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Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications

INTRODUCTION: Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdi...

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Autores principales: Wegiel, Jerzy, Flory, Michael, Schanen, N. Carolyn, Cook, Edwin H., Nowicki, Krzysztof, Kuchna, Izabela, Imaki, Humi, Ma, Shuang Yong, Wegiel, Jarek, London, Eric, Casanova, Manuel F., Wisniewski, Thomas, Brown, W. Ted
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603300/
https://www.ncbi.nlm.nih.gov/pubmed/26463344
http://dx.doi.org/10.1186/s40478-015-0241-z
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author Wegiel, Jerzy
Flory, Michael
Schanen, N. Carolyn
Cook, Edwin H.
Nowicki, Krzysztof
Kuchna, Izabela
Imaki, Humi
Ma, Shuang Yong
Wegiel, Jarek
London, Eric
Casanova, Manuel F.
Wisniewski, Thomas
Brown, W. Ted
author_facet Wegiel, Jerzy
Flory, Michael
Schanen, N. Carolyn
Cook, Edwin H.
Nowicki, Krzysztof
Kuchna, Izabela
Imaki, Humi
Ma, Shuang Yong
Wegiel, Jarek
London, Eric
Casanova, Manuel F.
Wisniewski, Thomas
Brown, W. Ted
author_sort Wegiel, Jerzy
collection PubMed
description INTRODUCTION: Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.1 duplication syndrome [dup(15)], autism, ID and epilepsy; eight age-matched subjects diagnosed with autism of unknown etiology (idiopathic autism) and seven control individuals was to establish whether defects of neuronal soma growth are a common denominator of developmental pathology in idiopathic and syndromic autism and how genetic modifications alter the trajectory of neuronal soma growth in dup(15) autism. RESULTS: Application of the Nucleator software to estimate neuronal size revealed significant neuronal soma volume deficits in 11 of 25 structures and their subregions (44 %) in subjects diagnosed with dup(15) autism, including consistent neuronal soma volume deficits in the limbic system (sectors CA2, 3 and 4 in Ammon’s horn, the second and third layers of the entorhinal cortex and in the amygdala), as well as in the thalamus, nucleus accumbens, external globus pallidus, and Ch3 nucleus in the magnocellular basal complex, and in the inferior olive in the brainstem. The second feature distinguishing dup(15) autism was persistent neuronal soma deficits in adolescents and young adults, whereas in idiopathic autism, neuronal volume deficit is most prominent in 4- to 8-year-old children but affects only a few brain regions in older subjects. CONCLUSIONS: This study demonstrates that alterations in the trajectory of neuronal growth throughout the lifespan are a core pathological features of idiopathic and syndromic autism. However, dup(15) causes persistent neuronal volume deficits in adolescence and adulthood, with prominent neuronal growth deficits in all major compartments of the limbic system. The more severe neuronal nuclear and cytoplasic volume deficits in syndromic autism found in this study and the more severe focal developmental defects in the limbic system in dup(15) previously reported in this cohort may contribute to the high prevalence of early onset intractable epilepsy and sudden unexpected death in epilepsy.
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spelling pubmed-46033002015-10-14 Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications Wegiel, Jerzy Flory, Michael Schanen, N. Carolyn Cook, Edwin H. Nowicki, Krzysztof Kuchna, Izabela Imaki, Humi Ma, Shuang Yong Wegiel, Jarek London, Eric Casanova, Manuel F. Wisniewski, Thomas Brown, W. Ted Acta Neuropathol Commun Research INTRODUCTION: Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.1 duplication syndrome [dup(15)], autism, ID and epilepsy; eight age-matched subjects diagnosed with autism of unknown etiology (idiopathic autism) and seven control individuals was to establish whether defects of neuronal soma growth are a common denominator of developmental pathology in idiopathic and syndromic autism and how genetic modifications alter the trajectory of neuronal soma growth in dup(15) autism. RESULTS: Application of the Nucleator software to estimate neuronal size revealed significant neuronal soma volume deficits in 11 of 25 structures and their subregions (44 %) in subjects diagnosed with dup(15) autism, including consistent neuronal soma volume deficits in the limbic system (sectors CA2, 3 and 4 in Ammon’s horn, the second and third layers of the entorhinal cortex and in the amygdala), as well as in the thalamus, nucleus accumbens, external globus pallidus, and Ch3 nucleus in the magnocellular basal complex, and in the inferior olive in the brainstem. The second feature distinguishing dup(15) autism was persistent neuronal soma deficits in adolescents and young adults, whereas in idiopathic autism, neuronal volume deficit is most prominent in 4- to 8-year-old children but affects only a few brain regions in older subjects. CONCLUSIONS: This study demonstrates that alterations in the trajectory of neuronal growth throughout the lifespan are a core pathological features of idiopathic and syndromic autism. However, dup(15) causes persistent neuronal volume deficits in adolescence and adulthood, with prominent neuronal growth deficits in all major compartments of the limbic system. The more severe neuronal nuclear and cytoplasic volume deficits in syndromic autism found in this study and the more severe focal developmental defects in the limbic system in dup(15) previously reported in this cohort may contribute to the high prevalence of early onset intractable epilepsy and sudden unexpected death in epilepsy. BioMed Central 2015-10-13 /pmc/articles/PMC4603300/ /pubmed/26463344 http://dx.doi.org/10.1186/s40478-015-0241-z Text en © Wegiel et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Wegiel, Jerzy
Flory, Michael
Schanen, N. Carolyn
Cook, Edwin H.
Nowicki, Krzysztof
Kuchna, Izabela
Imaki, Humi
Ma, Shuang Yong
Wegiel, Jarek
London, Eric
Casanova, Manuel F.
Wisniewski, Thomas
Brown, W. Ted
Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications
title Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications
title_full Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications
title_fullStr Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications
title_full_unstemmed Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications
title_short Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications
title_sort significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603300/
https://www.ncbi.nlm.nih.gov/pubmed/26463344
http://dx.doi.org/10.1186/s40478-015-0241-z
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