Two new studies add to the research that is cracking the complex genetic code behind restless legs syndrome (RLS).

Results of one study link periodic limb movements during sleep (PLMS) to a DNA variant of the “BTBD9” gene on the chromosome “6p.” PLMS occur in 80 percent to 90 percent of people who have RLS.

The complex study involved thousands of study participants and control subjects in Iceland. It was repeated on hundreds of subjects and controls in the United States. Results were the same for both population groups. Computer software analyzed more than 300,000 genetic “markers” in nearly 18,000 people. The study was published in the online version of the New England Journal of Medicine on July 18, 2007.

A similar study found a link between the same DNA variant and RLS. It also linked RLS with other genetic variants. But this study did not include PLMS in its analysis. The role that PLMS may play in the appearance of this genetic link is unclear. This study was published in the online version of Nature Genetics on July 18, 2007.

Human genome opens the door for new research

Both of these “genome-wide association studies” are examples of a new kind of medical research. They examine the “human genome” to find genetic variations. The human genome is a genetic map for scientists to study. It is a composite of the DNA sequences and genes of multiple people.

DNA is the chemical compound containing the instructions an organism needs to develop. A gene is a unit of DNA that carries instructions for making a protein. Genes control the traits that are passed from parents to their children. Chromosomes are strands of DNA that carry the genes. The human genome consists of about three billion DNA chemical pairs and 20,000 to 25,000 genes.

The completion of the human genome sequence in 2003 was a major scientific breakthrough. It was followed a few years later by the development of the “HapMap.” This is a map of the human genome that helps researchers find patterns of genetic variation.

These variations then can be linked to specific diseases. This helps clarify the hereditary nature of a disease. The genetic variation can be passed from one generation to another. Possessing the variation does not guarantee that a person will have the disease. But the presence of the genetic variation is a key risk factor.

More than half of people with RLS report a pattern of the sleep disorder in their families. The risk of RLS is about three to six times greater when an immediate relative has it. An early onset of RLS that occurs before 45 years of age points to a higher rate of RLS in the family. Genome-wide studies of a few families previously reported a link between RLS and three other chromosomes.

RLS disrupts sleep, quality of life

RLS is a common sleep disorder that produces an intense urge to move the legs. The intensity of this urge increases at night and as you lie or sit still. It is relieved only by walking or moving the legs. RLS often involves other burning, prickly, itching or tingling sensations deep in the legs. Symptoms of RLS tend to become more intense and last longer over time.

RLS may be caused by low iron levels, pregnancy, a nerve disorder, kidney disease and rheumatoid arthritis. It also is more common in people with type 2 diabetes. RLS occurs more often in women than in men.

PLMS are brief, involuntary muscle movements that occur repeatedly while you sleep. Most often they involve extending the big toe or flexing the foot or lower leg. Each movement can be as brief as half a second or as long as ten seconds. A typical movement lasts about five seconds or less. The movements tend to repeat every 20 to 40 seconds.

PLMS are more common in older people. They occur in about one-third of people over the age of 60. PLMS also are common in people who have narcolepsy and REM sleep behavior disorder.

Together, RLS and PLMS can cause severe sleep disruption. The RLS sensations can make it very hard for you to fall asleep. After you have fallen asleep, the periodic limb movements may wake you up. RLS then makes it hard for you to return to sleep. The two problems create a vicious cycle of fragmented sleep. People with severe RLS often sleep less than five hours per night.

This sleep loss often produces a reduction in daytime energy. People with RLS also may have higher rates of depression and anxiety.

Medications improve RLS symptoms

A cure for RLS has not yet been discovered. But a variety of medications are used to treat the symptoms. The drugs most commonly used are “dopamine agonists” such as pramipexole (Mirapex) or ropinirole (Requip). Dopamine is a neurotransmitter. It acts within the brain to help regulate movement.

Doctors also may prescribe sleeping pills and painkillers for people with RLS. Iron treatment is another option.

Symptoms can improve with these treatments. But each medication has a risk of side effects. Positive results also may diminish over time.

The new genetic research may lead to more effective treatments for RLS. But the National Institutes of Health reports that drugs based on this research are still 10 to 15 years away.

More Information
Learn more about restless legs syndrome and periodic limb movements.

Find help for restless legs syndrome at an accredited sleep disorders center near you.

Learn more about genetic research from the National Human Genome Research Institute.

Reviewed by David Kuhlmann, MD
Updated July 31, 2007