Expanding the clinical phenotype of SNCA duplication carriers.
SNCA duplication is a recognized cause of familial Parkinson's disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real-time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG-PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age-associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease-modifiers and may open novel avenues for future treatment.
Nishioka
Kenya
K
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Ross
Owen A
OA
Ishii
Kenji
K
Kachergus
Jennifer M
JM
Ishiwata
Kiichi
K
Kitagawa
Mayumi
M
Kono
Satoshi
S
Obi
Tomokazu
T
Mizoguchi
Koichi
K
Inoue
Yuichi
Y
Imai
Hisamasa
H
Takanashi
Masashi
M
Mizuno
Yoshikuni
Y
Farrer
Matthew J
MJ
Hattori
Nobutaka
N
D000328:Adult; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002247:Carbon Isotopes; D002874:Chromosome Mapping / Q000379:methods; D003042:Cocaine / Q000031:analogs & derivatives; D005192:Family Health; D005260:Female; D019788:Fluorodeoxyglucose F18; D018628:Gene Dosage; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D049268:Positron-Emission Tomography / Q000379:methods; D020187:REM Sleep Behavior Disorder / Q000209:etiology / Q000235:genetics; D020891:Raclopride; D012684:Sensory Thresholds / Q000502:physiology; D012903:Smell / Q000502:physiology; D055815:Young Adult; D051844:alpha-Synuclein / Q000235:genetics*
D002247:Carbon Isotopes; C497604:SNCA protein, human; D051844:alpha-Synuclein; D019788:Fluorodeoxyglucose F18; D020891:Raclopride; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine