The
            <i>LRRK2</i>
            G2019S mutation in Ashkenazi Jews with Parkinson disease

Orr-Urtreger, Avi; Shifrin, C; Rozovski, U.; Rosner, Serena; Bercovich, Dani; Gurevich, Tanya; Yagev-More, H; Bar‐Shira, Anat; Giladi, Nir

doi:10.1212/01.wnl.0000277637.33328.d8

Cited by 148 publications

(133 citation statements)

References 34 publications

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“…Although genetic determinants may be sexually dimorphic,21, 22 and a specific LRRK2 gender effect has been postulated,23 we confirm that the male predominance observed in Western populations with PD is not present in the G2019S mutation in LRRK2 PD 23, 24, 25. A higher relative proportion of LRRK2 carriers among women (45 vs. 55%) vs. men (40 vs. 60%) was observed 25, 26.…”

Section: Discussionsupporting

confidence: 76%

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD).Methods530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women.Results Among IPD: men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS‐IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among LRRK2 PD: Male predominance was not observed among G2019S LRRK2 cases. Women had worse UPDRS‐IV but better olfaction. Among same sex:LRRK2 men and women had better olfaction than IPD counterparts. LRRK2 men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and LRRK2 women had greater UDPRS‐IV and rates of dyskinesia.InterpretationThere were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by LRRK2, with LRRK2 men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in LRRK2 and IPD should consider gender stratification in design or analysis.

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Section: Discussionsupporting

confidence: 76%

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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“…Although a genetic predisposition has been identified in a subset of patients with PD and several other risk factors for PD have been identified, 1-3 the cause and etiology of PD are largely unknown. [1][2][3][4][5] In addition to multiple other effects, the impaired basal ganglia function in PD leads to alterations in gait and balance. These motor changes in PD often restrict functional independence and are a major cause of morbidity and mortality among these patients.…”

Section: Introductionmentioning

confidence: 99%

Gait dynamics in Parkinson’s disease: Common and distinct behavior among stride length, gait variability, and fractal-like scaling

Hausdorff

2009

Chaos: An Interdisciplinary Journal of Nonlinear Science

508

409

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Parkinson’s disease (PD) is a common, debilitating neurodegenerative disease. Gait disturbances are a frequent cause of disability and impairment for patients with PD. This article provides a brief introduction to PD and describes the gait changes typically seen in patients with this disease. A major focus of this report is an update on the study of the fractal properties of gait in PD, the relationship between this feature of gait and stride length and gait variability, and the effects of different experimental conditions on these three gait properties. Implications of these findings are also briefly described. This update highlights the idea that while stride length, gait variability, and fractal scaling of gait are all impaired in PD, distinct mechanisms likely contribute to and are responsible for the regulation of these disparate gait properties.

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“…2 Select PD populations, e.g., Ashkenazi Jews (AJ) (14.3%-18.8%) [3][4][5][6] and North African Berbers (39.3%), 7 have much higher frequencies of G2019S mutations. The frequency of LRRK2 G2019S is estimated at 2% among AJ population controls.…”

mentioning

confidence: 99%

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

et al. 2015

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Objective: Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers. Methods:The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available.Results: Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p , 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p 5 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p , 0.001). Conclusion:Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted. Neurology ® 2015;85:89-95 GLOSSARY AJ 5 Ashkenazi Jewish; CI 5 confidence interval; FHI 5 family history interview; GBA 5 glucocerebrosidase; HR 5 hazard ratio; PD 5 Parkinson disease.

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The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease

Cited by 148 publications

References 34 publications

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Gait dynamics in Parkinson’s disease: Common and distinct behavior among stride length, gait variability, and fractal-like scaling

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

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