Discovery of restless legs syndrome plasmatic biomarkers by proteomic analysis.

Elisa Bellei,Aldo Tomasi,Mesrure Koseoglu Bitnel,Selma Topaloglu Tuac,Emanuela Monari,Stefania Bergamini,Serkan Ozben

doi:10.1002/brb3.1062

Abstract

ObjectivesRestless legs syndrome (RLS) can lead to severe clinical consequences, thus negatively impacts on patients’ overall health and quality of life. Nevertheless, the pathophysiology of RLS is still unclear, resulting in underestimate, incorrect, or ignored diagnosis and in limited management and treatment. The aim of this study was to compare the plasma proteome of RLS patients and healthy controls, in the search of diagnostic biomarkers related to the disease severity.Materials and MethodsTwo‐dimensional gel electrophoresis coupled with liquid chromatography‐mass spectrometry was employed to analyze plasma samples of 34 patients with primary RLS, divided into two subgroups according to the disease severity: MMS group (mild‐moderate symptoms) and HS group (severe and very severe symptoms), and 17 age‐ and sex‐matched control subjects. Sleep quality, daytime sleepiness, and the level of depression were also evaluated.ResultsWe identified eight upregulated spots, corresponding to five unique proteins, in both RLS group vs. controls (alpha‐1B‐glycoprotein, alpha‐1‐acid glycoprotein 1, haptoglobin, complement C4‐A, and immunoglobulin kappa constant); five increased spots, consistent with three unique proteins, only in HS‐RLS (kininogen‐1, immunoglobulin heavy constant alpha 1, and immunoglobulin lambda constant 2); one downregulated spot in both patient's groups (complement C3) and another one only in HS‐RLS (alpha‐1‐antitrypsin).ConclusionsThe significantly different plasma proteins detected in RLS were mainly associated with inflammation, immune response, and cardiovascular disorders. Particularly, the gradual increasing in immunoglobulins could be indicative of the disease severity and evolution. Accordingly, these proteins may represent a valid set of useful biomarkers for RLS diagnosis, progression and treatment.

Highlights

Restless legs syndrome (RLS), called Willis–Ekbom disease, is a neurological sensorimotor condition characterized by unpleasant sensations in the legs, which leads to the pressing need to move the limbs, relieving the associated discomforts, such as paresthesias and dysesthesias (Allen et al, 2003)
The proteomic analysis of plasma from RLS patients revealed a defined protein cluster related to the involvement of biochemical networks principally linked to inflammatory and immune response; the increasing levels of immunoglobulins may account for the progression and severity of the disease
The underexpression of A1AT and the upregulation of KNG1 are reflective of a greater risk for high severity (HS)-RLS patients to develop CVD; these proteins may represent potential early diagnostic biomarkers for cardiovascular and autoimmune disorders

Summary

Introduction

Restless legs syndrome (RLS), called Willis–Ekbom disease, is a neurological sensorimotor condition characterized by unpleasant sensations in the legs, which leads to the pressing need to move the limbs, relieving the associated discomforts, such as paresthesias and dysesthesias (Allen et al, 2003). These symptoms occurring at rest and their intensity increase in the evening or night, often inducing spontaneous episodic jolting of the legs that, in turn, cause serious sleep disruption and impairs quality of life (Trotti, 2017). In support of this assumption is that the current agents of choice for moderate-to-severe RLS are non-ergot-derived dopamine receptor agonists, even if augmentation is a known complication of dopaminergic medications (Nagandla & De, 2013)

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