Case Report

Beal, Jules C.

doi:10.1177/0883073813510356

Cited by 18 publications

(11 citation statements)

References 14 publications

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“…MRI analysis in a case of confirmed 15q13.3 duplication presenting with ASD detected heterotopia in the parietal and occipital cortices, likely due to abnormal neuronal migration [26]. Mice with maternally derived duplication ( matDp /+), but not those with the paternal duplication ( patDp /+), show increased expression of Ube3a and Gabrα5 in the hippocampus.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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“…Abnormal radial migration is a major cause of structural abnormalities in these brain regions. Cases of ASD associated with pachygyria, dysplasia, and heterotopia have been frequently reported (Korkmaz et al, 2006; Beal, 2014; Zare et al, 2019), implying abnormal radial migration in these individuals.…”

Section: Are Neuronal Migration Deficits General Neuropathological Chmentioning

confidence: 99%

Toward a Better Understanding of Neuronal Migration Deficits in Autism Spectrum Disorders

Pan

Yuan

2019

Front. Cell Dev. Biol.

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Newborn neurons in developing brains actively migrate from germinal zones to designated regions before being wired into functional circuits. The motility and trajectory of migrating neurons are regulated by both extracellular factors and intracellular signaling cascades. Defects in the molecular machinery of neuronal migration lead to mis-localization of affected neurons and are considered as an important etiology of multiple developmental disorders including epilepsy, dyslexia, schizophrenia (SCZ), and autism spectrum disorders (ASD). However, the mechanisms that link neuronal migration deficits to the development of these diseases remain elusive. This review focuses on neuronal migration deficits in ASD. From a translational perspective, we discuss (1) whether neuronal migration deficits are general neuropathological characteristics of ASD; (2) how the phenotypic heterogeneity of neuronal migration disorders is generated; (3) how neuronal migration deficits lead to functional defects of brain circuits; and (4) how therapeutic intervention of neuronal migration deficits can be a potential treatment for ASD.

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“…The homozygous 15q13.3 microdeletion syndrome presents more serious symptomatology, which is more easily recognizable because it is characterized by retinal dysfunction, muscular hypotonia, profound intellectual disability, refractory epilepsy, and, occasionally, macrocytosis [86][87][88]. Instead, duplication has been associated with Autism Spectrum Disorder [80,89], Bipolar Disorder [80,90], intellectual disability [80], developmental disorders [89], behavioral disorders [89], language impairment [89,91], attention deficit hyperactivity disorder (ADHD) [92], obsessive compulsive disorder (OCD) [89,93] and epilepsy [94]. However, given the rarity of the 15q13.3 duplication, the relationship between this CNV and psychiatric disorders requires further studies.…”

Section: Within Bp4 and Bp5 There Is A Region Encompassing 6 Genesmentioning

confidence: 99%

A Link between Genetic Disorders and Cellular Impairment, Using Human Induced Pluripotent Stem Cells to Reveal the Functional Consequences of Copy Number Variations in the Central Nervous System—A Close Look at Chromosome 15

Casamassa

Ferrari

Gelati

et al. 2020

IJMS

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Recent cutting-edge human genetics technology has allowed us to identify copy number variations (CNVs) and has provided new insights for understanding causative mechanisms of human diseases. A growing number of studies show that CNVs could be associated with physiological mechanisms linked to evolutionary trigger, as well as to the pathogenesis of various diseases, including cancer, autoimmune disease and mental disorders such as autism spectrum disorders, schizophrenia, intellectual disabilities or attention-deficit/hyperactivity disorder. Their incomplete penetrance and variable expressivity make diagnosis difficult and hinder comprehension of the mechanistic bases of these disorders. Additional elements such as co-presence of other CNVs, genomic background and environmental factors are involved in determining the final phenotype associated with a CNV. Genetically engineered animal models are helpful tools for understanding the behavioral consequences of CNVs. However, the genetic background and the biology of these animal model systems have sometimes led to confusing results. New cellular models obtained through somatic cellular reprogramming technology that produce induced pluripotent stem cells (iPSCs) from human subjects are being used to explore the mechanisms involved in the pathogenic consequences of CNVs. Considering the vast quantity of CNVs found in the human genome, we intend to focus on reviewing the current literature on the use of iPSCs carrying CNVs on chromosome 15, highlighting advantages and limits of this system with respect to mouse model systems.

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Case Report

Cited by 18 publications

References 14 publications

Autism spectrum disorder: neuropathology and animal models

Autism spectrum disorder: neuropathology and animal models

Toward a Better Understanding of Neuronal Migration Deficits in Autism Spectrum Disorders

A Link between Genetic Disorders and Cellular Impairment, Using Human Induced Pluripotent Stem Cells to Reveal the Functional Consequences of Copy Number Variations in the Central Nervous System—A Close Look at Chromosome 15

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