Clinicopathological characterisation of the first Australian family with the p.G51D SNCA mutation.

PURPOSE: Parkinson's disease is one of the most common neurodegenerative disorders worldwide. We describe the first Australian family with the p.G51D glycine aspartate mutation in the alpha synuclein (SNCA) gene causing early onset Parkinson's disease and dementia. METHODS: The proband was referred to our Artemis Project - a community study of young onset dementia. The proband had an extrapyramidal syndrome with onset at age 38 and at 41 developed cognitive difficulties, which progressed to dementia and was shown to have extensive Lewy body pathology and the p.G51D SNCA gene mutation. His sister developed an extrapyramidal syndrome at age 51, cognitive decline at age 56 and remains alive with clinical diagnosis of Lewy body disease with the same mutation, as does her sister with onset at age 28 with Parkinsonism, who has recently developed dementia. The sister with older onset has a son, aged 27, with the mutation and subtle thumb tremor. The proband's neuropathological examination revealed Lewy body pathology in the substantia nigra and locus coeruleus with extensive Lewy bodies disseminated in the neocortex, brainstem, basal forebrain and limbic regions. Marked oro-lingual-cranial-cervical dystonia and anxiety complicated the natural history of the two sisters with the recent development of psychosis in one. CONCLUSION: This report expands the recognised phenotypic spectrum associated with the p.G51D SNCA mutation by documenting variable age-dependent expression, prominent cognitive decline, diffuse neocortical Lewy body pathology, and additional neuropsychiatric and dystonic manifestations. These findings contribute further evidence of the marked clinicopathological heterogeneity associated with pathogenic SNCA mutations.