Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication.
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.
Singleton
Amanda
A
Parkinson's Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Gwinn-Hardy
Katrina
K
Sharabi
Yehonotan
Y
Li
Sheng-Ting
ST
Holmes
Courtney
C
Dendi
Raghuveer
R
Hardy
John
J
Singleton
Andrew
A
Crawley
Anthony
A
Goldstein
David S
DS
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
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C029253:6-fluorodopamine; D004298:Dopamine