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Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.

Original publication

DOI

10.1002/ana.10795

Type

Journal article

Journal

Ann Neurol

Publication Date

02/2004

Volume

55

Pages

164 - 173

Keywords

Aged, Amino Acid Sequence, Base Sequence, Brain, DNA Mutational Analysis, DNA Primers, Female, Humans, Immunohistochemistry, Lewy Bodies, Lewy Body Disease, Male, Middle Aged, Molecular Sequence Data, Mutation, Nerve Degeneration, Nerve Tissue Proteins, Parkinson Disease, Pedigree, Polymerase Chain Reaction, Sequence Homology, Synucleins, Tomography, Emission-Computed, Single-Photon, alpha-Synuclein