Genetic study points to potential treatments for restless legs syndrome

Scientists have discovered genetic clues to the cause of restless legs syndrome, a common condition among the elderly. The detection can help identify those individuals at greatest risk of the condition and indicate possible ways to treat it.

Restless legs syndrome can cause an uncomfortable crawling sensation in the legs and an urge to move them. Some people experience symptoms only occasionally, while others experience symptoms every day. Symptoms usually worsen in the evening or at night and can severely impair sleep.

Despite the condition being relatively common – up to one in 10 older people experience symptoms, while 2-3% are severely affected and require medical attention – little is known about its causes. People with restless legs syndrome often have other conditions, such as depression or anxiety, cardiovascular disorders, hypertension and diabetes, but the reason why is not known.

Previous studies had identified 22 genetic risk loci – that is, regions of our genome that contain changes associated with an increased risk of developing the condition. But there are still no known biomarkers — such as genetic signatures — that can be used to objectively diagnose the condition.

To further explore the condition, an international team led by researchers at the Helmholtz Institute of Neurogenomics in Munich, the Institute of Human Genetics of the Technical University of Munich (TUM) and the University of Cambridge collected and analyzed data from three association studies in the whole genome. These studies compared the DNA of patients and healthy controls to look for differences more commonly found in those with restless legs syndrome. By combining the data, the team was able to create a robust dataset of more than 100,000 patients and over 1.5 million unaffected controls.

The results of the study were published today in Genetics of Nature.

Co-author Dr. Steven Bell from the University of Cambridge said: “This study is the largest of its kind into this common but poorly understood condition. By understanding the genetic basis of restless legs syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of affected people worldwide.”

The team identified over 140 new genetic risk sites, increasing the known number eightfold to 164, including three on the X chromosome. The researchers found no strong genetic differences between men and women, despite the condition being twice as common in women than men. This suggests that a complex interplay of genetics and environment (including hormones) may explain the gender differences we observe in real life.

Two of the genetic differences identified by the team involve genes known as glutamate receptors 1 and 4, which are important for nerve and brain function, respectively. These could potentially be targeted by existing drugs, such as anticonvulsants such as perampanel and lamotrigine, or used to develop new drugs. Early trials have already shown positive responses to these drugs in patients with restless legs syndrome.

The researchers say it would be possible to use basic information such as age, sex and genetic markers to accurately sort out who is most likely to have severe restless legs syndrome in nine out of ten cases.

To understand how restless legs syndrome may affect overall health, researchers used a technique called Mendelian randomization. This uses genetic information to examine cause-and-effect relationships. He found that the syndrome increases the risk of developing diabetes.

Although low blood iron levels are thought to cause restless legs syndrome—because they can lead to a drop in the neurotransmitter dopamine—the researchers found no strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor.

Professor Juliane Winkelmann from TUM, one of the senior authors of the study, said: “For the first time, we have achieved the ability to predict the risk of restless leg syndrome. It has been a long journey, but now we are empowered we not only treat, but also prevent the occurrence of this condition in our patients.”