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New Study Suggests Cause for Restless Legs Syndrome

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Underdiagnosed syndrome may affect 5 percent to 10 percent of U.S. population

Restless legs syndrome (RLS) may sound like something right out of a 1950s horror flick. And for some sufferers, it is. This affliction causes an irresistible urge to move the legs often accompanied by creepy-crawly sensations in the legs. The sensations are only relieved by movement, and become worse as the sun goes down. Night after night this sleeplessness occurs for the millions who suffer with RLS and their partners.

Because little is known about what causes RLS, researchers at Penn State College of Medicine and Johns Hopkins University went looking for answers. The team, led by James Connor, Ph.D., professor and interim chair, Department of Neuroscience and Anatomy, Penn State College of Medicine, performed the first-ever autopsy analysis of the brains of people with RLS. This research, presented on June 5, 2003 at the Association of Professional Sleep Societies meeting in Chicago, uncovered a possible explanation for this syndrome.

“We found that, although there are no unique pathological changes in the brains of patients with RLS, it appears that cells in a portion of the mid-brain aren’t getting enough iron,” Connor said. “It was a relief to many that there was no neurodegeneration, or loss or damage of brain cells, like we see in Parkinson’s and Alzheimer’s disease.” The discovery of a physical cause for this disorder establishes it as a sensory motor rather than a psychological disorder. Because cells aren’t lost or damaged but rather iron-deficient, there is more hope that treatments can be developed.

For the study, Connor examined brain tissue acquired through the Restless Legs Syndrome Foundation’s brain collection at the Harvard Brain Bank. Tissue from seven people with RLS was examined and five samples from people with no neurological conditions served as controls. Cross-sectional slides of the substantia nigra, the portion of the middle brain thought to play a role in RLS, allowed the research team to thoroughly examine the cells’ structures and functions. To avoid bias, during examination, the investigator did not know whether the sample was that of a patient with or without RLS.

Although it’s been long-suspected that iron deficiency had something to do with RLS, Connor’s study found that a specific receptor for iron transport is lacking in patients with RLS. When that mechanism malfunctions, enough iron gets into the brain cells to keep them alive, but not enough so that they function optimally. That missing iron may cause a misfiring of neural signals to the legs creating the creepy-crawly feelings.

“This doesn’t necessarily mean that a person has dietary iron-deficiency and needs supplements,” Connor said. “It means only that these receptors aren’t packaging and delivering an adequate amount of iron to the specific cells in this portion of the brain.” This explains why some patients find temporary relief from iron supplements, but it is important that any supplementation therapy be managed by a physician.

Although not FDA-approved for the treatment of RLS, a few prescription drugs, which have been approved for other conditions, have temporarily relieved symptoms in some patients. One such drug is that used in Parkinson’s disease to calm tremors. The cells in the brain in RLS that are iron deficient are the cells that make the neurotransmitter dopamine. Dopamine synthesis requires iron and this is the likely reason that small amounts of the drugs that are used to treat Parkinson’s patients can be effective in RLS.

Connor’s next step is to continue to pinpoint other potential breakdowns in the iron packaging and transport system to this part of the brain, including the genes that regulate the iron transport proteins.“We hope these discoveries lead to a test that could diagnose this syndrome, and a potential target for a therapy to bring long-term relief to those suffering with restless legs syndrome,” Connor said. 

This study was funded in part by grants from the National Institutes of Health and the Restless Legs Syndrome Foundation.

Other members of the research team were: P.J. Boyer, M.D., Ph.D., Departments of Neuroscience and Anatomy, and Pathology, S. L. Menzies, Department of Neuroscience and Anatomy, and B. Dellinger, Department of Pathology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center; R.P. Allen, Ph.D., Department of Neurology, Johns Hopkins Bayview Medical Center; W.G. Ondo, M.D., Department of Neurology, Baylor College of Medicine, Houston; C.J. Earley, M.D., Ph.D., Department of Neurology, Johns Hopkins Bayview Medical Center.

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