Clinical Short CommunicationMotor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls
Introduction
The autosomal dominant G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is amongst the most common genetic mutations associated with PD. [1] This mutation is responsible for 4% of familial PD and 1% of sporadic cases of PD [2], with a higher frequency of up to 18% of PD in Ashkenazi Jews (and up to 30% of familial cases) [3].
The clinical manifestations of PD in LRRK2 mutation carriers were generally similar to those of sporadic PD [4,5], although some studies found a milder motor phenotype in carriers [2,6]. Some authors found that G2019S carriers were more likely to display the postural instability-gait difficulty (PIGD) phenotype with falls [7,8]. The International LRRK2 Consortium found a higher incidence of tremor as the presenting symptom, greater prevalence of dystonia, slower motor progression, and lower incidence of cognitive impairment in carriers [2]. Some authors [9,10], but not others [[11], [12], [13], [14]], found less cognitive impairment in G2019S carriers compared to non-carriers with PD.
This cross-sectional data collection study sought to compare motor Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), and other characteristics between LRRK2 G2019S-positive subjects and matched PD controls without the mutation recruited from an academic medical center in Cleveland, Ohio.
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Clinical data collection
The protocol and consent form were approved by the University Hospitals Institutional Review Board. Consecutive PD patients in an academic Parkinson's and Movement Disorders Center were offered an opportunity to participate. Ashkenazi Jewish (AJ) patients, defined as two or more AJ grandparents, were preferentially recruited. Subjects gave written informed consent. De-identified data were entered into a secure REDCap electronic data capture database hosted at Case Western Reserve University.
Results
251 subjects gave informed consent, of whom 242 completed the study questionnaire. 231 subjects (54 AJ and 177 non-AJ), who had complete data sets including genetic testing and ethnicity data, were included in our analyses. Baseline characteristics subdivided by LRRK2 genetic status are listed in Table 1. In the LRRK2+ group, 4 subjects initially presented with rest tremor, 4 dragged or shuffled a foot, and 1 had dyscoordination.
Seven of 54 (12.96%) AJ subjects and 2 of 177 (1.13%) non-AJ
Discussion
There is a heterogeneity of PD clinical subtypes as well as a variety of genes that have been implicated in PD. In order to better predict future PD symptomatology as well as to tailor treatment to a particular genotype, the phenotypes of genetic PD must be better defined. This cross-sectional data collection study demonstrated no significant differences in motor and non-motor phenotype between LRRK2+ subjects and matched controls in our study population.
The prevalence of LRRK2 G2019S carrier
Contributions
Project Conception – S.G, D.R., A.W., S.C.; Clinical Project Execution – S.G., D.R., E.W., C.W.; Laboratory Project Execution – A.W., S.C., W.J., J.M., H.O.; Data Management – S.G.; Data Analysis – S.G., S.M.; Statistical Analysis – C.T., I.F., S.G.; Manuscript Authorship – S.G.; Review and Critique – D.R., A.W., S.C., C.T., W.J., J.M. All authors have approved the final article.
Declarations of interest
None.
Acknowledgements
This research was made possible by the Clinical and Translational Science Collaborative of Cleveland [grant number 4UL1TR000439] from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We utilized the RedCap database at Case Western Reserve University (Clinical and
References (14)
- et al.
Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study
Lancet Neurol.
(2008) - et al.
Group, genetic screening for a single common LRRK2 mutation in familial Parkinson's disease
Lancet
(2005) - et al.
Cognitive and behavioral symptoms in Parkinson's disease patients with the G2019S and R1441G mutations of the LRRK2 gene
Parkinsonism Relat. Disord.
(2015) - et al.
LRRK2 G2019S mutation in Parkinson's disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort
Parkinsonism Relat. Disord.
(2010) - et al.
Cognitive dysfunction in Tunisian LRRK2 associated Parkinson's disease
Parkinsonism Relat. Disord.
(2012) - et al.
Comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism
Neurobiol. Aging
(2014) - et al.
Genes associated with Parkinson syndrome
J. Neurol.
(2008)
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