the identification of further risk factors, to build new strategies for early interventions.
Collapse
Affiliation(s)
- Ilaria Cataldo
- Department of Psychology and Cognitive Science, University of Trento, Rovereto, Italy.,Mobile and Social Computing Lab, Fondazione Bruno Kessler, Trento, Italy
| | - Atiqah Azhari
- Division of Psychology, School of Social Sciences, Nanyang Technological University, Singapore, Singapore
| | - Gianluca Esposito
- Department of Psychology and Cognitive Science, University of Trento, Rovereto, Italy.,Division of Psychology, School of Social Sciences, Nanyang Technological University, Singapore, Singapore
| |
Collapse
|
|
25
|
Gu X, Yuan FF, Huang X, Hou Y, Wang M, Lin J, Wu J. Association of PIK3CG gene polymorphisms with attention-deficit/hyperactivity disorder: A case-control study. Prog Neuropsychopharmacol Biol Psychiatry 2018; 81:169-177. [PMID: 29097255 DOI: 10.1016/j.pnpbp.2017.10.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 10/27/2017] [Accepted: 10/28/2017] [Indexed: 12/14/2022]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a complicated neurodevelopmental disorder with high heritability. This study explores the association of PIK3CG gene single nucleotide polymorphisms (rs1129293, rs12536620, rs12667819, rs17847825, rs2230460) with ADHD in children and the relation of interaction between SNPs and environmental factors, including blood lead levels (BLLs) and feeding style. A case-control study was conducted with children aged 6-18years old, consisting of 389 children newly diagnosed with ADHD via the DSM-IV at the Wuhan Women and Children Medical Care Center, and 393 control participants were healthy children for physical examination during the same period. All participants were tested using the Chinese Wechsler Intelligence Scale for Children and Parent Symptom Questionnaire (PSQ). Furthermore, a self-designed questionnaire was used to investigate the general situation and related environmental factors, and the BLLs were measured by atomic absorption spectrophotometry. The genotyping was performed using Sequenom MassArray. In our study, PIK3CG gene rs12667819 was consistently shown to be associated with ADHD risk in dominant model (OR=1.656, 95% CI=1.229-2.232), ADHD-I type (OR=2.278, 95% CI=1.666-4.632), and symptom scores. Moreover, rs12536620 has been observed to be related to ADHD-C type and symptom scores. Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactions of rs12667819 collaborating with blood lead (Pmul=0.045) and feeding style (Pmul=0.041) to modify ADHD risk. Expression quantitative trait loci analysis suggested that rs12667819 may mediate PIK3CG gene expression. Therefore, our results suggest that selected PIK3CG gene variants may have a significant effect on ADHD risk.
Collapse
Affiliation(s)
- Xue Gu
- Key Laboratory of Environment and Health, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, People's Republic of China
| | - Fang-Fen Yuan
- Key Laboratory of Environment and Health, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, People's Republic of China
| | - Xin Huang
- Key Laboratory of Environment and Health, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, People's Republic of China
| | - Yuwei Hou
- Key Laboratory of Environment and Health, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, People's Republic of China
| | - Min Wang
- Key Laboratory of Environment and Health, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, People's Republic of China
| | - Jun Lin
- Department of Rehabilitation, Wuhan Women and Children Medical Care Center, No. 100 Hong Kong Road, Wuhan 430015, People's Republic of China
| | - Jing Wu
- Key Laboratory of Environment and Health, Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430030, People's Republic of China.
| |
Collapse
|
|
26
|
Takumi T, Tamada K. CNV biology in neurodevelopmental disorders. Curr Opin Neurobiol 2018; 48:183-192. [PMID: 29331932 DOI: 10.1016/j.conb.2017.12.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 11/27/2017] [Accepted: 12/10/2017] [Indexed: 12/29/2022]
Abstract
Copy number variants (CNVs), characterized in recent years by cutting-edge technology, add complexity to our knowledge of the human genome. CNVs contribute not only to human diversity but also to different kinds of diseases including neurodevelopmental delay, autism spectrum disorder and neuropsychiatric diseases. Interestingly, many pathogenic CNVs are shared among these diseases. Studies suggest that pathophysiology of disease may not be simply attributed to a single driver gene within a CNV but also that multifactorial effects may be important. Gene expression and the resulting phenotypes may also be affected by epigenetic alteration and chromosomal structural changes. Combined with human genetics and systems biology, integrative research by multi-dimensional approaches using animal and cell models of CNVs are expected to further understanding of pathophysiological mechanisms of neurodevelopmental disorders and neuropsychiatric disorders.
Collapse
Affiliation(s)
- Toru Takumi
- RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
| | - Kota Tamada
- RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
| |
Collapse
|
|
27
|
Howes OD, Rogdaki M, Findon JL, Wichers RH, Charman T, King BH, Loth E, McAlonan GM, McCracken JT, Parr JR, Povey C, Santosh P, Wallace S, Simonoff E, Murphy DG. Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. J Psychopharmacol 2018; 32:3-29. [PMID: 29237331 PMCID: PMC5805024 DOI: 10.1177/0269881117741766] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials.
