Motor and nonmotor heterogeneity of <i>LRRK2</i>‐related and idiopathic Parkinson's disease

Marras, Connie; Alcalay, Roy N.; Caspell‐Garcia, Chelsea; Coffey, Christopher S.; Chan, Piu; Duda, John E.; Facheris, Maurizio; Fernández‐Santiago, Rubén; Ruíz‐Martínez, Javier; Mestre, Tiago; Saunders‐Pullman, Rachel; Pont‐Sunyer, Claustre; Tolosa, Eduardo; Warø, Bjørg

doi:10.1002/mds.26614

Cited by 109 publications

(96 citation statements)

References 34 publications

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“…Male predominance was observed in IPD but not in LRRK2 PD (60:41 vs. 52:48, approaching significance at P = 0.01). Overall as a group, subjects with LRRK2 PD had a younger onset of PD by approximately 3 years, longer disease duration at study exam, and were on higher LED than those with IPD, as described in detail recently 9. As expected, having a LRRK2 mutation was associated with higher proportion of positive family history in first (42.9 vs. 22.2, P < 0.001) and second‐degree relatives (23.2 vs. 12.7, P < 0.001).…”

Section: Resultsmentioning

confidence: 63%

“…We also focused solely on G2019S mutation carriers, as data were most abundant for this group, and it is not clear whether these findings are applicable to other LRRK2 mutations, or to risk variant groups. We did not focus our analysis on comparing IPD and LRRK2 PD as a group, which has been recently reported using an overlapping sample with ours 9. We also cannot entirely exclude the possibility that recall bias accounts for some of the observed gender differences, although likely not all.…”

Section: Discussionmentioning

confidence: 87%

“…Description of study cohorts of the MJFF LRRK2 Consortium, and determination of LRRK2 status are as described (www.michaeljfox.org). 9 Data from the July 2014 data cut were utilized. A total of 1289 cases with PD, including 530 LRRK2 PD carriers and 759 noncarrier idiopathic or genetically undefined PD (IPD), were included.…”

Section: Subjects/materials and Methodsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 87%

Section: Subjects/materials and Methodsmentioning

confidence: 99%

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Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Luciano

Wang

Ortega

et al. 2017

Ann Clin Transl Neurol

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“…Fox LRRK2 Cohort Consortium established in 2009 10 to examine the genetic and environmental factors associated with disease onset in first-degree relatives of PD probands with p.G2019S mutations (relatives of carrier probands) and relatives of PD probands without p.G2019S mutations (relatives of non-carrier probands). Written informed consent was obtained from each proband and institutional review boards at each site approved the protocol.…”

Section: Methodsmentioning

confidence: 99%

Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non‐Ashkenazi Jewish ancestry

et al. 2017

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Background Penetrance estimates of the LRRK2 p.G2019S mutation for Parkinson’s disease (PD) vary widely (24%–100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. Methods The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at eight sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included, when available. Results Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% CI: 26.3 – 65.8%) to age 80 which is not significantly higher than the previously estimated 25% (95% CI: 16.7 – 34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the non-carrier relatives, as seen in Ashkenazi Jewish relatives. Conclusions The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25–42.5% at age 80 in all populations analyzed.

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“…Among the several genetic mutations implicated in PD aetiology, those associated with the leucine-rich repeat kinase 2 gene (LRRK2) are actually known as responsible for the most common familial and sporadic disorder cases [16–18]. Two more common variations in the LRRK2 gene have been described: G2019S and G2385R [19]. Among them, the most common (G2019S) accounts for 3–6% of familial dominant PD and for 1-2% of sporadic forms with a north-south gradient of G2019S frequency in European countries and reaching frequency up to 41% in North African cases [20], while the second variation (G2385R) is common mainly in Asian populations [19, 21].…”

Section: Introductionmentioning

confidence: 99%

DrosophilaMutant Model of Parkinson’s Disease Revealed an Unexpected Olfactory Performance: Morphofunctional Evidences

Rose

Corda

Solari

et al. 2016

Parkinson's Disease

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Parkinson's disease (PD) is one of the most common neurodegenerative diseases characterized by the clinical triad: tremor, akinesia, and rigidity. Several studies have suggested that PD patients show disturbances in olfaction as one of the earliest, nonspecific nonmotor symptoms of disease onset. We sought to use the fruit fly Drosophila melanogaster as a model organism to explore olfactory function in LRRK loss-of-function mutants, which was previously demonstrated to be a useful model for PD. Surprisingly, our results showed that the LRRK mutant, compared to the wild flies, presents a dramatic increase in the amplitude of the electroantennogram responses and this is coupled with a higher number of olfactory sensilla. In spite of the above reported results, the behavioural response to olfactory stimuli in mutant flies is impaired compared to that obtained in wild type flies. Thus, behaviour modifications and morphofunctional changes in the olfaction of LRRK loss-of-function mutants might be used as an index to explore the progression of parkinsonism in this specific model, also with the aim of studying and developing new treatments.

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Motor and nonmotor heterogeneity of LRRK2‐related and idiopathic Parkinson's disease

Cited by 109 publications

References 34 publications

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease

Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non‐Ashkenazi Jewish ancestry

DrosophilaMutant Model of Parkinson’s Disease Revealed an Unexpected Olfactory Performance: Morphofunctional Evidences

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