title: Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication.
abstract: Parkinson's disease patients frequently have symptoms and signs of autonomic nervous dysfunction that are the source of considerable disability. Recent studies have revealed that most patients with Parkinson's disease, and all with Parkinson's disease-associated orthostatic hypotension, have a loss of cardiac sympathetic innervation. Familial Parkinson's disease, caused by mutation of the gene encoding alpha-synuclein, also features orthostatic hypotension, sympathetic neurocirculatory failure and cardiac sympathetic denervation. We have recently described a whole-gene triplication of alpha-synuclein causing Lewy body parkinsonism in a large, well characterized family called the 'Iowa kindred'. Here we report the results of cardiac PET scanning using the sympathoneural imaging agent, 6-[18F]fluorodopamine in affected and unaffected members of this kindred. Four family members were studied, two with parkinsonism, one clinically normal and one with benign essential tremor alone. Both affected members had obvious loss of cardiac sympathetic innervation; the unaffected member had normal innervation, as did the member with isolated essential tremor. The results indicate that, in this family, where disease is caused by overexpression of normal alpha-synuclein, cardiac sympathetic denervation cosegregates with parkinsonism. Post-mortem studies have demonstrated synuclein-positive Lewy body formation in the brains of individuals with parkinsonism who were also in the family described here and who also carry this triplication. These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein.
authors.affiliation: Parkinson's Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Singleton
authors.forename: Katrina
authors.initials: K
authors.lastname: Gwinn-Hardy
authors.forename: Yehonotan
authors.initials: Y
authors.lastname: Sharabi
authors.forename: Sheng-Ting
authors.initials: ST
authors.lastname: Li
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.forename: Raghuveer
authors.initials: R
authors.lastname: Dendi
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Anthony
authors.initials: A
authors.lastname: Crawley
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
mesh_terms: D000368:Aged; D001342:Autonomic Nervous System Diseases / Q000000981:diagnostic imaging / Q000235:genetics; D004298:Dopamine / Q000031:analogs & derivatives*; D006321:Heart / Q000294:innervation*; D006801:Humans; D007024:Hypotension, Orthostatic / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D051843:Synucleins; D014055:Tomography, Emission-Computed; D014636:Valsalva Maneuver; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C029253:6-fluorodopamine; D004298:Dopamine