Collapse
Affiliation(s)
- Oliver D Howes
- 1 MRC London Institute of Medical Sciences, London, UK
- 2 Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Maria Rogdaki
- 1 MRC London Institute of Medical Sciences, London, UK
| | - James L Findon
- 3 Sackler Institute for Translational Neurodevelopment, King's College London, London, UK
| | - Robert H Wichers
- 3 Sackler Institute for Translational Neurodevelopment, King's College London, London, UK
| | - Tony Charman
- 4 Department of Psychology, King's College London, London UK
| | - Bryan H King
- 5 Department of Psychiatry, University of California at San Francisco, San Francisco, USA
| | - Eva Loth
- 3 Sackler Institute for Translational Neurodevelopment, King's College London, London, UK
| | - Gráinne M McAlonan
- 6 The Sackler Centre and Forensic and Neurodevelopmental Science Behavioural and Developmental Psychiatry, Clinical Academic Group, South London and Maudsley NHS Foundation Trust, London, UK
- 7 NIHR-BRC for Mental Health, South London and Maudsley NHS Foundation Trust, London, UK
| | - James T McCracken
- 8 Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, USA
| | - Jeremy R Parr
- 9 Institute of Neuroscience, Newcastle University, Newcastle, UK
| | - Carol Povey
- 10 The National Autistic Society, London, UK
| | - Paramala Santosh
- 11 Department of Child Psychiatry, King's College London, London, UK
| | | | - Emily Simonoff
- 13 Department of Child and Adolescent Psychiatry, King's College London, London, UK
| | - Declan G Murphy
- 6 The Sackler Centre and Forensic and Neurodevelopmental Science Behavioural and Developmental Psychiatry, Clinical Academic Group, South London and Maudsley NHS Foundation Trust, London, UK
- 7 NIHR-BRC for Mental Health, South London and Maudsley NHS Foundation Trust, London, UK
| |
Collapse
|
|
28
|
Clinical and molecular characterization of three genomic rearrangements at chromosome 22q13.3 associated with autism spectrum disorder. Psychiatr Genet 2017; 27:23-33. [PMID: 27846046 DOI: 10.1097/ypg.0000000000000151] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Chromosome 22q13 is a hot region of genomic rearrangements that may result in deletion, duplication, and translocation, and that may lead to neurodevelopmental disorders in affected patients. MATERIALS AND METHODS We carried out an array-based comparative genomic hybridization analysis to detect copy number variations (CNVs) of genomic DNA in patients with autism spectrum disorders (ASD) who were consecutively recruited into our molecular genetic study of ASD. Karyotyping, fluorescent in-situ hybridization analysis, and real time-quantitative PCR were used for validation tests. RESULTS We completed a genome-wide CNV analysis of 335 patients with ASD from Taiwan. Three unrelated male patients were found to carry three different CNVs at 22q13.3, respectively, including a de novo terminal deletion of ∼106 kb at 22q13.33, a de novo interstitial duplication of ∼1.8 Mb at 22q13.32-q13.33, and a microdeletion of ∼147 kb at 22q13.33. These three CNVs all involved the dosage change of the SHANK3 gene. The last patient also carried a genomic duplication of ∼3.86 Mb at 19q13.42-q13.4 in addition to a microdeletion of ∼147 kb at 22q13.33. His younger sister also carried these two CNVs, but she had developmental delay and other neurological deficits without ASD. These two CNVs were transmitted from their unaffected father, who carried a balanced translocation between chromosome 22q and 19q. CONCLUSION Our data support that recurrent genomic rearrangements at 22q13.3 are part of the genetic landscape of ASD in our patients and changes in SHANK3 dosage are associated with neurodevelopmental disorders. However, the clinical symptoms of patients with 22q13.3 rearrangements can vary depending on other genetic and nongenetic factors, not limited to genes involved in CNVs in this region.
Collapse
|
|
29
|
Chen CH, Chen HI, Chien WH, Li LH, Wu YY, Chiu YN, Tsai WC, Gau SSF. High resolution analysis of rare copy number variants in patients with autism spectrum disorder from Taiwan. Sci Rep 2017; 7:11919. [PMID: 28931914 PMCID: PMC5607249 DOI: 10.1038/s41598-017-12081-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 09/04/2017] [Indexed: 12/27/2022] Open
Abstract
Rare genomic copy number variations (CNVs) (frequency <1%) contribute a part to the genetic underpinnings of autism spectrum disorders (ASD). The study aimed to understand the scope of rare CNV in Taiwanese patients with ASD. We conducted a genome-wide CNV screening of 335 ASD patients (299 males, 36 females) from Taiwan using Affymetrix Genome-Wide Human SNP Array 6.0 and compared the incidence of rare CNV with that of 1093 control subjects (525 males, 568 females). We found a significantly increased global burden of rare CNVs in the ASD group compared to the controls as a whole or when the rare CNVs were classified by the size and types of CNV. Further analysis confirmed the presence of several rare CNVs at regions strongly associated with ASD as reported in the literature in our sample. Additionally, we detected several new private pathogenic CNVs in our samples and five patients carrying two pathogenic CNVs. Our data indicate that rare genomic CNVs contribute a part to the genetic landscape of our ASD patients. These CNVs are highly heterogeneous, and the clinical interpretation of the pathogenic CNVs of ASD is not straightforward in consideration of the incomplete penetrance, varied expressivity, and individual genetic background.
Collapse
Affiliation(s)
- Chia-Hsiang Chen
- Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
- Department and Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-I Chen
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Wei-Hsien Chien
- Department of Occupational Therapy, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Ling-Hui Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yu-Yu Wu
- Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Yen-Nan Chiu
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Wen-Che Tsai
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Susan Shur-Fen Gau
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
- Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.
- Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
| |
Collapse
|
|
30
|
Lewis KE, Sharan K, Takumi T, Yadav VK. Skeletal Site-specific Changes in Bone Mass in a Genetic Mouse Model for Human 15q11-13 Duplication Seen in Autism. Sci Rep 2017; 7:9902. [PMID: 28851986 PMCID: PMC5575059 DOI: 10.1038/s41598-017-09921-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 08/01/2017] [Indexed: 12/13/2022] Open
Abstract
Children suffering from autism have been reported to have low bone mineral density and increased risk for fracture, yet the cellular origin of the bone phenotype remains unknown. Here we have utilized a mouse model of autism that duplicates 6.3 Mb region of chromosome 7 (Dp/+) corresponding to a region of chromosome 15q11-13, duplication of which is recurrent in humans to characterize the bone phenotype. Paternally inherited Dp/+ (patDp/+) mice showed expected increases in the gene expression in bone, normal postnatal growth and body weight acquisition compared to the littermate controls. Four weeks-old patDp/+ mice develop a low bone mass phenotype in the appendicular but not the axial skeleton compared to the littermate controls. This low bone mass in the mutant mice was secondary to a decrease in the number of osteoblasts and bone formation rate while the osteoclasts remained relatively unaffected. Further in vitro cell culture experiments and gene expression analysis revealed a major defect in the proliferation, differentiation and mineralization abilities of patDp/+ osteoblasts while osteoclast differentiation remained unchanged compared to controls. This study therefore characterizes the structural and cellular bone phenotype in a mouse model of autism that can be further utilized to investigate therapeutic avenues to treat bone fractures in children with autism.
Collapse
Affiliation(s)
- Kirsty E Lewis
- Department of Mouse and Zebrafish Genetics, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, United Kingdom.,Department of Physiology, Pharmacology, Neuroscience, University of Bristol, Bristol, BS8 1TD, United Kingdom
| | - Kunal Sharan
- Department of Mouse and Zebrafish Genetics, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, United Kingdom.,Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysore, India
| | - Toru Takumi
- RIKEN Brain Science Institute (BSI), Wako, Saitama, Japan.,Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan
| | - Vijay K Yadav
- Department of Mouse and Zebrafish Genetics, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, United Kingdom. .,Metabolic Research Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
| |
Collapse
|
|
31
|
Dykens EM, Roof E, Hunt-Hawkins H, Dankner N, Lee EB, Shivers CM, Daniell C, Kim SJ. Diagnoses and characteristics of autism spectrum disorders in children with Prader-Willi syndrome. J Neurodev Disord 2017; 9:18. [PMID: 28592997 PMCID: PMC5458479 DOI: 10.1186/s11689-017-9200-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 05/10/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND A small percentage of people with autism spectrum disorders (ASD) have alterations in chromosome 15q11.2-q3, the critical region for Prader-Willi syndrome (PWS). Data are limited, however, on the rates and characteristics of ASD in PWS. Previous estimates of ASD in PWS (25 to 41%) are questionable as they are based solely on autism screeners given to parents. Inaccurate diagnoses of ASD in PWS can mislead intervention and future research. METHODS One hundred forty-six children and youth with PWS aged 4 to 21 years (M = 11) were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). An expert clinical team-made best-estimate ASD diagnoses based on ADOS-2 videotapes, calibrated severity scores, and children's developmental histories and indices of current functioning. Children were also administered the Kaufman Brief Intelligence Test-2, and parents completed the Repetitive Behavior Scale-Revised and Vineland Adaptive Behavior Scales. Scores were compared across children with PWS + ASD versus PWS only. The performance of an ASD screener, the Social Communication Questionnaire (SCQ) and the ADOS-2 were evaluated in relation to best-estimate diagnoses. RESULTS Best-estimate diagnoses of ASD were made in 18 children, or 12.3% of the sample, and the majority of them had the maternal uniparental disomy (mUPD) PWS genetic subtype. Compared to the PWS-only group, children with PWS + ASD had lower verbal and composite IQ's and adaptive daily living and socialization skills, as well as elevated stereotypies and restricted interests. Regardless of ASD status, compulsivity and insistence on sameness in routines or events were seen in 76-100% of children and were robustly correlated with lower adaptive functioning. The SCQ yielded a 29-49% chance that screen-positive cases will indeed have ASD. The ADOS-2 had higher sensitivity, specificity and predictive values. Communication problems were seen in children who were ADOS-2 positive but deemed not to have ASD by the clinical team. CONCLUSIONS Autism screeners should not be the sole index of probable ASD in PWS; children need to be directly observed and evaluated. Compulsivity and insistence on sameness are salient in PWS and likely impede adaptive functioning. Most children with PWS only evidenced sub-threshold problems in social interactions that could signal risks for other psychopathologies.
Collapse
Affiliation(s)
- Elisabeth M Dykens
- Departments of Psychology and Human Development, Psychiatry and Pediatrics, One Magnolia Circle, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37203 USA
| | - Elizabeth Roof
- Departments of Psychology and Human Development, Psychiatry and Pediatrics, One Magnolia Circle, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37203 USA
| | - Hailee Hunt-Hawkins
- Departments of Psychology and Human Development, Psychiatry and Pediatrics, One Magnolia Circle, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37203 USA
| | - Nathan Dankner
- Departments of Psychology and Human Development, Psychiatry and Pediatrics, One Magnolia Circle, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37203 USA
| | - Evon Batey Lee
- Departments of Psychology and Human Development, Psychiatry and Pediatrics, One Magnolia Circle, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37203 USA
| | - Carolyn M Shivers
- Department of Human Development, Virginia Polytechnic Institute and State University, 366 Wallace Hall, Blacksburg, VA 24061 USA
| | - Christopher Daniell
- Departments of Psychology and Human Development, Psychiatry and Pediatrics, One Magnolia Circle, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37203 USA
| | - Soo-Jeong Kim
- Department of Psychiatry and Behavioral Science, University of Washington, 4909 25th Ave NE, Seattle, WA 98105 USA
| |
Collapse
|
|
32
|
Nakai N, Nagano M, Saitow F, Watanabe Y, Kawamura Y, Kawamoto A, Tamada K, Mizuma H, Onoe H, Watanabe Y, Monai H, Hirase H, Nakatani J, Inagaki H, Kawada T, Miyazaki T, Watanabe M, Sato Y, Okabe S, Kitamura K, Kano M, Hashimoto K, Suzuki H, Takumi T. Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice. SCIENCE ADVANCES 2017; 3:e1603001. [PMID: 28691086 PMCID: PMC5479676 DOI: 10.1126/sciadv.1603001] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 04/26/2017] [Indexed: 05/21/2023]
Abstract
Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.
