Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.
The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Roy N
RN
Alcalay
Anat
A
Mirelman
Rachel
R
Saunders-Pullman
Ming-X
MX
Tang
Helen
H
Mejia Santana
Deborah
D
Raymond
Ernest
E
Roos
Martha
M
Orbe-Reilly
Tanya
T
Gurevich
Anat
A
Bar Shira
Mali
M
Gana Weisz
Kira
K
Yasinovsky
Maayan
M
Zalis
Avner
A
Thaler
Andres
A
Deik
Matthew James
MJ
Barrett
Jose
J
Cabassa
Mark
M
Groves
Ann L
AL
Hunt
Naomi
N
Lubarr
Marta
M
San Luciano
Joan
J
Miravite
Christina
C
Palmese
Rivka
R
Sachdev
Harini
H
Sarva
Lawrence
L
Severt
Vicki
V
Shanker
Matthew Carrington
MC
Swan
Jeannie
J
Soto-Valencia
Brooke
B
Johannes
Robert
R
Ortega
Stanley
S
Fahn
Lucien
L
Cote
Cheryl
C
Waters
Pietro
P
Mazzoni
Blair
B
Ford
Elan
E
Louis
Oren
O
Levy
Llency
L
Rosado
Diana
D
Ruiz
Tsvyatko
T
Dorovski
Michael
M
Pauciulo
William
W
Nichols
Avi
A
Orr-Urtreger
Laurie
L
Ozelius
Lorraine
L
Clark
Nir
N
Giladi
Susan
S
Bressman
Karen S
KS
Marder
D000368:Aged; D005260:Female; D005838:Genotype; D005998:Glycine / Q000235:genetics*; D006801:Humans; D007585:Jews / Q000235:genetics; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000208:ethnology / Q000235:genetics*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012044:Regression Analysis; D012694:Serine / Q000235:genetics*; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires
D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005998:Glycine
LRRK2; Parkinson; genetics; postural instability and gait difficulty