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Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset

From The Genetic Institute (Z.G.-O., U.R., C.S., S.R., A.B.-S., A.O.-U.) and Movement Disorders Unit, Parkinson Center, Department of Neurology (N.G., C.S., T.G.), Tel-Aviv Sourasky Medical Center; and The Sackler Faculty of Medicine (Z.G.-O., N.G., C.S., T.G., A.O.-U.), Tel-Aviv University, Israel.

Address correspondence and reprint requests to Dr. Avi Orr-Urtreger, Director, Genetic Institute, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel aviorr{at}tasmc.health.gov.il

Background: Mutations in GBA and LRRK2 genes have been implicated in Parkinson disease (PD), particularly in Ashkenazi Jews.

Methods: An Israeli Ashkenazi cohort of 420 patients with PD, 333 elderly controls, and 3,805 young controls was screened for eight GBA mutations, which are associated with mild (N370S, R496H) and severe (84GG, IVS2 + 1, V394L, D409H, L444P, RecTL) Gaucher disease. Patients with PD and elderly controls were also genotyped for LRRK2 G2019S.

Results: GBA carrier frequency was 17.9% in patients with PD compared to 4.2% in elderly and 6.35% in young controls. The proportion of severe mutation carriers among PD patient GBA carriers was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and affected the average age at PD onset (AAO), 55.7 and 57.9 years, compared to 60.7 years in patients without known GBA or LRRK2 mutations.

Conclusions: These data demonstrate genotype-phenotype correlations between different GBA mutations and Parkinson disease (PD) risk and AAO in Ashkenazi Jews. Additionally, an earlier AAO was observed in LRRK2 G2019S carrier PD patients. Finally, these data demonstrate that a surprisingly high frequency, more than one third of our patient population, carried a mutation in GBA or LRRK2.

Abbreviations: AAO = age at onset; ANOVA = analysis of variance; GD = Gaucher disease; HWE = Hardy-Weinberg equilibrium; PD = Parkinson disease.

Supplemental data at www.neurology.org

Editoral, page 2272

e-Pub ahead of print on April 23, 2008, at www.neurology.org.

Supported by grants from M.K. Humanitarian Fund, National Parkinson Foundation, Miami, FL, Tel Aviv Sourasky Medical Center Grant of Excellence, and Wolfson and Kahn Foundations.

Disclosure: The authors report no disclosures.

Received August 15, 2007. Accepted in final form October 22, 2007.

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