Iron-deficient cells in the brain are mixing up central nervous system signals to the legs and arms, causing the irresistible urge to move the arms and legs and "creepy-crawly" sensations that characterize restless legs (limbs) syndrome (RLS), a Penn State College of Medicine study reports.
"Our previous studies established a physical cause for RLS showing certain cells in the brain were iron-deficient," said James R. Connor, Ph.D., professor and vice chair for neurosurgery, at Penn State's Milton S. Hershey Medical Center. "We have now found a sequence of events that may connect that cellular iron deficiency to the uncontrollable movements of the disorder."
Xinsheng Wang, M.D., Ph.D., postdoctoral fellow in Dr. Connor's laboratory, presented the study at the Society for Neuroscience scientific meeting, held in San Diego in October 2004. RLS affects 5 to 10 percent of the U.S. population. The sensations are relieved only by movement, and they become worse as the sun goes down, causing many nights of sleeplessness for those with RLS and their partners.
In normal individuals, cells in a portion of the middle brain, called the substantia nigra, control the production of tyrosine hydroxylase (TH), an enzyme. The cells also determine how much TH is phosphorylated, or activated. The active enzyme regulates the production of dopamine, a substance in the brain that transmits messages from the brain and central nervous system to the body, giving it instructions for normal functioning.
Dr. Connor's team found that people with RLS had high levels of active TH. Although this should result in more dopamine being made, in fact, the proper regulation of dopamine production is possible only with both active TH and adequate levels of iron.
"We think the 'active form' has lost its feedback mechanism," Dr. Connor says. "The cell is getting a signal that more dopamine is needed so TH is made and shifted to the active form, but the activity is compromised because less iron is available. If the iron was present in sufficient amounts, the feedback process would signal the cells to stop or slow TH production."
"This shows us that developmental iron deficiency can be reversed, but that extended iron deficiency cannot be," Dr. Connor said.
In a second study using a human cell culture model, his team exposed PC12 cells, which create dopamine, to a substance that removes iron from cells. As more of the substance was added to the cells and, consequently more iron was removed, the expression of TH grew, connecting the cellular iron deficiency to elevated TH in human cells.
In a third study, brain tissues from eight individuals with RLS were compared with tissues from the brains of five healthy individuals. The brain tissue was acquired through the Restless Legs Syndrome Foundation's brain collection at the Harvard Brain Bank. The autopsy analysis of the brains of those with RLS showed that iron-deficient cells from the middle brain expressed high levels of TH compared with the non-RLS group.
"These results continue to support the idea that the brain dopaminergic system is altered in RLS and that the differences in the dopaminergic system are consistent with insufficient iron," Dr. Connor explained.
These findings explain why some patients with RLS find relief from taking dopaminergic drugs. Although these drugs have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of RLS, they are used to calm tremors in those with Parkinson's disease. The dopaminergic agents replace dopamine in the brain and temporarily improve the nerve signal transmission to the body.
"Our next steps are to continue investigations of treatment strategies for RLS involving iron supplementation and dopamine agents to attempt to reach the normal balance between iron and dopamine in the brain," Dr. Connor stated.
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