Collapse
Affiliation(s)
- Nobuhiro Nakai
- RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
- Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan
- Graduate School of Biostudies, Kyoto University, Sakyo, Kyoto 606-8501, Japan
| | - Masatoshi Nagano
- Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8602, Japan
| | - Fumihito Saitow
- Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8602, Japan
| | - Yasuhito Watanabe
- Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan
- Department of Clinical Neurobiology, University Hospital and German Cancer Research Center, Heidelberg 69120, Germany
- Corresponding author. (T.T.); (H.S.); (Yasuhito Watanabe)
| | - Yoshinobu Kawamura
- Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan
| | - Akiko Kawamoto
- Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan
| | - Kota Tamada
- RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
- Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan
| | - Hiroshi Mizuma
- RIKEN Center for Life Science Technologies, Chuo, Kobe 650-0047, Japan
| | - Hirotaka Onoe
- RIKEN Center for Life Science Technologies, Chuo, Kobe 650-0047, Japan
| | | | - Hiromu Monai
- RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
| | - Hajime Hirase
- RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
| | - Jin Nakatani
- Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Hirofumi Inagaki
- Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8602, Japan
| | - Tomoyuki Kawada
- Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8602, Japan
| | - Taisuke Miyazaki
- Department of Anatomy and Embryology, Hokkaido University Graduate School of Medicine, Kita, Sapporo 060-8638, Japan
| | - Masahiko Watanabe
- Department of Anatomy and Embryology, Hokkaido University Graduate School of Medicine, Kita, Sapporo 060-8638, Japan
| | - Yuka Sato
- Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113-8654, Japan
| | - Shigeo Okabe
- Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113-8654, Japan
| | - Kazuo Kitamura
- Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113-8654, Japan
| | - Masanobu Kano
- Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113-8654, Japan
| | - Kouichi Hashimoto
- Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan
| | - Hidenori Suzuki
- Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8602, Japan
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan
- Corresponding author. (T.T.); (H.S.); (Yasuhito Watanabe)
| | - Toru Takumi
- RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
- Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan
- Corresponding author. (T.T.); (H.S.); (Yasuhito Watanabe)
| |
Collapse
|
|
33
|
|
|
34
|
Bennett JA, Hodgetts S, Mackenzie ML, Haqq AM, Zwaigenbaum L. Investigating Autism-Related Symptoms in Children with Prader-Willi Syndrome: A Case Study. Int J Mol Sci 2017; 18:ijms18030517. [PMID: 28264487 PMCID: PMC5372533 DOI: 10.3390/ijms18030517] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 02/13/2017] [Accepted: 02/23/2017] [Indexed: 12/27/2022] Open
Abstract
Prader-Willi syndrome (PWS), a rare genetic disorder caused by the lack of expression of paternal genes from chromosome 15q11-13, has been investigated for autism spectrum disorder (ASD) symptomatology in various studies. However, previous findings have been variable, and no studies investigating ASD symptomatology in PWS have exclusively studied children. We aimed to characterize social communication functioning and other ASD-related symptoms in children with PWS, and assessed agreement across measures and rates of ASD diagnosis. Measures included the Autism Diagnostic Observation Schedule-2 (ADOS-2), the Social Communication Questionnaire (SCQ), Social Responsiveness Scale-2 (SRS-2), Social Skills Improvement System-Rating Scales (SSIS-RS), and the Vineland Adaptive Behavioral Scales-II (VABS-II). General adaptive and intellectual skills were also assessed. Clinical best estimate (CBE) diagnosis was determined by an experienced developmental pediatrician, based on history and review of all available study measures, and taking into account overall developmental level. Participants included 10 children with PWS, aged 3 to 12 years. Three of the 10 children were male and genetic subtypes were two deletion (DEL) and eight uniparental disomy (UPD) (with a total of 6 female UPD cases). Although 8 of the 10 children exceeded cut-offs on at least one of the ASD assessments, agreement between parent questionnaires (SCQ, SRS-2, SSIS-RS) and observational assessment (ADOS-2) was very poor. None of the children were assigned a CBE diagnosis of ASD, with the caveat that the risk may have been lower because of the predominance of girls in the sample. The lack of agreement between the assessments emphasizes the complexity of interpreting ASD symptom measures in children with PWS.
Collapse
Affiliation(s)
- Jeffrey A Bennett
- Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 11405 87 Avenue, Edmonton, AB T6G1C9, Canada.
