Parkinson disease phenotype in Ashkenazi jews with and without LRRK2 G2019S mutations

Authors

  • Roy N. Alcalay MD, MS,

    Corresponding author
    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    2. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    • Correspondence to: Dr. Roy N. Alcalay, 710 West 168th Street, New York, NY 10032; rna2104@columbia.edu

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  • Anat Mirelman PhD,

    1. Movement Disorders Unit, Department of Neurology, Tel-Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    2. School of Health-Related Professions, Ben Gurion University, Beer Sheba, Israel
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  • Rachel Saunders-Pullman MD, MPH,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
    2. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA
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  • Ming-X Tang PhD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Helen Mejia Santana MS,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Deborah Raymond MS,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Ernest Roos MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Martha Orbe-Reilly MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Tanya Gurevich MD,

    1. Movement Disorders Unit, Department of Neurology, Tel-Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Anat Bar Shira PhD,

    1. Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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  • Mali Gana Weisz PhD,

    1. Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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  • Kira Yasinovsky BS,

    1. Movement Disorders Unit, Department of Neurology, Tel-Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Maayan Zalis DMD,

    1. Movement Disorders Unit, Department of Neurology, Tel-Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Avner Thaler MD,

    1. Movement Disorders Unit, Department of Neurology, Tel-Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Andres Deik MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Matthew James Barrett MD, MS,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Jose Cabassa MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Mark Groves MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Ann L. Hunt DO,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Naomi Lubarr MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
    2. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA
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  • Marta San Luciano MD, MS,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Joan Miravite NP,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Christina Palmese PhD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
    2. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA
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  • Rivka Sachdev MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
    2. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA
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  • Harini Sarva MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Lawrence Severt MD, PhD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Vicki Shanker MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
    2. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA
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  • Matthew Carrington Swan MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Jeannie Soto-Valencia BA,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Brooke Johannes MS,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Robert Ortega MS,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Stanley Fahn MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Lucien Cote MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Cheryl Waters MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Pietro Mazzoni MD, PhD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Blair Ford MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Elan Louis MD, MSc,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    2. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Oren Levy MD, PhD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    2. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Llency Rosado MD,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Diana Ruiz BSc,

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Tsvyatko Dorovski MS, MBA,

    1. Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Michael Pauciulo MBA,

    1. Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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  • William Nichols PhD,

    1. Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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  • Avi Orr-Urtreger MD, PhD,

    1. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    2. Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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  • Laurie Ozelius PhD,

    1. Departments of Genetics and Genomic Sciences and Neurology, Mount Sinai School of Medicine, New York, New York, USA
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  • Lorraine Clark PhD,

    1. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    2. Center for Human Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA
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  • Nir Giladi MD,

    1. Movement Disorders Unit, Department of Neurology, Tel-Aviv Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Susan Bressman MD,

    1. The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York, USA
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  • Karen S. Marder MD, MPH

    1. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    2. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    3. Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    4. Department of Psychiatry, Columbia University Medical Center, NYC, New York, USA
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  • Funding agencies: This study was funded by the Michael J. Fox Foundation and the National Institute of Health (through grants R56NS036630, K02NS080915, NS050487, NS060113, and UL1 TR000040; formerly the National Center for Research Resources, grant UL1 RR024156 and NINDS 10628097).

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

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. © 2013 International Parkinson and Movement Disorder Society

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