Clinical feature and alpha-synuclein level of restless legs syndrome with leucine-rich repeat kinase 2 encoding gene mutation

Xin Guo; Pei Wang; Yumeng Huang; Jianfang Ma

doi:10.1016/j.parkreldis.2025.107944

Clinical feature and alpha-synuclein level of restless legs syndrome with leucine-rich repeat kinase 2 encoding gene mutation

Parkinsonism Relat Disord. 2025 Jul 7:138:107944. doi: 10.1016/j.parkreldis.2025.107944. Online ahead of print.

Authors

Xin Guo¹, Pei Wang², Yumeng Huang³, Jianfang Ma⁴

Affiliations

¹ Department of Neurology and Institute of Neurology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China.
² Department of Neurology and Institute of Neurology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China; Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Department of Neurology and Institute of Neurology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China; Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA.
⁴ Department of Neurology and Institute of Neurology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China. Electronic address: mjf10924@rjh.com.cn.

PMID: 40652856
DOI: 10.1016/j.parkreldis.2025.107944

Abstract

Introduction: Restless leg syndrome (RLS) has been reported associated with Parkinson's Disease (PD). However, it remained largely unknown of the mechanism underlying this association between RLS and PD.

Methods: 199 idiopathic RLS and 114 PD were diagnosed and recruited by neurologists from Ruijin Hospital affiliated to Shanghai Jiao Tong University. And 273 health controls were recruited from community. Eight LRRK2 pathogenic variants were sequenced. Clinical data was collected including symptoms, comorbidities, family history, and iron level. ELISA was used to measure plasma level of α-synuclein.

Results: The G2385R variant was found significantly higher in PD group after Bonferroni correction (p = 0.018). Taking all LRRK2 mutations as one risk covariant, further logistic regression analysis showed a marginal association of LRRK2 with RLS (OR = 1.847, 95 %CI:1.022-3.337, p = 0.042) after adjusting age and gender. In terms of clinical feature, it was found that RLS-LRRK2 carriers usually reported a positive family history of neurological or psychiatric disorders including PD, RLS, dementia and depression (48.3 % vs 27.6 %)(p = 0.026) and a higher foot involvement of sensory symptoms (33.3 % vs 14.0 %)(p = 0.042). Plasma α-synuclein level in RLS (p = 0.021) and PD (p = 0.018) was both significantly increased compared to non-manifesting carriers.

Conclusion: Our study showed that LRRK2 mutation was associated with Chinese PD patients but only showed a possible trend of association with RLS. Positive neurological or psychiatric family history and foot discomfort in RLS were important features of indication of LRRK2 mutation in RLS. Plasma α-syn was increased in LRRK2-RLS as well as LRRK2-PD, indicating a possible association of RLS with PD in LRRK2 carriers.

Keywords: Alpha-synuclein; LRRK2; Parkinson's disease; Restless legs syndrome.