- Autism Research Centre-E209, Glenrose Rehabilitation Hospital, 10230 111 Avenue, Edmonton, AB T5G 0B7, Canada.
| | - Sandra Hodgetts
- Faculty of Rehabilitation Medicine, University of Alberta, 8205 114 Street, Edmonton, AB T6G 2G4, Canada.
| | - Michelle L Mackenzie
- Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 11405 87 Avenue, Edmonton, AB T6G1C9, Canada.
| | - Andrea M Haqq
- Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 11405 87 Avenue, Edmonton, AB T6G1C9, Canada.
| | - Lonnie Zwaigenbaum
- Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 11405 87 Avenue, Edmonton, AB T6G1C9, Canada.
- Autism Research Centre-E209, Glenrose Rehabilitation Hospital, 10230 111 Avenue, Edmonton, AB T5G 0B7, Canada.
| |
Collapse
|
|
35
|
Anatomy and Cell Biology of Autism Spectrum Disorder: Lessons from Human Genetics. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2017; 224:1-25. [PMID: 28551748 DOI: 10.1007/978-3-319-52498-6_1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Until recently autism spectrum disorder (ASD) was regarded as a neurodevelopmental condition with unknown causes and pathogenesis. In the footsteps of the revolution of genome technologies and genetics, and with its high degree of heritability, ASD became the first neuropsychiatric disorder for which clues towards molecular and cellular pathogenesis were uncovered by genetic identification of susceptibility genes. Currently several hundreds of risk genes have been assigned, with a recurrence below 1% in the ASD population. The multitude and diversity of known ASD genes has extended the clinical notion that ASD comprises very heterogeneous conditions ranging from severe intellectual disabilities to mild high-functioning forms. The results of genetics have allowed to pinpoint a limited number of cellular and molecular processes likely involved in ASD including protein synthesis, signal transduction, transcription/chromatin remodelling and synaptic function all playing an essential role in the regulation of synaptic homeostasis during brain development. In this context, we highlight the role of protein synthesis as a key process in ASD pathogenesis as it might be central in synaptic deregulation and a potential target for intervention. These current insights should lead to a rational design of interventions in molecular and cellular pathways of ASD pathogenesis that may be applied to affected individuals in the future.
Collapse
|
|
36
|
Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort. Int J Mol Sci 2016; 17:ijms17101765. [PMID: 27782075 PMCID: PMC5085789 DOI: 10.3390/ijms17101765] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/05/2016] [Accepted: 10/12/2016] [Indexed: 12/31/2022] Open
Abstract
Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 × 10−6 for the European controls; odds ratio = 2.42, p-value = 6.33 × 10−3 for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence.
Collapse
|
|
37
|
Iourov IY, Vorsanova SG, Korostelev SA, Vasin KS, Zelenova MA, Kurinnaia OS, Yurov YB. [Structural variations of the genome in autistic spectrum disorders with intellectual disability]. Zh Nevrol Psikhiatr Im S S Korsakova 2016; 116:50-54. [PMID: 27500877 DOI: 10.17116/jnevro20161167150-54] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIM To analyze structural variations in the genome in children with autism and intellectual disability. MATERIAL AND METHODS Using high-resolution karyotyping (AffymetrixCytoScan HD Array) and original bioinformatic technology, 200 children with autism and intellectual disability were studied. RESULTS AND CONCLUSION Data on structural variations in the genome in children with autism and intellectual disability are provided. Causative genomic pathology (chromosome abnormalities and copy number variations - CNV) was determined in 97 cases (48.5%). Based on these RESULTS 24 candidate genes for autism with intellectual disability were selected. In 16 cases (8%), the chromosome mosaicism manifested as aneuploidy of whole autosomes and sex chromosomes (gonosomes) was identified. In 87 children (43.5%), there were genomic variations, which are characteristic of the so-called «grey zone» of genetic pathology in mental illnesses. Bioinformatic analysis showed that these genomic variations had a pleiotropic effect on the phenotype.
Collapse
Affiliation(s)
- I Yu Iourov
- Mental Health Research Center, Moscow, Russia; Veltishev Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia; Russian Medical Academy of Postgraduate Education, Moscow, Russia
| | - S G Vorsanova
- Mental Health Research Center, Moscow, Russia; Veltishev Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia; Moscow State University of Psychology and Education, Moscow, Russia
| | | | - K S Vasin
- Mental Health Research Center, Moscow, Russia; Veltishev Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia; Moscow State University of Psychology and Education, Moscow, Russia
| | - M A Zelenova
- Mental Health Research Center, Moscow, Russia; Veltishev Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia; Moscow State University of Psychology and Education, Moscow, Russia
| | - O S Kurinnaia
- Mental Health Research Center, Moscow, Russia; Veltishev Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia; Moscow State University of Psychology and Education, Moscow, Russia
| | - Yu B Yurov
- Mental Health Research Center, Moscow, Russia; Veltishev Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia; Moscow State University of Psychology and Education, Moscow, Russia
| |
Collapse
|
|
38
|
DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond. Int J Mol Sci 2016; 17:ijms17060856. [PMID: 27258260 PMCID: PMC4926390 DOI: 10.3390/ijms17060856] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 05/12/2016] [Accepted: 05/27/2016] [Indexed: 12/16/2022] Open
Abstract
Schizophrenia and autism spectrum disorder (ASD) are multi-factorial and multi-symptomatic psychiatric disorders, each affecting 0.5%-1% of the population worldwide. Both are characterized by impairments in cognitive functions, emotions and behaviour, and they undermine basic human processes of perception and judgment. Despite decades of extensive research, the aetiologies of schizophrenia and ASD are still poorly understood and remain a significant challenge to clinicians and scientists alike. Adding to this unsatisfactory situation, patients with schizophrenia or ASD often develop a variety of peripheral and systemic disturbances, one prominent example of which is cancer, which shows a direct (but sometimes inverse) comorbidity in people affected with schizophrenia and ASD. Cancer is a disease characterized by uncontrolled proliferation of cells, the molecular origin of which derives from mutations of a cell's DNA sequence. To counteract such mutations and repair damaged DNA, cells are equipped with intricate DNA repair pathways. Oxidative stress, oxidative DNA damage, and deficient repair of oxidative DNA lesions repair have been proposed to contribute to the development of schizophrenia and ASD. In this article, we summarize the current evidence of cancer comorbidity in these brain disorders and discuss the putative roles of oxidative stress, DNA damage and DNA repair in the aetiopathology of schizophrenia and ASD.
