06 June 2024

Whole-genome DNA analysis indicated treatment options for restless legs syndrome

A major international study has identified the genetic basis of restless legs syndrome, a little-studied but common condition in the elderly. Scientists expect their findings to help identify people at greatest risk of the disorder and suggest new ways of treating it.

People suffering from restless legs syndrome experience uncomfortable itching and scraping sensations in their lower limbs, as well as an overwhelming urge to move them. Usually the symptoms manifest themselves in a sitting or lying position. To alleviate the condition, patients are forced to stretch and bend their legs, shake and massage them, stand up, walk around the room and so on. During movement, unpleasant sensations weaken or disappear, but it is worth lying down or even just stop, as they again intensify.

Some people have such manifestations from time to time, and others - every day. Symptoms usually increase in the evening and at night, which often leads to sleep disturbances.

Restless legs syndrome occurs in different age groups, but more often in the elderly. It affects about one in ten older adults, and two to three per cent seek medical attention due to the severity of symptoms.

Despite its relative prevalence, little is known about the underlying causes of the disorder. People with restless legs syndrome often have other conditions, such as depression or anxiety, cardiovascular abnormalities, hypertension and diabetes, but there is no clear understanding among medical professionals as to how these relate to each other.

In an attempt to find the roots of the syndrome, scientists have previously turned to genetics and identified 22 genetic risk loci, that is, areas of the genome with certain changes in the DNA-sequence, which are associated with an increased likelihood of the disease. However, "biomarkers" or genetic signatures that could be used for diagnosis do not yet exist.

A large group of experts from the UK, Germany, France and other European countries, as well as the US and Canada, have set out to further investigate the origins of the disease. They analysed the data from three studies on a genome-wide association studies (Genome-wide association studies, GWAS), which compared information about the DNA of sufferers of restless legs syndrome and healthy people. As a result, the scientists formed a large sample of more than 100,000 patients and 1.5 million control group participants without the disease. The new study was published in the journal Nature Genetics.

At the end of the work, scientists expanded the list of established genetic risk loci to 164, including three on the X chromosome. Although in women restless legs syndrome occurs twice as often as in men, the researchers found no pronounced genetic differences in predisposition to the disease between the sexes. This means that a complex of genetic and environmental factors probably contribute to these gender differences in incidence.

Using Mendelian randomisation (MR), the researchers determined that restless legs syndrome increases the risk of developing diabetes. Notably, the scientists found no strong genetic correlation with iron metabolism, although low levels of iron in the blood are thought to trigger restless legs syndrome due to its effect on the hormone and neurotransmitter dopamine production.

Two of the risk loci identified by the team are linked to genes, glutamate receptors 1 and 4, which are important for nervous system and brain function. These can be targeted with existing drugs: for example, anticonvulsants like perampanel and lamotrigine. In addition, the data will be useful for pharma developers creating new drugs. The first trials of such drugs have already shown positive results in patients with restless legs syndrome.

In summary, the authors of the study noted that their findings will make it possible to accurately identify people at risk of restless legs syndrome in nine out of 10 cases.

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