Restless Leg and Periodic Limb Movement Disorder: Genes and Solutions

Twitchy legs, restless sleep… That urge to move your legs at night or being woken up with your leg moving rhythmically all take a toll on sleep quality. Did you know that your genes impact your risk for RLS and PLMD?

I’m going to dive into the genetics of restless leg syndrome and periodic limb movement disorder to show how the root cause can affect treatment options.  No magic bullet cures here… but perhaps some options that you haven’t yet tried.

RLS and PLMD: Solving the problems so that you can sleep like a baby

Restless leg syndrome (RLS) is characterized by a feeling that you have to move your legs, usually at night when you are in bed. In some people, it can also affect the need to move the arms also.  Restless leg syndrome is estimated to affect between 4 and 14% of adults. It is most prevalent in older women, but it can affect both men and women at any age.

Periodic Limb Movement Disorder (PLMD) causes repetitive jerking motions in the foot/leg or in the hands/arm. In contrast to RLS, PLMD is more prevalent in men than women.[ref]

PLMD is also called Periodic Limb Movements in Sleep (PLMS).

Restless leg and PLMD coincide for many people, but they can also exist on their own. Much of the research groups the two topics together, and genetically they may have a common cause.

In a study of older men, restless leg syndrome was associated with a higher mortality rate, even when controlling for a bunch of other variables.[ref]

Is restless leg syndrome genetic?

Twin studies show that there is a strong genetic element to RLS, but there are also environmental factors that add to the risk for it.[ref]

Often when researchers don’t really understand the root cause of a condition, they will use Genome-Wide Association Studies (GWAS) to see if they can detect which genetic variants and which genes are involved.  It is an approach that takes away any preconceived notions of why a disease occurs, but it can also at times give red-herrings.

In 2007, genome-wide studies found that the BTBD9 and MEIS1 genes were linked with an increased risk of both restless leg syndrome and periodic limb movement disorder.[ref][ref]  Numerous studies have been conducted since then in an effort to replicate the findings and figure out why those two genes are so important to RLS and PLMD.

Why these genes?

Almost all studies agree that BTBD9 and MEIS1 are important in restless leg and periodic limb movement disorders, but the question for many researchers is ‘why?”

MEIS1 gene function:

The MEIS1 gene codes for a homeobox protein that is involved in turning on and off genes during the development of a fetus – specifically in the development of the limbs. It also is thought to be involved in neurodevelopment and is expressed in the substantia nigra – the region of the brain involved in dopamine production. MEIS1 is also thought to be involved in the formation of blood cells.[ref]

The substantia nigra is the region of the brain that causes the dopamine-related issues in Parkinson’s disease. This is important in RLS and PLMD because the prescription medications that are often used are Parkinson’s medications.

People with Parkinson’s are at an elevated risk of also having RLS.[ref] But is restless leg a precursor or predictor of Parkinson’s disease? The research doesn’t really show that, but there are a lot of confounders, such as disturbed circadian rhythm and dopaminergic medication intake, in trying to figure this out.[ref]

Interestingly, MEIS1 mice that have only half of the normal gene function are restless and move a lot more (16% more) than normal mice. The mice weren’t anxious: they just moved more, traveled longer distances, and were a little speedier.[ref]

Other studies show that decreased MEIS1 causes changes to the cholinergic neurons in the region of the brain that controls voluntary movement (the striatum).[ref]

BTBD9 gene function: 

The BTBD9 gene codes for a protein “which modulates transcription, cytoskeletal arrangement, ion conductance, and protein ubiquitination”. Let me break that down a little bit…

If you delete the BTBD9 gene, it alters neurotransmission in the animal. A recent study shows that mice without the BTBD9 gene had enhanced brain activity in the striatum, which is part of the basal ganglia which controls voluntary movement.  The neurons in this area are mostly dopaminergic neurons that contain either dopamine 1 receptors or dopamine 2 receptors. (See my article on dopamine receptors for more info). The study showed that lacking BTBD9 caused enhanced activity and excitability in these dopaminergic neurons in the striatum. Of note, these are calcium-dependent neurons that are inhibited by GABA. These mice without BTBD9 were more active when they should be resting, had disturbed sleep, and were more sensitive to temperature.[ref]

To sum up – increased excitability in the neurons that control movement when there isn’t enough BTBD9.  This caused more activity when the mice should be sleeping — and don’t forget the thermal sensitivity…

Do brain changes cause RLS?

Is there anything different about the brains of people with RLS or PLMD?

MRI, PET scans, and SPECT scans have all been done to look at the brains of people with RLS.  Some people (but not all) with RLS have lower iron stores that show up on MRI’s. Many of the other studies were inconclusive or had contradictory results.

A study that looked at the results of several different types of brain scans came to the conclusion that there could be an evening and night-time dopamine deficit in the striatum due to increased daytime receptor function.[ref] There is an overall circadian rhythm to dopamine production, and it is naturally lower at night and higher during the daytime.

Inflammation and RLS/PLMD:

A couple of studies point to a role of higher inflammatory cytokine in people with restless leg syndrome and/or PLMD. [ref]

The question in my mind was whether the inflammation caused RLS/PLMD or if the sleep disruption increased inflammation. Genetics points to a possible inflammatory cause.

A genetics study identified that people with variants in the IL1B (interleukin 1B) and IL-17A genes are at a higher risk of RLS/PLMD. IL-1B and IL-17A are inflammatory cytokines, and the researchers theorize that higher levels of inflammation in the brain could affect dopamine. [ref]

Iron and RLS:

A number of studies point to low iron in the brain being a contributing factor in some people with RLS. This is based on studies that show that people with RLS are more likely to have low cerebrospinal fluid ferritin.  Most studies, though, show that serum ferritin levels don’t differ in people with RLS.[ref]

Not everyone with restless leg has low iron levels. Researchers have investigated to see if genetic variants that cause high iron (HFE gene) are protective against RLS, but the conclusion was that the mutations that give people high iron levels are not protective against restless leg.[ref]

Thus, while iron may be part of the picture for some people with RLS, it isn’t the whole story by far.

