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Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation

Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation
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 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 ?-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal ?-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had ?-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated ?-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.
parkinson’s disease, multiple system atrophy, ?-synuclein, clinical features, phosphorylation, mutation, SNCA
1750-1326
1-17
Kiely, A.P.
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Ling, H.
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Asi, Y.T.
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Kara, E.
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Proukakis, C.
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Schapira, A.H.
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Morris, H.R.
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Roberts, H.C.
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Lubbe, S.
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Limousin, P.
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Lewis, P.A.
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Lees, A.J.
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Quinn, N.
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Hardy, J.
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Love, S.
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Revesz, T.
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Houlden, H
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Holton, J.L.
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Kiely, A.P.
ca6dccd2-a931-4042-97e9-8367dfa6c29d
Ling, H.
58688144-f0a7-4996-8ff2-9261dbdcfc29
Asi, Y.T.
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Kara, E.
dcf44b44-cf7f-4bbe-9254-9c55741365b0
Proukakis, C.
894c08f4-4846-46c5-99d3-c8649b17936a
Schapira, A.H.
32603cac-30aa-4bc9-8cf7-5322df979f0a
Morris, H.R.
b3edc656-955b-4cd9-925e-33c9c0c45a92
Roberts, H.C.
5ea688b1-ef7a-4173-9da0-26290e18f253
Lubbe, S.
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Limousin, P.
96708b9d-161c-48a9-9dc3-b642c16f8eb9
Lewis, P.A.
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Lees, A.J.
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Quinn, N.
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Hardy, J.
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Love, S.
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Revesz, T.
e5a3813b-4e1b-4846-a51f-838427820661
Houlden, H
888c5cd1-cf0b-4fe8-b38f-5413ecd577f3
Holton, J.L.
ec4a1937-0717-41b2-958b-e88271950630

Kiely, A.P., Ling, H., Asi, Y.T., Kara, E., Proukakis, C., Schapira, A.H., Morris, H.R., Roberts, H.C., Lubbe, S., Limousin, P., Lewis, P.A., Lees, A.J., Quinn, N., Hardy, J., Love, S., Revesz, T., Houlden, H and Holton, J.L. (2015) Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation. Molecular Neurodegeneration, 10, 1-17, [41]. (doi:10.1186/s13024-015-0038-3). (PMID:26306801)

Record type: Article

Abstract

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 ?-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal ?-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had ?-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated ?-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.

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More information

Accepted/In Press date: 13 August 2015
e-pub ahead of print date: 27 August 2015
Published date: 27 August 2015
Keywords: parkinson’s disease, multiple system atrophy, ?-synuclein, clinical features, phosphorylation, mutation, SNCA
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 384718
URI: http://eprints.soton.ac.uk/id/eprint/384718
ISSN: 1750-1326
PURE UUID: 90693933-50d1-46cf-ba95-aa0feb6a4e63
ORCID for H.C. Roberts: ORCID iD orcid.org/0000-0002-5291-1880

Catalogue record

Date deposited: 14 Dec 2015 15:13
Last modified: 18 Feb 2021 17:00

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Contributors

Author: A.P. Kiely
Author: H. Ling
Author: Y.T. Asi
Author: E. Kara
Author: C. Proukakis
Author: A.H. Schapira
Author: H.R. Morris
Author: H.C. Roberts ORCID iD
Author: S. Lubbe
Author: P. Limousin
Author: P.A. Lewis
Author: A.J. Lees
Author: N. Quinn
Author: J. Hardy
Author: S. Love
Author: T. Revesz
Author: H Houlden
Author: J.L. Holton

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