Collapse
|
|
39
|
Siu WK, Lam CW, Mak CM, Lau ETK, Tang MHY, Tang WF, Poon-Mak RSM, Lee CC, Hung SF, Leung PWL, Kwong KL, Yau EKC, Ng GSF, Fong NC, Chan KY. Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong. Clin Transl Med 2016; 5:18. [PMID: 27271878 PMCID: PMC4896892 DOI: 10.1186/s40169-016-0098-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 05/04/2016] [Indexed: 11/25/2022] Open
Abstract
Background Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong. Methods A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array. Results We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort). Conclusions In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong. Electronic supplementary material The online version of this article (doi:10.1186/s40169-016-0098-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Wai-Kwan Siu
- Department of Pathology, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.,Kowloon West Cluster Laboratory Genetics Service, Department of Pathology, Princess Margaret Hospital, Hong Kong, China
| | - Ching-Wan Lam
- Department of Pathology, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.
| | - Chloe Miu Mak
- Kowloon West Cluster Laboratory Genetics Service, Department of Pathology, Princess Margaret Hospital, Hong Kong, China
| | - Elizabeth Tak-Kwong Lau
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Mary Hoi-Yin Tang
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Wing-Fai Tang
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | | | - Chi-Chiu Lee
- Department of Psychiatry, Kwai Chung Hospital, Hong Kong, China
| | - Se-Fong Hung
- Department of Psychiatry, Kwai Chung Hospital, Hong Kong, China
| | | | - Karen Ling Kwong
- Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong, China
| | - Eric Kin-Cheong Yau
- Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China
| | - Grace Sui-Fun Ng
- Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China
| | - Nai-Chung Fong
- Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China
| | - Kwok-Yin Chan
- Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China
| |
Collapse
|
|
40
|
DiStefano C, Gulsrud A, Huberty S, Kasari C, Cook E, Reiter LT, Thibert R, Jeste SS. Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome. J Neurodev Disord 2016; 8:19. [PMID: 27158270 PMCID: PMC4858912 DOI: 10.1186/s11689-016-9152-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 04/17/2016] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND One of the most common genetic variants associated with autism spectrum disorder (ASD) are duplications of chromosome 15q11.2-q13.1 (Dup15q syndrome). To identify distinctive developmental and behavioral features in Dup15q syndrome, we examined the social communication, adaptive, and cognitive skills in clinic-referred subjects and compared the characteristics of children with Dup15q syndrome to age/IQ-matched children with non-syndromic ASD. Behavior and development were also analyzed within the Dup15q group for differences related to copy number or epilepsy. METHODS Participants included 13 children with Dup15q syndrome and 13 children with non-syndromic ASD, matched on chronological and mental age, ages 22 months-12 years. In the Dup15q group, ten participants had isodicentric and three had interstitial duplications. Four children had active epilepsy (all isodicentric). Participants were assessed for verbal and non-verbal cognition, ASD characteristics based on the Autism Diagnostic Observation Schedule (ADOS), and adaptive function based on the Vineland Adaptive Behavior Scales (VABS). Group comparisons were performed between Dup15q and ASD participants, as well as within the Dup15q group based on duplication type and epilepsy status. RESULTS All children with Dup15q syndrome met the criteria for ASD; ASD severity scores were significantly lower than children in the non-syndromic ASD group. ADOS profiles demonstrated a relative strength in items related to social interest. Children with Dup15q syndrome also demonstrated significantly more impairment in motor and daily living skills. Within the Dup15q group, children with epilepsy demonstrated significantly lower cognitive and adaptive function than those without epilepsy. CONCLUSIONS The relative strength observed in social interest and responsiveness in the context of impaired motor skills represents an important avenue for intervention, including aggressive treatment of epilepsy, early and consistent focus on motor skills, and intervention targeting joint attention and language within a play context, in order to build on social interest to further develop social communication abilities. Longitudinal research beginning in early development will elucidate the temporal relationships between developmental domains and neurological comorbidities in these children at high risk for neurodevelopmental disorders.
