title: Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation.
abstract: 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.
authors: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK. a.kiely@ucl.ac.uk.
authors: Aoife P
authors: AP
authors: Kiely
authors: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK. h.ling@ucl.ac.uk.
authors: Helen
authors: H
authors: Ling
authors: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK. yasmineasi@gmail.com.
authors: Yasmine T
authors: YT
authors: Asi
authors: Alzheimer's Disease Research Centre, Harvard medical school & Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA. eleanna.kara.10@ucl.ac.uk.
authors: Eleanna
authors: E
authors: Kara
authors: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. c.proukakis@ucl.ac.uk.
authors: Christos
authors: C
authors: Proukakis
authors: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. a.schapira@ucl.ac.uk.
authors: Anthony H
authors: AH
authors: Schapira
authors: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. h.morris@ucl.ac.uk.
authors: Huw R
authors: HR
authors: Morris
authors: Academic Geriatric Medicine, University of Southampton, Southampton, UK. h.c.roberts@soton.ac.uk.
authors: Helen C
authors: HC
authors: Roberts
authors: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. s.lubbe@ucl.ac.uk.
authors: Steven
authors: S
authors: Lubbe
authors: Sobell Department of Motor Neuroscience and Movement Disorders, Unit of Functional Neurosurgery, UCL Institute of Neurology, UCL, London, UK. p.limousin@ucl.ac.uk.
authors: Patricia
authors: P
authors: Limousin
authors: Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK. p.a.lewis@reading.ac.uk.|School of Pharmacy, University of Reading, Whiteknights, Reading, UK. p.a.lewis@reading.ac.uk.
authors: Patrick A
authors: PA
authors: Lewis
authors: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK. andrew.lees@ucl.ac.uk.|Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK. andrew.lees@ucl.ac.uk.
authors: Andrew J
authors: AJ
authors: Lees
authors: National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. n.quinn@ucl.ac.uk.
authors: Niall
authors: N
authors: Quinn
authors: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK. j.hardy@ucl.ac.uk.|Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK. j.hardy@ucl.ac.uk.
authors: John
authors: J
authors: Hardy
authors: Clinical Neurosciences, University of Bristol, Bristol, UK. seth.love@bristol.ac.uk.
authors: Seth
authors: S
authors: Love
authors: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK. t.revesz@ucl.ac.uk.
authors: Tamas
authors: T
authors: Revesz
authors: Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK. h.houlden@ucl.ac.uk.
authors: Henry
authors: H
authors: Houlden
authors: Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK. janice.holton@ucl.ac.uk.
authors: Janice L
authors: JL
authors: Holton
mesh_terms: D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001921:Brain / Q000473:pathology*; D003062:Codon / Q000235:genetics; D003704:Dementia / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D020440:Gene Duplication; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D010375:Pedigree; D017354:Point Mutation; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D063189:Symptom Assessment; D055815:Young Adult; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics*
chemical_list: D000978:Antiparkinson Agents; D003062:Codon; D051844:alpha-Synuclein