**4. RLS pathogenesis**

The scientific basis of RLS remains unclear but appears to be related in part to the dopaminergic pathways and iron metabolism in the substantia nigra. In 2003, Connor et. al. published an autopsy-based study suggesting that the cause of RLS was related to a defect in the regulation of transferrin receptors in the brain (Connor JR, et al., 2003). In addition, MRI, PET, and SPECT imaging studies have likewise shown alterations in the dopaminergic receptors of the brain (Michaud M et al., 2002). Recently, further evidence has accumulated to support that there is a primary iron insufficiency leading to an overly activated dopaminergic system (Connor JR et al., 2009, Quiroz C et al., 2010). Low iron levels can increase extracellular dopamine and decrease D2 receptors (Earley CJ et al., 2011). Thus, overall the pathophysiologic basis of RLS is not fully understood but there is increasing evidence of iron deficiency related dopaminergic abnormalities. In addition to dopamine and iron physiology, there are clear familial clusterings and genetic linkages. In 2007, researchers in Iceland reported on the first genetic variant associated with a susceptibility to periodic limb movements of sleep (Stefansson H et al., 2007). A total of 4 main genetic variants have since been discovered which account for approximately 80% of primary RLS.
