Restless Leg Syndrome Through the Magnifying Glass of Genetics

Restless leg syndrome (RLS) is a sensorimotor disorder clinically characterized by unpleasant sensations associated to urge to move the legs, predominantly manifested at resting or in the evening. RLS is considered a complex genetic disease, and a strong familial component has been proposed also in the primary RLS. While a role of genetics in this form is well established, the aetiopathogenesis of the disease remains somewhat uncertain, and genetic studies are still an important pillar of RLS research. This chapter discusses the contribution of genetics in the pathogenesis of primary RLS, with a focus on how genetics is able to drive the clinical and imaging phenotype. Genome-wide association studies have been decisive in the identification of genes (MEIS1, BTBD9, and MAP 2K5/SKOR1) strongly related with RLS in the Caucasian and Asian populations. These disease-associated genes encode for proteins involved in the ferritin expression and iron metabolism and dopaminergic system activity. Finally, using a neuroimaging approach, we also provide to identify potential vulnerable areas for the development of RLS. Structural/functional white and gray matter changes and changes due to the iron storage alterations have been questioned, in order to decode the possible association to RLS neuropathology.