Roy N Alcalay1, Tama Dinur2, Timothy Quinn1, Karina Sakanaka1, Oren Levy1, Cheryl Waters1, Stanley Fahn1, Tsvyatko Dorovski3, Wendy K Chung4, Michael Pauciulo5, William Nichols6, Huma Q Rana7, Manisha Balwani7, Louise Bier7, Deborah Elstein2, Ari Zimran2. 1. The Taub Institute, Department of Neurology, Columbia University Medical Center, New York, New York. 2. Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, Israel. 3. Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York. 4. Department of Pediatrics, Columbia University Medical Center, New York, New York5Department of Medicine, Columbia University Medical Center, New York, New York. 5. Department of Medicine, Columbia University Medical Center, New York, New York. 6. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. 7. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York.
Abstract
IMPORTANCE: Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations. OBJECTIVE: To estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes. DESIGN, SETTING, AND PARTICIPANTS: The study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n = 332) and Mount Sinai School of Medicine, New York, New York (n = 95). GBA noncarrier non-PD spouse control participants were recruited at the Center for Parkinson's Disease at Columbia University, New York (n = 77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation. MAIN OUTCOMES AND MEASURES: The main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n = 427), among their parents who are obligate GBA mutation carriers (heterozygotes, n = 694), and among noncarriers (parents of non-PD, non-GD control participants, n = 154). The age-specific risk was compared among groups using the log-rank test. RESULTS: Among those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P = .003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers (P = .008, log-rank test) and in heterozygotes than noncarriers (P = .03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes (P = .07, log-rank test). CONCLUSIONS AND RELEVANCE: Patients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset.
IMPORTANCE: Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations. OBJECTIVE: To estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes. DESIGN, SETTING, AND PARTICIPANTS: The study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n = 332) and Mount Sinai School of Medicine, New York, New York (n = 95). GBA noncarrier non-PD spouse control participants were recruited at the Center for Parkinson's Disease at Columbia University, New York (n = 77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation. MAIN OUTCOMES AND MEASURES: The main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n = 427), among their parents who are obligate GBA mutation carriers (heterozygotes, n = 694), and among noncarriers (parents of non-PD, non-GD control participants, n = 154). The age-specific risk was compared among groups using the log-rank test. RESULTS: Among those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P = .003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers (P = .008, log-rank test) and in heterozygotes than noncarriers (P = .03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes (P = .07, log-rank test). CONCLUSIONS AND RELEVANCE: Patients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset.
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