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Restless legs syndrome, or RLS, has been called “the most common disorder you never heard of,” and some critics still question its validity as a real disorder. Now, a study published in the August 16 issue of the New England Journal of Medicine demonstrates a biological basis for RLS that may serve to prove its authenticity. Typically, restless legs syndrome exhibits both sensory and motor symptoms. A strong urge to move the legs during rest or inactivity at night or in the evening is often accompanied by involuntary leg movements during sleep, which can lead to poor-quality sleep. Anemia and low iron levels contribute to more severe RLS symptoms. Roughly 3 percent of North Americans and Europeans have RLS, and it is more common after the age of 40.
Scientists have known for some time that the disorder often runs in families, but proving a genetic link has been a challenge. Knowing the genetic basis for RLS is important because it could lead to effective treatments.
In an effort to identify this link, an international group of researchers performed tests for genetic variations on two groups of participants over a four-year period. In response to written questionnaires, the subjects with RLS described having an extreme urge to move the legs - often accompanied by itching, tingling or stinging sensations.
Initially, a group of 451 people who reported symptoms of RLS and 514 of their first-degree relatives were tested. The researchers used periodic limb movements of the foot and lower leg as a physical manifestation of the genetic variant. They identified three gene variants that were risk factors for periodic limb movements in sleep. To validate these results, they tested a second group of 123 and 1,233 control subjects.
Study participants wore ankle bracelets to record the number of kicks during their sleep. Those who kicked 21 or more times per hour were twice as likely to have the variant gene, researchers found. Those with two copies - one inherited from each parent - kicked most.
“A study demonstrates a biological basis for RLS that may serve to prove its authenticity.”
“A study demonstrates a biological basis for RLS that may serve to prove its authenticity.”
People with the genetic variant identified by the researchers were 50 percent more likely to have RLS with periodic limb movement during sleep. Additionally, iron levels were decreased by as much as 26 percent in those with the genetic variant.
“Although the authenticity of RLS has recently been questioned,” the study authors wrote, “our study provides evidence that periodic limb movements in sleep is a genuine syndrome with an ascertainable phenotype and a genetic basis.”
In an editorial accompanying the study, John W. Winkelman, MD, medical director of the Sleep Health Center at Brigham and Women’s Hospital in Boston, called the findings “exciting and important news.”
“The genetic findings reported by Stefansson et al. offers hope to patients with periodic limb movements in sleep and RLS that the syndrome’s pathophysiology will be understood and that such knowledge will lead to additional effective and durable treatments,” he wrote.
A second study, from the Institute of Human Genetics in Munich, Germany, published August 2007 in Nature Genetics , confirms the involvement of the genetic variant Stefansson’s group found and adds two other possible variants to the mix, all of which were associated with a more than 50 percent increased risk for RLS.
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The New England Journal of Medicine study, along with the study published in Nature Genetics , provides insights that may ultimately lead to a better understanding of restless legs syndrome (RLS) and perhaps to improved diagnosis and treatment. The discovery of a genetic variant that may be associated with RLS should come as no surprise in light of the frequently reported family history. It provides compelling evidence that the condition is a genuine syndrome with a possible genetic basis.
“It is likely that the genetic variant is not a cause but simply reflects a predisposition to develop RLS.”
I have no doubt that RLS is a real disorder. It was first described more than 300 years ago. There is a consistency in the symptoms that patients exhibit and there are treatments that relieve their symptoms.
People with RLS describe having a powerful urge to move their legs as well as a “creepy, crawly, electric” feeling in their legs, which is relieved by movement. The symptoms are typically worse during the evening but can occur during the daytime when they are sitting still. Approximately 80 percent of patients with RLS experience periodic leg movements of sleep, or PLM. Although these movements may occur during waking hours, they usually occur during sleep and are frequently noted by the bed partner who reports being kicked throughout the night.
Because RLS may lead to difficulty falling asleep or cause frequent awakenings, approximately 90 percent of patients suffer daytime fatigue and may be referred to a sleep specialist for an evaluation. Some may initially see a movement disorders specialist because of PLM or the urge to move. Treatment for RLS over the years relies on the same sort of drugs used in patients with Parkinson’s disease; however, a direct link between the two conditions has not been established.
The New England Journal of Medicine study did not actually discover the gene that causes RLS but, rather, identified a gene variant for PLM. For the diagnosis of PLM of sleep, the muscle on the front of the lower leg should show activation of at least four contractions lasting 0.5 - 5.0 seconds every 5 -90 seconds. You don’t necessarily have these multiple leg movements during sleep with RLS, and some people don’t have them at all. It’s not clear whether the gene variant is a marker for a subset of patients with RLS or simply diagnostic of PLM.
A hallmark of RLS is that patients can’t sit still. They need to keep moving. If they’re in a movie theater or on a plane they have to get up and walk around for relief. If they’re driving, they’ll frequently have to stop the car to get out. One of my patients told me she had to get up multiple times in the night, lean against the wall and bend her ankles to get relief.
RLS is more common after middle age. Only about one-third of the patients who develop it are under the age of 20. There is frequently a long lapse of time from the onset of symptoms until patients seek medical attention. For instance, I’ve had patients in their 50s and 60s who tell me they’ve had the disorder all their lives.
Usually a diagnosis of RLS can be made by obtaining the patient’s history and ruling out other conditions. For example, there is an association with RLS and low iron stores, which can be determined by measuring the serum protein ferritin. The New England Journal of Medicine article reported that people with the genetic variants also showed decreases in their serum ferritin levels. Low iron stores are a major risk factor for RLS, along with peripheral neuropathy in people with end-stage renal disease.
“Recently developed drugs such as Requip and Mirapex that act like dopamine can be taken orally and are highly effective in treating the symptoms of RLS as well as PLM.”
For most patients with RLS where there is no apparent cause, the most effective drugs mimic the action of dopamine, a naturally produced compound in the brain that functions as a neurotransmitter. Although a clear-cut deficiency of dopamine in RLS has not been demonstrated, iron is a key factor in dopamine synthesis, so there may be an iron-dopamine-RLS connection that researchers are trying to determine.
Recently developed drugs such as Requip and Mirapex that act like dopamine can be taken orally and are highly effective in treating the symptoms of RLS as well as PLM. Although these drugs have some side effects, the biggest drawback is their high price, approximately $200 to $300 a month, but insurance pays a portion of the cost.
Investigational studies are currently under way at Johns Hopkins, looking at levels of serum ferritin in people who have RLS and the usefulness of IV iron therapy. They’re also examining the relationship between low iron as measured by low ferritin and the dopamine system. Animal models with depleted iron stores have shown dopamine abnormalities as well as increased spontaneous limb movements.
As far as the possible genetic link to RLS, there may be other environmental as well as genetic factors contributing to the disorder. It is likely that the genetic variant is not the cause but simply reflects a predisposition to develop RLS. Many factors may be shown to ultimately contribute to RLS, and understanding the genetics of this relatively common disorder is an important step in unraveling its possible causes.
Dr. Maragos is a neurologist with the UK Comprehensive Movement Disorders Clinic and associate professor of neurology, anatomy and neurobiology in the UK College of Medicine.
Each issue of Advances & Insights summarizes an important piece of medical news, accompanied by commentary from a UK expert.
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