Frequency of
            <i>LRRK2</i>
            mutations in early- and late-onset Parkinson disease

Clark, Lorraine N.; Wang, Y.; Karlins, Eric; Saito, Lynne Y.; Mejia‐Santana, Helen; Harris, Juliette; Louis, Elan D.; Côté, Lucien J.; Andrews, Howard; Fahn, Stanley; Waters, Cheryl; Ford, Blair; Frucht, Steven J.; Ottman, Ruth; Marder, Karen

doi:10.1212/01.wnl.0000244345.49809.36

Cited by 167 publications

(139 citation statements)

References 23 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: 72%

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: 72%

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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“…These pathogenic changes are clustered in 10 exons, mostly encoding the carboxyterminal region of the protein. By far the most frequent and best-studied mutation is c.6055G .A ( p.G2019S) that accounts for as many as 40% of cases of Arab descent (Lesage et al 2006), about 20% of Ashkenazi Jewish patients (Ozelius et al 2006), and 1% -7% of PD patients of European origin (Clark et al 2006;Zabetian et al 2006). Interestingly, three different founders have been described for the p.G2019S mutation and at least 29 patients have been reported to carry the mutation in the homozygous state (Klein and Lohmann-Hedrich 2007).…”

Section: Lrrk2 (Park8)mentioning

confidence: 99%

Genetics of Parkinson's Disease

Klein

Westenberger

2012

Cold Spring Harbor Perspectives in Medicine

1,088

780

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Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

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“…Identified genetic causes are responsible for only a small percentage of Parkinson's disease (PD) cases, and the lifetime penetrance of the most common causal mutation, LRRK2 G2019S, is estimated at approximately 30% [1][2][3][4]. Twin studies have found similar PD concordance rates in monozygotic and dizygotic twin pairs, suggesting a primary role for environmental etiologic determinants [5,6].…”

mentioning

confidence: 99%