The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease - Is there a gender effect?

Tel Aviv University, Tell Afif, Tel Aviv, Israel
Neurology (Impact Factor: 8.29). 11/2007; 69(16):1595-602. DOI: 10.1212/01.wnl.0000277637.33328.d8
Source: PubMed


Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson disease (PD) identified to date, and have been implicated in both familial and sporadic forms of the disease. The G2019S change in LRRK2 exon 41 has been associated with disease at varying frequencies in Asian, European, North American, and North African populations, and is particularly prevalent among Ashkenazi Jews.
We assessed the occurrence of the LRRK2 G2019S, I2012T, I2020T, and R1441G/C/H mutations in our cohort of Jewish Israeli patients with PD, and determined the LRRK2 haplotypes in 76 G2019S-carriers detected and in 50 noncarrier Ashkenazi patients, using six microsatellite markers that span the entire gene.
Only the G2019S mutation was identified among our patients with PD, 14.8% in the Ashkenazi and 2.7% in the non-Ashkenazi patients, and in 26% and 10.6% of the Ashkenazi familial and apparently sporadic cases. The carrier frequencies in the Ashkenazi and non-Ashkenazi control samples were 2.4% and 0.4%. A common shared haplotype was detected in all non-Ashkenazi and half-Ashkenazi carriers and in all full-Ashkenazi carriers tested, except two. Women and patients with a positive family history of PD were significantly over-represented among the G2019S mutation carriers. Age at disease onset was similar in carriers and noncarriers.
Our data suggest that the LRRK2 G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients. Although testing symptomatic patients may help establish the diagnosis of PD, the value of screening asymptomatic individuals remains questionable until the penetrance and age-dependent risk of this mutation are more accurately assessed, and specific disease prevention or modifying interventions become available.

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Available from: Uri Rozovski, Aug 18, 2014
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    • "The LRRK2 G2019S mutation is particularly common among AJ with PD. It was identified in 14.8 % of all AJ with PD and in 26 % of those with familial PD; resulting in approximately a 9 fold increased chance of developing PD in mutation carriers compared to age and sex matched controls (Giladi et al. 2011; Orr-Urtreger et al. 2007). In the Michael J Fox AJ Consortium, the largest systematically examined to date, 19.9 % of Ashkenazi PD cases had LRRK2 G2019S mutations, after excluding cases with glucocerebrosidase (GBA) mutations (Alcalay et al. 2013). "
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    ABSTRACT: Our objective was to explore interest in genetic testing among Ashkenazi Jewish (AJ) Parkinson's Disease (PD) cases and first-degree relatives, as genetic testing for LRRK2 G2019S is widely available. Approximately 18 % of AJ PD cases carry G2019S mutations; penetrance estimations vary between 24 and 100 % by age 80. A Genetic Attitude Questionnaire (GAQ) was administered at two New York sites to PD families unaware of LRRK2 G2019S mutation status. The association of G2019S, age, education, gender and family history of PD with desire for genetic testing (outcome) was modeled using logistic regression. One-hundred eleven PD cases and 77 relatives completed the GAQ. Both PD cases and relatives had excellent PD-specific genetic knowledge. Among PD, 32.6 % "definitely" and 41.1 % "probably" wanted testing, if offered "now." Among relatives, 23.6 % "definitely" and 36.1 % "probably" wanted testing "now." Desire for testing in relatives increased incrementally based on hypothetical risk of PD. The most important reasons for testing in probands and relatives were: if it influenced medication response, identifying no mutation, and early prevention and treatment. In logistic regression, older age was associated with less desire for testing in probands OR = 0.921 95%CI 0.868-0.977, p = 0.009. Both probands and relatives express interest in genetic testing, despite no link to current treatment or prevention.
    Full-text · Article · Aug 2014 · Journal of Genetic Counseling
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    • "These results suggest that PBL from PD-patients serve as an important, easily accessible tool, that might help in the study of mechanisms underlying Parkinson's disease pathogenesis. Our data also demonstrated that the selection of a relatively homogeneous group of RNA samples from Ashkenazi women that do not carry either GBA or LRRK2 founder mutations [14,15] increased the ability to detect novel expression changes in PD patients' PBL. "
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    ABSTRACT: Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations. Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status. Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD.
    Full-text · Article · Sep 2011 · Molecular Neurodegeneration
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    • "For UK, Sweden, Italy, Spain, USA and other developed countries, rate ranges were: 60–350/100,000 for prevalence, 5–26/100,000 for incidence [4–7, 23]. Since data about ethnic origin was unavailable from MHS databases, our estimations do not account for ethnicity, although this factor may be relevant in the mixed Israeli population: Among Ashkenazi Jews rates may be higher, due to the high frequency of PD-associated mutations in LRRK2 (G2019S) and GBA genes among this population in Israel [25] [26]; This may account for the high occurrence we observed. However, Arab ethnicity also might be of relevance – PD prevalence rates among Israeli Arabs (∼10% of Israel's population > 50 years) were suggested to be lower [27] [28]. "
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    ABSTRACT: Estimating rates of Parkinson's disease (PD) is essential for health services planning and studies of disease determinants. However, few PD registries exist. We aimed to estimate annual prevalence and incidence of PD in a large Israeli population over the past decade using computerized drug purchase data. Based on profiles of anti-parkinsonian drugs, age at first purchase, purchase density, and follow-up time, we developed a refined algorithm for PD assessment (definite, probable or possible) and validated it against clinical diagnoses. We used the prescription database of the second largest Health Maintenance Organization in Israel (covers ~25% of population), for the years 1998-2008. PD rates by age, gender and year were calculated and compared using Poisson models. The algorithm was found to be highly sensitive (96%) for detecting PD cases. We identified 7,134 prevalent cases (67% definite/probable), and 5,288 incident cases (65% definite/probable), with mean age at first purchase 69 ± 13 years. Over the years 2000-2007, PD incidence rate of 33/100,000 was stable, and the prevalence rate increased from 170/100,000 to 256/100,000. For ages 50+, 60+, 70+, median prevalence rates were 1%, 2%, 3%, respectively. Incidence rates also increased with age (RR = 1.76, 95%CI 1.75-1.77, ages 50+, 5-year interval). For ages 50+, rates were higher among men for both prevalence (RR = 1.38, 95%CI 1.37-1.39) and incidence (RR = 1.45, 95%CI 1.42-1.48). In conclusion, our refined algorithm for PD assessment, based on computerized drug purchases data, may be a reliable tool for population-based studies. The findings indicate a burden of PD in Israel higher than previously assumed.
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