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Study Links Restless Legs Syndrome to Poor Iron Uptake in the Brain

For release: Monday, August 11, 2003

Results of the first-ever autopsy study of brains from people with restless legs syndrome (RLS) suggest that the disorder may result from inefficient processing of iron in certain brain cells. The findings provide a possible explanation for this disorder and may lead to new ways of treating the disease.

The researchers found no evidence of lost or damaged cells in the RLS brains. Instead, they found that receptors which help cells absorb iron are abnormally regulated in cells that produce the nerve-signaling chemical dopamine. The study, led by James R. Connor, Ph.D., of Penn State University College of Medicine in Hershey, Pennsylvania, was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the August 12, 2003, issue of Neurology. *

RLS affects more than 12 million people in the United States. It causes unpleasant sensations often described by people as burning, creeping, tugging, or like insects crawling inside the legs. Lying down and trying to relax makes the symptoms worse. As a result, most people with RLS have difficulty falling asleep and staying asleep, which leads to exhaustion and daytime fatigue.

A number of studies have linked RLS to deficiencies of dopamine and iron. Medications that affect dopamine levels, such as the drug levodopa, relieve symptoms of the disease in some people. Injections of large doses of iron also sometimes relieve symptoms, even in people who don't have an iron deficiency. However, it has never been clear exactly what causes the symptoms of this disease.

In the new study, the researchers obtained autopsied tissue from 7 RLS patients who had donated their brains to the RLS Foundation Collection at the Harvard Brain Tissue Resource Center in Belmont, Massachusetts. The researchers compared the RLS brains to autopsied brains from 5 people with no history of neurological disease. They found no evidence of brain damage in any of the brains they studied. However, the amount of iron in brain cells from a region called the substantia nigra was extremely low, and there were very few receptors for transferrin, a protein that binds to iron and transports it into cells. Levels of several other proteins linked to iron storage and transport were also low.

The lack of iron in the cells may cause them to malfunction, leading to the symptoms of RLS, Dr. Connor says. "This may explain why treatment strategies tend to work," he adds. "In RLS, we just need to tweak the system to improve cell function, rather than replacing lost cells."

The results do not mean that people with RLS have an iron deficiency, Dr. Connor says. Instead, the iron in their bodies is not being delivered to specific brain cells in an effective way. The findings help to confirm that RLS is a neurological problem and not a psychological disorder, as many people have suspected, he adds.

People shouldn't start taking iron supplements without a physician's advice, Dr. Connor cautions. Most studies that have found a benefit from iron supplementation have used very large doses of iron, administered intravenously. Taking too much iron can lead to problems such as dizziness, headaches, low blood pressure, coma, and even death. Studies have suggested that high levels of iron also can increase the risk of Alzheimer's and Parkinson's disease, he adds.

The researchers are now focusing on studies to determine precisely how iron transport is altered in people with RLS, why the transferrin receptors are decreased, and how the iron deficit affects cells. One of these studies has suggested that alterations in a specific protein interfere with connections between neurons. Other work suggests that the abnormally low level of transferrin receptors in RLS results from disruption of a regulatory protein, possibly due to a gene defect. However, more work is needed to confirm these findings.

In the future, Dr. Connor hopes to study how iron supplementation works in people with RLS. He also hopes to find drugs or medical techniques that can specifically target the problem with iron uptake in the brain. This type of therapy should be more effective and less dangerous than injecting high doses of iron into the blood. "I feel this is an area that's ripe for new therapeutic approaches," he says.

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.

*Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ. "Neuropathological Examination Suggests Impaired Brain Iron Acquisition in Restless Legs Syndrome." Neurology, August 12, 2003, Vol. 61, No. 3, pp. 304-309.

-by Natalie Frazin


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Last Modified July 27, 2015