Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease.
OBJECTIVE
To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype.


METHODS
Cross-sectional observational study.


METHODS
Thirteen movement disorders centers.


METHODS
Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years.


METHODS
LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease.


RESULTS
Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001).


CONCLUSIONS
Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.
Alcalay
Roy N
RN
Department of Neurology, Columbia University, New York, NY 10032, USA.
Mejia-Santana
Helen
H
Tang
Ming Xin
MX
Rosado
Llency
L
Verbitsky
Miguel
M
Kisselev
Sergey
S
Ross
Barbara M
BM
Louis
Elan D
ED
Comella
Cynthia L
CL
Colcher
Amy
A
Jennings
Danna
D
Nance
Martha A
MA
Bressman
Susan
S
Scott
William K
WK
Tanner
Caroline
C
Mickel
Susan F
SF
Andrews
Howard F
HF
Waters
Cheryl H
CH
Fahn
Stanley
S
Cote
Lucien J
LJ
Frucht
Steven J
SJ
Ford
Blair
B
Rezak
Michael
M
Novak
Kevin
K
Friedman
Joseph H
JH
Pfeiffer
Ronald
R
Marsh
Laura
L
Hiner
Bradley
B
Siderowf
Andrew
A
Caccappolo
Elise
E
Ottman
Ruth
R
Clark
Lorraine N
LN
Marder
Karen S
KS
D000328:Adult; D017668:Age of Onset; D003430:Cross-Sectional Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D019957:Motor Skills Disorders / Q000235:genetics* / Q000503:physiopathology; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases