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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.

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