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Severe white matter damage in SHANK3 deficiency: a human and translational study
OBJECTIVE: Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan–McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952316/ https://www.ncbi.nlm.nih.gov/pubmed/31788990 http://dx.doi.org/10.1002/acn3.50959 |
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author | Jesse, Sarah Müller, Hans‐Peter Schoen, Michael Asoglu, Harun Bockmann, Juergen Huppertz, Hans‐Juergen Rasche, Volker Ludolph, Albert C. Boeckers, Tobias M. Kassubek, Jan |
author_facet | Jesse, Sarah Müller, Hans‐Peter Schoen, Michael Asoglu, Harun Bockmann, Juergen Huppertz, Hans‐Juergen Rasche, Volker Ludolph, Albert C. Boeckers, Tobias M. Kassubek, Jan |
author_sort | Jesse, Sarah |
collection | PubMed |
description | OBJECTIVE: Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan–McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function. METHODS AND RESULTS: Diffusion tensor imaging‐based and automatic volumetric brain mapping were performed in 12 SHANK3‐deficient participants (mean age 19 ± 15 years) versus 14 age‐ and gender‐matched controls (mean age 29 ± 5 years). Using whole brain–based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with SHANK3 mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto‐occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back‐translational approach, we observed similar white matter alterations in heterozygous isoform–specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model. INTERPRETATION: In summary, these translational data provide strong evidence that the SHANK3‐deficiency–associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of SHANK3 during early axonal pathfinding/wiring and in myelin formation. |
format | Online Article Text |
id | pubmed-6952316 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69523162020-01-10 Severe white matter damage in SHANK3 deficiency: a human and translational study Jesse, Sarah Müller, Hans‐Peter Schoen, Michael Asoglu, Harun Bockmann, Juergen Huppertz, Hans‐Juergen Rasche, Volker Ludolph, Albert C. Boeckers, Tobias M. Kassubek, Jan Ann Clin Transl Neurol Research Articles OBJECTIVE: Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan–McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function. METHODS AND RESULTS: Diffusion tensor imaging‐based and automatic volumetric brain mapping were performed in 12 SHANK3‐deficient participants (mean age 19 ± 15 years) versus 14 age‐ and gender‐matched controls (mean age 29 ± 5 years). Using whole brain–based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with SHANK3 mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto‐occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back‐translational approach, we observed similar white matter alterations in heterozygous isoform–specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model. INTERPRETATION: In summary, these translational data provide strong evidence that the SHANK3‐deficiency–associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of SHANK3 during early axonal pathfinding/wiring and in myelin formation. John Wiley and Sons Inc. 2019-12-02 /pmc/articles/PMC6952316/ /pubmed/31788990 http://dx.doi.org/10.1002/acn3.50959 Text en © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Jesse, Sarah Müller, Hans‐Peter Schoen, Michael Asoglu, Harun Bockmann, Juergen Huppertz, Hans‐Juergen Rasche, Volker Ludolph, Albert C. Boeckers, Tobias M. Kassubek, Jan Severe white matter damage in SHANK3 deficiency: a human and translational study |
title | Severe white matter damage in SHANK3 deficiency: a human and translational study |
title_full | Severe white matter damage in SHANK3 deficiency: a human and translational study |
title_fullStr | Severe white matter damage in SHANK3 deficiency: a human and translational study |
title_full_unstemmed | Severe white matter damage in SHANK3 deficiency: a human and translational study |
title_short | Severe white matter damage in SHANK3 deficiency: a human and translational study |
title_sort | severe white matter damage in shank3 deficiency: a human and translational study |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952316/ https://www.ncbi.nlm.nih.gov/pubmed/31788990 http://dx.doi.org/10.1002/acn3.50959 |
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