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

Aoife P Kiely,Janice L Holton,John Hardy,Yasmine T Asi,Steven Lubbe,Niall Quinn,Patrick A Lewis,Anthony H Schapira,Seth Love,Helen Ling,Henry Houlden,Patricia Limousin,Tamas Revesz,Helen C Roberts,Christos Proukakis,Andrew J Lees,Eleanna Kara,Huw R Morris

doi:10.1186/s13024-015-0038-3

Abstract

BackgroundWe 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.ResultsAll 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.ConclusionsOur 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 materialThe online version of this article (doi:10.1186/s13024-015-0038-3) contains supplementary material, which is available to authorized users.

Highlights

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)
We have demonstrated in this detailed clinical and neuropathological study that G51D mutation cases share a constellation of features of parkinsonism with dementia, visual hallucination and autonomic dysfunction, with abundant α-synuclein pathology with characteristics of both PD and MSA
We have previously shown that α-synuclein inclusions in case one are phosphorylated at both the S129 and Y125 epitopes, which is of interest as phosphorylation at the S129 epitope is believed to promote-aggregation into fibrils while Y125 phosphorylation is suggested to result in oligomer formation [16,17,18]

Summary

Introduction

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. We recently reported a novel G51D SNCA mutation [6], which resulted in clinical and neuropathological features with some similarities to both PD and MSA. A genetic cause has not been demonstrated in MSA, recessive COQ2 mutations have been suggested to underlie a subset of familial MSA cases in the Japanese population [9]

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