Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome

Neurology. 2003 Aug 12;61(3):304-9. doi: 10.1212/01.wnl.0000078887.16593.12.


Objective: To assess neuropathology in individuals with restless legs syndrome (RLS).

Methods: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls.

Results: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased.

Conclusions: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cation Transport Proteins / biosynthesis
  • Female
  • Ferritins / biosynthesis
  • Ferritins / deficiency
  • Humans
  • Immunohistochemistry
  • Iron / deficiency*
  • Iron / metabolism
  • Iron-Binding Proteins / biosynthesis
  • Male
  • Melanins / biosynthesis
  • Middle Aged
  • Neurons / metabolism
  • Neurons / pathology
  • Receptors, Transferrin / metabolism
  • Restless Legs Syndrome / metabolism
  • Restless Legs Syndrome / pathology*
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology*
  • Transferrin / metabolism
  • Tyrosine 3-Monooxygenase / biosynthesis


  • Cation Transport Proteins
  • Iron-Binding Proteins
  • Melanins
  • Receptors, Transferrin
  • Transferrin
  • metal transporting protein 1
  • neuromelanin
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • Ferritins
  • Iron
  • Tyrosine 3-Monooxygenase