A potential role for zinc in restless legs syndrome

Abstract

Study Objectives Evaluate serum and brain non-iron metals in the pathology and genetics of restless legs syndrome (RLS). Methods In two independent studies (Cohorts 1 and 2), in which subjects either remained on medications or tapered off medications, we analyzed serum levels of iron, calcium, magnesium, manganese, copper and zinc both in RLS patients and controls, and assessed the prevalence of the MEIS1 and BTBD9 risk alleles previously established through genome wide association studies. Human brain sections and a nematode genetic model were also quantified for metal levels using mass spectrometry. Results We found a significant enrichment for the BTBD9 risk genotype in the RLS affected group compared to control (p=0.0252), consistent with previous literature. Serum (p=0.0458 and p=0.0139 for Study Cohort 1 and 2, respectively) and brain (p=0.0413) zinc levels were significantly elevated in the RLS patients versus control subjects. Conclusion We show for the first time that serum and brain levels of zinc are elevated in RLS. Further, we confirm the BTBD9 genetic risk factor in a new population, although the zinc changes were not significantly associated with risk genotypes. Zinc and iron homeostasis are interrelated, and zinc biology impacts neurotransmitter systems previously linked to RLS. Given the modest albeit statistically significant increase in serum zinc of ~20%, and the lack of association with two known genetic risk factors, zinc may not represent a primary etiology for the syndrome. Further investigation into the pathogenetic role that zinc may play in restless legs syndrome is needed.

Serum Trace Elements Concentrations in Patients with Restless Legs Syndrome

“…In the current study, we could not confirm the results of the previous report that found increased serum zinc concentrations in patients diagnosed with RLS [ 26 ]. Moreover, we observed a statistically non-significant decreased average concentration of zinc in RLS patients compared to control individuals.…”

“…The main objective of the present study was to replicate the previously reported increase in serum zinc concentrations [ 26 ] in a larger series of Spanish Caucasian patients diagnosed with iRLS and in healthy controls. We also assessed in these study groups the serum levels of several trace elements involved in oxidative stress or causing peripheral nerve toxicity, with the aim of establishing a possible association with RLS development.…”

“…A recent study has described increased zinc levels in the substantia nigra from 4 patients with RLS compared with 4 controls, and increased serum zinc levels in 30 patients diagnosed with RLS compared with 29 controls, suggesting a role of zinc in the pathogenesis of RLS [ 26 ]. In the same study, serum levels of magnesium, calcium, manganese, iron, and copper did not differ significantly between RLS patients and controls.…”

“…In the same study, serum levels of magnesium, calcium, manganese, iron, and copper did not differ significantly between RLS patients and controls. [ 26 ]. Another previous study showed similar cerebrospinal fluid and serum magnesium levels in 11 RLS patients and 9 controls [ 27 ].…”

BTBD9 is a novel component of IGF signaling and regulates manganese-induced dopaminergic dysfunction

“…However, direct evidence in people with excessive Mn levels and RLS symptoms is needed to evaluate whether Mn is a causative risk factor for RLS. Due to the limited sample size in our study cohort and other RLS cohorts (Chen et al, 2020), high blood Mn levels have not been reported in those diagnosed with RLS yet.…”