Clinical Heterogeneity Among LRRK2 Variants in Parkinson's Disease: A Meta-Analysis

Abstract

Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Variants in the LRRK2 gene have been shown to be associated with PD. However, the clinical characteristics of LRRK2-related PD are heterogeneous. In our study, we performed a comprehensive pooled analysis of the association between specific LRRK2 variants and clinical features of PD.Methods: Articles from the Medline, Embase, and Cochrane databases were included in the meta-analysis. Strict inclusion criteria were applied, and detailed information was extracted from the final original articles included. Revman 5.3 software was used for publication biases and pooled and sensitivity analyses.Results: In all, 66 studies having the clinical manifestations of PD patients with G2019S, G2385R, R1628P, and R1441G were included for the final analysis. The prominent clinical features of LRRK2-G2019S-related PD patients were female sex, higher rates of early-onset PD (EOPD), and family history (OR: 0.77 [male], 1.37, 2.62; p < 0.00001, 0.02, < 0.00001). PD patients with G2019S were more likely to have high scores of Schwab & England (MD: 1.49; p < 0.00001), low GDS scores, high UPSIT scores (MD: 0.43, 4.70; p = 0.01, < 0.00001), and good response to L-dopa (OR: 2.33; p < 0.0001). Further, G2019S carriers had higher LEDD (MD: 115.20; p < 0.00001) and were more likely to develop motor complications, such as dyskinesia and motor fluctuations (OR: 2.18, 2.02; p < 0.00001, 0.04) than non-carriers. G2385R carriers were more likely to have family history (OR: 2.10; p = 0.007) than non-G2385R carriers and lower H-Y and higher MMSE scores (MD: −0.13, 1.02; p = 0.02, 0.0007). G2385R carriers had higher LEDD and tended to develop motor complications, such as motor fluctuations (MD: 53.22, OR: 3.17; p = 0.01, < 0.00001) than non-carriers. Other clinical presentations did not feature G2019S or G2385R. We observed no distinct clinical features for R1628P or R1441G. Our subgroup analyses in different ethnic group for specific variant also presented with relevant clinical characteristics of PD patients.Conclusions: Clinical heterogeneity was observed among LRRK2-associated PD in different variants in total and in different ethnic groups, especially for G2019S and G2385R.

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

“…In our study, patients with the G2019S mutation had a mean AAO of ~52 years, a high proportion of patients with late AAO (>50 years), a good response to levodopa, a predominance of tremor as a first symptom of PD, about a quarter had cognitive impairment, about 10% had dysautonomia, but no other atypical signs after a mean disease duration of ~10 years. Although the clinical features of the LRRK2 Gly2019Ser carriers compared with patients with idiopathic PD in literature are conflicting [meta-analysis in ( 25 )], even for the same ethnic PD population [i.e., of North-African origin; ( 26 – 31 )], our data are consistent with those of 724 LRRK2 mutation carriers listed in the MDSGene database. Like LRRK2 mutation carriers, VPS35 Asp620Asn carriers had a phenotype very similar overall to that of idiopathic PD: absence of atypical signs, excellent levodopa response, normal cognition, and absence of neuropsychiatric features.…”

A Comprehensive Analysis of Population Differences in LRRK2 Variant Distribution in Parkinson's Disease

“…G2385R carriers tended to have family history, lower Hoehn and Yahr rating (H-Y) and higher Mini Mental State Examination (MMSE) scores. However, both G2019S and G2385R carriers were more likely to develop motor complications than non-carriers (Shu et al, 2018). Therefore, for the purposes of clinical genetic counseling and testing, the symptoms exhibited by the patient could be useful in guiding the decision of which LRRK2 variant to screen for.…”

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

“…Finally, mutations in LRRK2 and ALS2 genes have been reported in early-onset, sporadic form of PD and in patients with MND, respectively [78,79,80].…”