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.

中文翻译：

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与 SNCA 重复和 H50Q 突变相比，G51D SNCA 突变病例具有独特的临床和神经病理学特征。

背景我们和其他人已经描述了由 G51D SNCA 突变引起的神经退行性疾病，其具有帕金森病 (PD) 和多系统萎缩 (MSA) 的特征。本研究的目的是通过研究来自其他 G51D SNCA 亲属的另外两个病例，扩展对 G51D 突变体 SNCA 相关疾病的临床和神经病理学特征的描述，并将该组的特征与 SNCA 重复病例进行比较， H50Q SNCA 突变病例。结果 所有三名 G51D 患者的临床特征均为帕金森病、痴呆、幻视、自主神经功能障碍和锥体征，发病年龄和左旋多巴反应各不相同。H50Q SNCA 突变病例的临床表现类似于晚发特发性 PD，具有良好且持续的左旋多巴反应。SNCA重复病例呈现额颞叶痴呆的临床表型，伴有明显的行为改变、锥体征、体位性低血压和短暂性左旋多巴反应性帕金森病。对所有病例进行了详细的尸检神经病理学分析。所有 3 例 G51D 病例均具有丰富的 α-突触核蛋白病理，具有 PD 和 MSA 的特征。其中包括广泛的皮质和皮质下神经元 α-突触核蛋白内含物以及少突胶质细胞中少量类似于神经胶质细胞质内含物 (GCI) 的内含物。相比之下，H50Q 和 SNCA 重复病例的 α-突触核蛋白病理类似于无 GCI 的特发性 PD。磷酸化 α-突触核蛋白存在于 G51D 病例的所有包涵体类型中，但在 SNCA 重复和 H50Q 突变中受到更多限制。内含物也对 5G4 抗体具有免疫反应性，表明它们高度聚集且可能呈纤维状状态。结论 我们对目前小系列 G51D SNCA 突变病例的临床和神经病理学特征的表征应该有助于识别这种临床病理实体。这些病例的神经病理学特征始终具有 PD 和 MSA 的特征，并且与携带 H50Q 或 SNCA 重复的 PD 患者不同。结论 我们对目前小系列 G51D SNCA 突变病例的临床和神经病理学特征的表征应该有助于识别这种临床病理实体。这些病例的神经病理学特征始终具有 PD 和 MSA 的特征，并且与携带 H50Q 或 SNCA 重复的 PD 患者不同。结论 我们对目前小系列 G51D SNCA 突变病例的临床和神经病理学特征的表征应该有助于识别这种临床病理实体。这些病例的神经病理学特征始终具有 PD 和 MSA 的特征，并且与携带 H50Q 或 SNCA 重复的 PD 患者不同。