Observed genes

Polygenic score

Influential genes: BTBD9,MAP2K5 

The MAP2K5 gene may affect the dopaminergic system, which is known to be involved in RLS.

The BTBD9 gene plays a role in regulating brain iron levels, which are believed to contribute to the development of Restless Leg Syndrome.

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Overview

Restless leg syndrome (RLS), also known as Willis-Ekbom disease, is a condition characterized by an urge to move caused by unpleasant feelings (tingling, pulling, the need to move, etc.) deep in your legs. It affects around 5-15% of the population. The risk factors include your geographic region and ethnicity, age, sex, family history, low iron stores, uremia, neuropathy, spinal cord disease, pregnancy, multiple sclerosis, and Parkinson's disease.

Around 40-60% of cases have a positive family history suggesting a strong genetic influence. The symptoms are usually present during the night (inactivity) and can be relieved with movement, walking, or some maneuvers (rubbing, massaging, etc). RLS can lead to poor sleep, fatigue, daytime sleepiness, and depression. The diagnosis is based on the symptoms. The treatment includes lifestyle changes and medications. It is beneficial to have good sleep hygiene, avoid caffeine, and exercise regularly.  

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Prevalence & Risk factors

The prevalence of RLS is estimated to be 5-15% and it varies by region, ethnicity, age, and sex.^[1] It is highest in the Northern European countries and declines in regions further east and south. The prevalence is increasing with age and is higher in females especially during pregnancy.^[8] There are various risk factors predisposing the individual to RLS, including family history, low iron stores, uremia, neuropathy, spinal cord disease, pregnancy, multiple sclerosis, and Parkinson's disease.

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Genetics

RLS is a syndrome with a strong genetic background. The number of possible associated (susceptibility) genes is still increasing, due to technological progress. However, there are other risk factors, such as ethnicity, age, sex, low iron stores, neuropathy, or pregnancy.

Available reports suggest mainly autosomal dominant inheritance patterns with variable expressivity (the degree of expression of the phenotype of people with specific genotypes). Twin and family studies have indicated the contribution of genetics up to 70%. Approximately 50-60% of RLS cases have an affected first-degree relative.^[2,3]

The complexity of RLS has been proved by the increasing number of identified susceptibility loci (position on a chromosome where a particular gene or genetic marker is located) in the genome-wide association studies (GWAS), including MEIS1, BTBD9, PTPRD, MAP2K5, SKOR1, and TOX3 genes. The MEIS1 gene has the strongest association with RLS, but further research is needed. However, progress in the technological area is quite promising in terms of the identification of other genes.^[4,5] 

Genetic testing allows us to detect whether you have the predisposition to develop this disease. In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

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Signs & Symptoms

RLS is characterized by an unpleasant feeling in the legs which causes an urge to move them. Rarely RLS can involve arms as well, mostly in severe cases. RLS symptoms emerge during periods of inactivity, especially at night. The feeling is described as a "need to move", "crawling," "tingling," "restless," "cramping," "creeping," "pulling," "electric," "tension," "discomfort," "soreness," and "itching". Typically sensations are deep and occur between the knee and ankle. The symptoms are relieved with walking, other movements, and various maneuvers like rubbing, stretching, cold/hot water, etc. Some medications (antihistamines, dopamine antagonists, antidepressants) can worsen the symptoms.

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Diagnosis

The diagnosis is made based on the medical history. Some additional tests (blood tests for iron levels and uremia) can be ordered as well and can help identify the cause. 

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Therapy

The treatment is focused on treating the underlying cause (e.g. iron deficiency treated with iron supplementation). If there is no clear cause, lifestyle changes can be beneficial. Baths, massages, and warm or cold packs can relax the legs and relieve the symptoms. It’s also important to have good sleep hygiene and exercise. If these aren’t effective, some medications can reduce the symptoms as well. These include medications that increase dopamine in the brain, drugs affecting calcium channels, muscle relaxants, sleep medications, and opioids. ‍‍

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Prevention

You can prevent the symptoms of RLS with some lifestyle modifications. Fatigue tends to worsen RLS, so good sleep hygiene is important. It includes going to bed at the same time every day, getting at least 7 hours of sleep, and a comfortable quiet sleeping environment. Regular moderate exercise is favorable as well, but overdoing it or exercising in the evening may worsen the symptoms. It is also recommended to avoid caffeine. 

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Prognosis

RLS is associated with poor sleep and insomnia. People tend to wake up during the night because of  unpleasant feelings. This can lead to fatigue, daytime sleepiness, depression, etc.  

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Recommendations

• If you experience the symptoms, visit your doctor. 
• Improve your symptoms through good sleep hygiene, caffeine avoidance, and regular exercise.
• To ease your symptoms try soaking your legs in warm water, massaging, rubbing, etc.

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