Iron-deficient cells in the brain are mixing up central nervous system signals to the legs and arms causing the irresistible urges to move and creepy-crawly sensations that characterize restless legs 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, Penn State College of Medicine, Penn State 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."
The study was presented today (Oct. 25, 2004) by Xinsheng Wang, M.D., Ph.D., postdoctoral fellow in Connor's laboratory, at the Society for Neuroscience's scientific meeting, Neuroscience 2004, held in San Diego. RLS, a syndrome that may affect 5 percent to 10 percent of the U.S. population, causes irresistible urges to move the legs and arms and is often accompanied by creepy-crawly sensations in the limbs. The sensations are only relieved by movement and become worse as the sun goes down, causing night after night 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 of the TH is phosphorylated, or activated. The active TH 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.
Connor's team found that people with RLS have very high levels of active TH. Although this should result in more dopamine being made, in fact, the proper regulation of dopamine production is only possible with both active TH and adequate levels of iron.
"We think the 'active form' has lost its feedback mechanism," Connor said. "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."
Connor's team first made the connection between iron deficiency and elevated TH levels by examining the brains of iron deficient rats. After weaning, the rats were divided into two groups. One group was given a normal diet, and the second, an iron deficient diet. Half of those that were given the iron deficient diet were later put on a normal iron diet. At 65 days, all rats, regardless of diet, had elevated levels of TH drawing the connection between cellular iron deficiency in the brain and elevated TH. However, the TH levels of the rats that had started a normal diet immediately after weaning eventually returned to normal.