title: Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology.
abstract: We describe the clinical, neuropathological, and genetic features of a Finnish patient with a novel α-synuclein (SNCA) mutation A53E. The patient was clinically diagnosed with atypical Parkinson's disease (PD) with age of onset at 36 years. In the neuropathological analysis performed at the age of 60 years, highly abundant SNCA pathology was observed throughout the brain and spinal cord showing features of multiple system atrophy and PD. Neuronal and glial (including oligodendroglial) SNCA inclusions and neurites were found to be particularly prominent in the putamen, caudatus, amygdala, temporal and insular cortices, gyrus cinguli, and hippocampus CA2-3 region. These areas as well as the substantia nigra and locus coeruleus showed neuronal loss and gliosis. We also found TDP-43 positive but mostly SNCA negative perinuclear inclusions in the dentate fascia of the hippocampus. The A53E mutation was found in 2 other relatives who had parkinsonism. Our results suggest that the novel SNCA A53E substitution is a causative mutation resulting clinically in parkinsonism and pathologically in severe multiple system atrophy- and PD-type phenotype.
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Finland; Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
authors.forename: Petra
authors.initials: P
authors.lastname: Pasanen
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Finland; Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland. Electronic address: liisa.myllykangas@helsinki.fi.
authors.forename: Liisa
authors.initials: L
authors.lastname: Myllykangas
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Siitonen
authors.affiliation: Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Raunio
authors.affiliation: Department of Neurology, University of Helsinki and University Central Hospital, Helsinki, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Kaakkola
authors.affiliation: Department of Neurology, University of Helsinki and University Central Hospital, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Lyytinen
authors.affiliation: Department of Neurology, University of Helsinki and University Central Hospital, Helsinki, Finland; Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland.
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.affiliation: Folkhälsan Institute of Genetics, Biomedicum Helsinki, Finland; Department of Clinical Genetics, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Pöyhönen
authors.affiliation: Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D016501:Neurites / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051844:alpha-Synuclein
keywords: A53E; Genetics; Neuropathology; Parkinsonism; SNCA; Synucleinopathy