Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome

James R. Connor, Padmavathi Ponnuru, Byeong Yeul Lee, Gerald D. Podskalny, Shoaib Alam, Richard P. Allen, Christopher J. Earley, Qing X. Yang

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Background: Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs and has been shown in many studies with abnormally low brain iron. Iron deficiency is associated with hypomyelination in brains of animals. Therefore we hypothesized that a myelin deficit should be present in the brains of patients with RLS. Methods: We performed Western blot analysis on myelin isolated from RLS (n= 11) and control (n= 11) brain tissue obtained at autopsy for the expression of the integral myelin proteins, myelin basic protein (MBP), and proteolipid protein (PLP) and the oligodendrocyte specific enzyme 3'5'-cyclic nucleotide phosphohydrolase (CNPase). To expand the postmortem findings to in vivo, we analyzed the brains of RLS patients (n= 23) and controls (n= 23) using voxel-based morphometry (VBM). Results: The expression of MBP, PLP and CNPase in the myelin from RLS was decreased by approximately 25% (p< 0.05) compared to controls. The amounts of transferrin (Tf) and H-ferritin (H-Frt) in the myelin fraction were also significantly decreased in RLS compared to controls. The imaging analysis revealed significant small decreases in white matter volume in RLS patients compared to controls in the corpus callosum, anterior cingulum and precentral gyrus. Conclusion: A decrease in myelin similar to that reported in animal models of iron deficiency was found in the brains of individuals with RLS. The evidence for less myelin and loss of myelin integrity in RLS brains, coupled with decreased ferritin and transferrin in the myelin fractions, is a compelling argument for brain iron insufficiency in RLS. These data also indicate the need to look beyond the sensorimotor symptoms that typically define the syndrome and its assumed relation to the dopaminergic system. Understanding the full range of RLS pathology may help us better understand the complex, intermittent nature and diversity of the clinical features of RLS and expand our consideration of treatment options for RLS.

Original languageEnglish (US)
Pages (from-to)614-619
Number of pages6
JournalSleep Medicine
Issue number6
StatePublished - Jun 2011

Bibliographical note

Funding Information:
This work was supported by a Program Project Grant from the NIH (1 P01 AG021190) awarded to the group studying pathophysiology of RLS (CJE) and a Grant from the PA Department of Health (JRC). The authors are grateful to the Restless Legs Syndrome Foundation for access to the RLS Brain Donation Center maintained at the Harvard Brain Bank. The control tissue was provided by the Harvard Brain Bank (R24 MH068855-06).


  • Ferritin
  • Iron
  • Myelin proteins
  • Oligodendrocytes
  • Transferrin
  • Voxel-based morphometry


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