Collapse
Affiliation(s)
- Charlotte DiStefano
- />Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA USA
| | - Amanda Gulsrud
- />Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA USA
| | - Scott Huberty
- />Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA USA
| | - Connie Kasari
- />Department of Human Development and Psychology, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience, University of California, Los Angeles, CA USA
| | - Edwin Cook
- />Department of Psychiatry, University of Illinois at Chicago, Chicago, IL USA
| | - Lawrence T. Reiter
- />Department of Neurology, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN USA
| | - Ronald Thibert
- />Department of Neurology, Department of Pediatrics, Massachusetts General Hospital, Boston, MA USA
| | - Shafali Spurling Jeste
- />Department of Neurology, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA USA
| |
Collapse
|
|
41
|
Ziats MN, Rennert OM. The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder. Front Genet 2016; 7:65. [PMID: 27200076 PMCID: PMC4844926 DOI: 10.3389/fgene.2016.00065] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 04/08/2016] [Indexed: 11/24/2022] Open
Abstract
The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants. The rapidly improving ability to identify genetic mutations because of advances in next generation sequencing, coupled with previous epidemiological studies demonstrating high heritability of ASD, have led to many recent attempts to identify causative genetic mutations underlying the ASD phenotype. However, although hundreds of mutations have been identified to date, they are either rare variants affecting only a handful of ASD patients, or are common variants in the general population conferring only a small risk for ASD. Furthermore, the genes implicated thus far are heterogeneous in their structure and function, hampering attempts to understand shared molecular mechanisms among all ASD patients; an understanding that is crucial for the development of targeted diagnostics and therapies. However, new work is beginning to suggest that the heterogeneous set of genes implicated in ASD may ultimately converge on a few common pathways. In this review, we discuss the parallel evolution of our diagnostic and genetic understanding of autism spectrum disorders, and highlight recent attempts to infer common biology underlying this complicated syndrome.
Collapse
Affiliation(s)
- Mark N. Ziats
- Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- Department of Physiology, Development and Neuroscience, University of CambridgeCambridgeshire, UK
- Medical Scientist Training Program, Baylor College of MedicineHouston, TX, USA
| | - Owen M. Rennert
- Laboratory of Clinical and Developmental Genomics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
42
|
Navon D, Eyal G. Looping Genomes: Diagnostic Change and the Genetic Makeup of the Autism Population. AJS; AMERICAN JOURNAL OF SOCIOLOGY 2016; 121:1416-1471. [PMID: 27092389 DOI: 10.1086/684201] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
This article builds on Hacking's framework of "dynamic nominalism" to show how knowledge about biological etiology can interact with the "kinds of people" delineated by diagnostic categories in ways that "loop" or modify both over time. The authors use historical materials to show how "geneticization" played a crucial role in binding together autism as a biosocial community and how evidence from genetics research later made an important contribution to the diagnostic expansion of autism. In the second part of the article, the authors draw on quantitative and qualitative analyses of autism rates over time in several rare conditions that are delineated strictly according to genomic mutations in order to demonstrate that these changes in diagnostic practice helped to both increase autism's prevalence and create its enormous genetic heterogeneity. Thus, a looping process that began with geneticization and involved the social effects of genetics research itself transformed the autism population and its genetic makeup.
Collapse
|
|
43
|
Huguet G, Benabou M, Bourgeron T. The Genetics of Autism Spectrum Disorders. RESEARCH AND PERSPECTIVES IN ENDOCRINE INTERACTIONS 2016. [DOI: 10.1007/978-3-319-27069-2_11] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
44
|
Sacrey LAR, Bennett JA, Zwaigenbaum L. Early Infant Development and Intervention for Autism Spectrum Disorder. J Child Neurol 2015; 30:1921-9. [PMID: 26323499 DOI: 10.1177/0883073815601500] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 07/25/2015] [Indexed: 01/08/2023]
Abstract
OBJECTIVE The objective is to overview recent findings on early detection/diagnosis of autism spectrum disorders, as well as clinical trials of early interventions for toddlers at risk for/diagnosed with autism spectrum disorder. FINDINGS Prospective studies of infants at high risk of autism spectrum disorder have yielded significant advances in understanding early development in autism spectrum disorder. Findings from prospective studies indicate that abnormalities in social communication and repetitive behaviors emerge during the second year, whereas additional "prodromal features" (motor and sensory abnormalities) emerge in the first year. Subsequently, exciting progress has been made in establishing the efficacy of autism spectrum disorder-specific interventions for toddlers as young as 15 months. Finally, efforts occur to characterize autism spectrum disorder-specific characteristics in genetic syndromes with concurrent autism spectrum disorder symptomatology. CONCLUSION Substantial progress in characterizing early developmental trajectories as well as the identification of specific behavioral markers has aided early detection. Work remains to ensure that research findings are translated into clinical practice for uptake in the health care system.
Collapse
Affiliation(s)
- Lori-Ann R Sacrey
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada Autism Research Centre, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada
| | - Jeffrey A Bennett
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Lonnie Zwaigenbaum
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada Autism Research Centre, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada
| |
Collapse
|
|
45
|
Reiner O, Karzbrun E, Kshirsagar A, Kaibuchi K. Regulation of neuronal migration, an emerging topic in autism spectrum disorders. J Neurochem 2015; 136:440-56. [PMID: 26485324 DOI: 10.1111/jnc.13403] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 09/04/2015] [Accepted: 10/09/2015] [Indexed: 12/14/2022]
Abstract
Autism spectrum disorders (ASD) encompass a group of neurodevelopmental diseases that demonstrate strong heritability, however, the inheritance is not simple and many genes have been associated with these disorders. ASD is regarded as a neurodevelopmental disorder, and abnormalities at different developmental stages are part of the disease etiology. This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration. We propose that neuronal migration impairment may be an important common pathophysiology in autism spectrum disorders (ASD). This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration.
Collapse
Affiliation(s)
- Orly Reiner
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eyal Karzbrun
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Aditya Kshirsagar
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Kozo Kaibuchi
- Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya, Japan
| |
Collapse
|
|
46
|
Hua R, Wei M, Zhang C. The complex genetics in autism spectrum disorders. SCIENCE CHINA-LIFE SCIENCES 2015; 58:933-45. [PMID: 26335739 DOI: 10.1007/s11427-015-4893-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Autism spectrum disorders (ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Genetic changes/heritability is one of the major contributing factors, and hundreds to thousands of causative and susceptible genes, copy number variants (CNVs), linkage regions, and microRNAs have been associated with ASD which clearly indicates that ASD is a complex genetic disorder. Here, we will briefly summarize some of the high-confidence genetic changes in ASD and their possible roles in their pathogenesis.
