title: Restless legs syndrome: update on pathogenesis.
abstract: OBJECTIVE
  Much recent progress has been made in understanding restless legs syndrome (RLS), focusing mainly on genetic predisposition and dysregulation of iron metabolism and the dopaminergic system. We provide in this review an update of the most recent scientific advances on the pathophysiology of primary RLS.
  
  
  RESULTS
  Genome-wide association studies identified six genetic variants including MEIS1 and BTBD9 with potential relationships with iron. Brain iron level is low in RLS and neuropathological studies have shown significant decreases in dopamine D2 receptors in the putamen that correlated with RLS severity, and increased tyrosine hydroxylase in the substantia nigra. An overly activated dopaminergic system was reported in both animal and cell models of iron insufficiency thus suggesting that in at least a subgroup of RLS patients altered iron metabolism plays a role in the disorder. Also, dysregulation of iron uptake and storage within brain microvessels was recently reported and might play a role in a subgroup of RLS patients.
  
  
  CONCLUSIONS
  RLS is a genetically heterogeneous complex trait with high prevalence but large phenotype variability. Current theories of RLS pathophysiology emphasize brain iron deficiency with abnormal dopaminergic consequences, together with a strong underlying genetic background.
authors.affiliation: aService de Neurologie, Unité des Troubles du Sommeil, Hôpital Gui-de-Chauliac Montpellier bINSERM U1061, Montpellier, France cNeurologische Klinik, Klinikum rechts der Isar, Institut für Humangenetik, Technische Universität München, Institut für Humangenetik, Helmholtz Zentrum München, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany dNeurology and Neuroscience, Stanford University, Palo Alto, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
mesh_terms: D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D008297:Male; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins; D011788:Quality of Life; D012148:Restless Legs Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C522207:BTBD9 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D007501:Iron; D004298:Dopamine