Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a 
sensorimotor disorder for which the exact pathophysiology remains unclear. Brain 
iron insufficiency and altered dopaminergic function appear to play important 
roles in the etiology of the disorder. This concept is based partly on extensive 
research studies using cerebrospinal fluid (CSF), autopsy material, and brain 
imaging indicating reduced regional brain iron and on the clinical efficacy of 
dopamine receptor agonists for alleviating RLS symptoms. Finding causal 
relations, linking low brain iron to altered dopaminergic function in RLS, has 
required however the use of animal models. These models have provided insights 
into how alterations in brain iron homeostasis and dopaminergic system may be 
involved in RLS. The results of animal models of RLS and biochemical, 
postmortem, and imaging studies in patients with the disease suggest that 
disruptions in brain iron trafficking lead to disturbances in striatal dopamine 
neurotransmission for at least some patients with RLS. This review examines the 
data supporting an iron deficiency-dopamine metabolic theory of RLS by relating 
the results from animal model investigations of the influence of brain iron 
deficiency on dopaminergic systems to data from clinical studies in patients 
with RLS.