Objective: To determine potential connection between serum Alpha-synuclein (α-syn) concentrations and restless legs syndrome (RLS), and explore the impact of intravenous (IV) iron supplementation on serum α-syn.

Background: Alpha-synuclein is a neuronal protein that interacts both with iron and dopamine. Accumulation of α-syn is heavily implicated in Parkinson’s disease but minimally studied in RLS.

Method: We collected clinical data on 113 RLS patients (age, sex, age of onset, family history, iron studies, treatments, and intravenous iron history). Serum α-syn levels were quantified using a specific ELISA kit and compared to a group of 34 age matched controls. Multivariate linear regression was performed to analysis association of serum α-syn levels with features of RLS. A subset of RLS patients who received intravenous iron underwent pre- and post-treatment sampling to assess α-syn and ferritin response.

Results: Family history of RLS was reported by 62.8% of patients, and current dopaminergic augmentation was observed in 31.0%. Patients’ serum ferritin levels varied (range: 5-1105 μg/L, 95% CI ± 351.4), with 39.8% below 75 μg/L. Serum α-syn levels were decreased in RLS patients (mean: 7.7 ng/ml, 95% CI: 6.3–9.1, n=113) compared to controls (mean: 10.7 ng/ml, 95% CI: 7.1–14.3, n=34, p=0.04). Stratification based on sex or age of RLS onset did not find significant differences in α-syn. In a subset of RLS patients (n=9) who received IV iron treatment, a linear correlation between fold change in α-syn and ferritin was observed (R: 0.7, p=0.04). The temporal relation between serum α-syn and IV iron treatment showed a gradual decline of α-syn and ferritin by time correlation (P: 0.023, R: -0.739).

Conclusion: Our study explores the complex relationship between iron and α-syn and adds to our understanding of RLS pathophysiology. The association between RLS, which seems to have impaired dopamine transmission, and lower α-syn could result either from a direct causal effect on dopamine transmission (which requires α-syn), or a reciprocal effect of dopamine transmission or reduced iron (seen in RLS) on the production and diffusion of α-syn.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/serum-alpha-synuclein-levels-are-decreased-in-patients-with-restless-legs-syndrome-and-restored-by-intravenous-iron-therapy-in-correlation-with-ferritin/