Collapse
Affiliation(s)
- Rui Hua
- State Key Laboratory of Membrane Biology, School of Life Sciences; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
| | - MengPing Wei
- State Key Laboratory of Membrane Biology, School of Life Sciences; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
| | - Chen Zhang
- State Key Laboratory of Membrane Biology, School of Life Sciences; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
| |
Collapse
|
|
47
|
Maruani A, Huguet G, Beggiato A, ElMaleh M, Toro R, Leblond CS, Mathieu A, Amsellem F, Lemière N, Verloes A, Leboyer M, Gillberg C, Bourgeron T, Delorme R. 11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures. Am J Med Genet A 2015; 167A:3019-30. [DOI: 10.1002/ajmg.a.37345] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 08/12/2015] [Indexed: 01/24/2023]
Affiliation(s)
- Anna Maruani
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
- Department of Child Psychiatry; Robert Debré Hospital, APHP; Paris France
| | - Guillaume Huguet
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
| | - Anita Beggiato
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
- Department of Child Psychiatry; Robert Debré Hospital, APHP; Paris France
| | - Monique ElMaleh
- Department of Radiology; Robert Debré Hospital, APHP; Paris France
| | - Roberto Toro
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
| | - Claire S. Leblond
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
| | - Alexandre Mathieu
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
| | | | - Nathalie Lemière
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
| | - Alain Verloes
- Department of Human Genetics; Robert Debré Hospital, APHP; Paris France
| | - Marion Leboyer
- INSERM U955, Team 15; Faculty of Medicine; Creteil France
- Department of Adult Psychiatry; Henri Mondor-Albert Chenevier Hospitals AP-HP; Creteil France
- Fondation FondaMental; French National Science Foundation; Creteil France
| | - Christopher Gillberg
- Gillberg Neuropsychiatry Centre; Gothenburg University; Göteborg Sweden
- Saint George's Hospital Medical School; London United Kingdom
| | - Thomas Bourgeron
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
- Diderot Paris 7; University Paris; Paris France
| | - Richard Delorme
- Human Genetics and Cognitive Functions; Institut Pasteur; Paris France
- CNRS URA 2182; Institut Pasteur; Paris France
- Department of Child Psychiatry; Robert Debré Hospital, APHP; Paris France
- Fondation FondaMental; French National Science Foundation; Creteil France
| |
Collapse
|
|
48
|
Nakai N, Otsuka S, Myung J, Takumi T. Autism spectrum disorder model mice: Focus on copy number variation and epigenetics. SCIENCE CHINA-LIFE SCIENCES 2015; 58:976-84. [DOI: 10.1007/s11427-015-4891-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
49
|
Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D, Bill BR, Berg JM, Gao F, Coppola G, Abrahams BS, Geschwind DH. Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. Mol Psychiatry 2015; 20:1069-78. [PMID: 25311365 PMCID: PMC4409498 DOI: 10.1038/mp.2014.124] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Revised: 07/18/2014] [Accepted: 08/21/2014] [Indexed: 12/22/2022]
Abstract
Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.
Collapse
Affiliation(s)
- A Oguro-Ando
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
,Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
| | - C Rosensweig
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - E Herman
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - Y Nishimura
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - D Werling
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - BR Bill
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - JM Berg
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - F Gao
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - G Coppola
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
,Semel Institute, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South, Los Angeles, CA 90095-1761
| | - BS Abrahams
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
| | - DH Geschwind
- Programs in Neurogenetics, Department of. Neurology and Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South Los Angeles, CA 90095-1761
,Dept. of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, 2309 Gonda Bldg, 695 Charles E. Young Dr. South, Los Angeles, CA 90095-1761
,
| |
Collapse
|
|
50
|
Molecular underpinnings of prefrontal cortex development in rodents provide insights into the etiology of neurodevelopmental disorders. Mol Psychiatry 2015; 20:795-809. [PMID: 25450230 PMCID: PMC4486649 DOI: 10.1038/mp.2014.147] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 09/12/2014] [Accepted: 09/17/2014] [Indexed: 12/20/2022]
Abstract
The prefrontal cortex (PFC), seat of the highest-order cognitive functions, constitutes a conglomerate of highly specialized brain areas and has been implicated to have a role in the onset and installation of various neurodevelopmental disorders. The development of a properly functioning PFC is directed by transcription factors, guidance cues and other regulatory molecules and requires the intricate and temporal orchestration of a number of developmental processes. Disturbance or failure of any of these processes causing neurodevelopmental abnormalities within the PFC may contribute to several of the cognitive deficits seen in patients with neurodevelopmental disorders. In this review, we elaborate on the specific processes underlying prefrontal development, such as induction and patterning of the prefrontal area, proliferation, migration and axonal guidance of medial prefrontal progenitors, and their eventual efferent and afferent connections. We furthermore integrate for the first time the available knowledge from genome-wide studies that have revealed genes linked to neurodevelopmental disorders with experimental molecular evidence in rodents. The integrated data suggest that the pathogenic variants in the neurodevelopmental disorder-associated genes induce prefrontal cytoarchitectonical impairments. This enhances our understanding of the molecular mechanisms of prefrontal (mis)development underlying the four major neurodevelopmental disorders in humans, that is, intellectual disability, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia, and may thus provide clues for the development of novel therapies.
Collapse
|