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Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation
BACKGROUND: We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hal...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549856/ https://www.ncbi.nlm.nih.gov/pubmed/26306801 http://dx.doi.org/10.1186/s13024-015-0038-3 |
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author | Kiely, Aoife P. Ling, Helen Asi, Yasmine T. Kara, Eleanna Proukakis, Christos Schapira, Anthony H. Morris, Huw R. Roberts, Helen C. Lubbe, Steven Limousin, Patricia Lewis, Patrick A. Lees, Andrew J. Quinn, Niall Hardy, John Love, Seth Revesz, Tamas Houlden, Henry Holton, Janice L. |
author_facet | Kiely, Aoife P. Ling, Helen Asi, Yasmine T. Kara, Eleanna Proukakis, Christos Schapira, Anthony H. Morris, Huw R. Roberts, Helen C. Lubbe, Steven Limousin, Patricia Lewis, Patrick A. Lees, Andrew J. Quinn, Niall Hardy, John Love, Seth Revesz, Tamas Houlden, Henry Holton, Janice L. |
author_sort | Kiely, Aoife P. |
collection | PubMed |
description | BACKGROUND: We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case. RESULTS: All three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant α-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal α-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had α-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated α-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state. CONCLUSIONS: Our characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-015-0038-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4549856 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45498562015-08-27 Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation Kiely, Aoife P. Ling, Helen Asi, Yasmine T. Kara, Eleanna Proukakis, Christos Schapira, Anthony H. Morris, Huw R. Roberts, Helen C. Lubbe, Steven Limousin, Patricia Lewis, Patrick A. Lees, Andrew J. Quinn, Niall Hardy, John Love, Seth Revesz, Tamas Houlden, Henry Holton, Janice L. Mol Neurodegener Research Article BACKGROUND: We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case. RESULTS: All three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant α-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal α-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had α-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated α-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state. CONCLUSIONS: Our characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-015-0038-3) contains supplementary material, which is available to authorized users. BioMed Central 2015-08-27 /pmc/articles/PMC4549856/ /pubmed/26306801 http://dx.doi.org/10.1186/s13024-015-0038-3 Text en © Kiely et al. 2015 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Kiely, Aoife P. Ling, Helen Asi, Yasmine T. Kara, Eleanna Proukakis, Christos Schapira, Anthony H. Morris, Huw R. Roberts, Helen C. Lubbe, Steven Limousin, Patricia Lewis, Patrick A. Lees, Andrew J. Quinn, Niall Hardy, John Love, Seth Revesz, Tamas Houlden, Henry Holton, Janice L. Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation |
title | Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation |
title_full | Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation |
title_fullStr | Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation |
title_full_unstemmed | Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation |
title_short | Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation |
title_sort | distinct clinical and neuropathological features of g51d snca mutation cases compared with snca duplication and h50q mutation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549856/ https://www.ncbi.nlm.nih.gov/pubmed/26306801 http://dx.doi.org/10.1186/s13024-015-0038-3 |
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