Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome.
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.
Connor
J R
JR
Department of Neuroscience & Anatomy, Penn State University College of Medicine, M.S. Hershey Medical Center, Hershey, PA 17033, USA. jrc3@psu.edu
Boyer
P J
PJ
Menzies
S L
SL
Dellinger
B
B
Allen
R P
RP
Ondo
W G
WG
Earley
C J
CJ
D000368:Aged; D000369:Aged, 80 and over; D027682:Cation Transport Proteins / Q000096:biosynthesis; D005260:Female; D005293:Ferritins / Q000096:biosynthesis / Q000172:deficiency; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D033862:Iron-Binding Proteins / Q000096:biosynthesis; D008297:Male; D008543:Melanins / Q000096:biosynthesis; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011990:Receptors, Transferrin / Q000378:metabolism; D012148:Restless Legs Syndrome / Q000378:metabolism / Q000473:pathology*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D014168:Transferrin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D005293:Ferritins; D007501:Iron; D033862:Iron-Binding Proteins; D008543:Melanins; D011990:Receptors, Transferrin; D014168:Transferrin; D014446:Tyrosine 3-Monooxygenase; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C014121:neuromelanin