Dopamine and RLS:

In addition to the genetic connections with dopaminergic neuron function, there are a couple of other things that point to dopamine being important in RLS and PLMD.

Commonly, doctors will treat RLS and PLMD with dopamine agonist medications that are traditionally used for Parkinson’s disease (a low dopamine disease).  These medications are effective for some people, but they can come with side effects. For example, Sinemet is a dopamine agonist often prescribed with a long list of side effects.

Too much dopamine in the brain can cause psychosis, and atypical antipsychotic drugs block the dopamine receptors.  It turns out that a side effect of some of the atypical antipsychotics is that they can cause or aggravate RLS.[ref]


RLS and PLMD: Genotype Report

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MEIS1 gene:

Check your genetic data for rs2300478 (23andMe v4, v5; AncestryDNA):

  • G/G: greater than 1.7x risk of RLS, increased sympathovagal balance during N3 sleep stage[ref][ref]; increased risk of PLMD[ref] low MEIS1 gene expression[ref]
  • G/T: 1.7x risk of RLS, increased risk of PLMD
  • T/T: typical risk of RLS

Members: Your genotype for rs2300478 is .

Check your genetic data for rs12469063 (AncestryDNA only):

  • G/G: increased risk of PLMD[ref]; increased risk of RLS[ref] low MEIS1 gene expression[ref]
  • A/G: somewhat increased risk of PLMD and RLS;
  • A/A: typical risk of RLS, PLMD

Members: Your genotype for rs12469063 is .

 

BTBD9 gene:

Check your genetic data for rs3923809: (23andMe v4, v5; AncestryDNA):

  • A/A: increased risk of PLMD[ref]; increased risk of RLS[ref]1.9x risk of PLMD without RLS, serum ferritin levels decreased  26%[ref]
  • A/G: somewhat increased risk of RLS and PLMD, serum ferritin levels decreased 13%
  • G/G: typical risk of RLS

Members: Your genotype for rs3923809 is .

Check your genetic data for rs9357271 (23andMe v4, v5; AncestryDNA):

  • C/C: lower risk (<0.63) of RLS[ref]
  • C/T: slightly lower risk of RLS
  • T/T: typical risk of RLS; increase PLMD risk[ref]

Members: Your genotype for rs9357271 is .

PTPRD gene:

Check your genetic data for rs1975197 (23andMe v4, v5; AncestryDNA):

  • A/A: increased (1.8x) risk of RLS[ref]; increased risk of PLMD[ref]
  • A/G: increased risk of RLS and PLMD
  • G/G: typical risk of RLS

Members: Your genotype for rs1975197 is .

MAP2K5 gene:

Check your genetic data for rs6494696 (23andMe v4; AncestryDNA):

  • G/G: increased risk of PLMD (most common allele)[ref]
  • C/G: decreased risk of RLS
  • C/C: decreased risk of RLS[ref]

Members: Your genotype for rs6494696 is .

IL-1B gene:

IL1B encodes an inflammatory cytokine.

Check your genetic data for rs1143643 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of RLS[ref]
  • C/T: typical risk
  • C/C: typical risk

Members: Your genotype for rs1143643 is .

 

IL-17A encodes an inflammatory cytokine

Check your genetic data for rs8193036 (23andMe v4; AncestryDNA):

  • C/C: increased risk of RLS[ref]
  • C/T: typical
  • T/T: typical

Members: Your genotype for rs8193036 is .

GABA Receptors:

A study of patients with restless leg syndrome found that GABA receptor variants may affect restless leg syndrome. GABA is the main inhibitory neurotransmitter — it keeps the neurons from being overexcited.[ref]

Check your genetic data for rs2229940 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • G/T: earlier age of onset for RLS
  • T/T: earlier age of onset for RLS[ref] (also, faster motor reaction times[ref])

Members: Your genotype for rs2229940 is .


Lifehacks for Restless Leg or PLMD:

Lifestyle changes:

According to the MayoClinic, all you need to do is take a warm bath, have good sleep habits, get some daily exercise, and cut back on caffeine…  Not sure how helpful that advice will be for you :-)

Let’s see what else research shows us:

Acupuncture:
A randomized-controlled trial of acupuncture plus gabapentin vs gabapentin alone found that sleep quality increased for those people getting acupuncture with their gabapentin. [ref]  Another study of acupuncture alone concluded that it ‘might help’, but the data doesn’t show a lot of improvement.[ref]

Hypoxia – Low oxygen:
There are several studies pointing to peripheral hypoxia (low oxygen in the legs, arms) as being a contributing factor in RLS and PLMD. One study found that PLMD symptoms were worsened by sleeping at high altitudes.[ref] Another study found poor endothelial function in people with RLS.[ref] And another study found lower oxygen levels just in the legs of patients with RLS.

Exercise may help with low oxygen levels in the legs. A recent study on a small group of patients with both restless leg and peripheral artery disease found that frequent, low-intensity exercise helped reduce symptoms.[ref] Other studies also point to exercise (possibly) helping with restless leg.[ref] Yoga was shown in one small (10 people) study to help with restless leg symptoms.[ref]

Whole-body vibration:
A study tested whether blood flow would be increased using whole-body vibration. The results showed that skin blood flow in the legs did not increase — but that whole-body vibration did help with RLS.[ref]

Supplements for Restless Leg and PLMD:

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Related Articles and Genes:

Circadian Rhythms: Genes at the Core of Our Internal Clocks
Circadian rhythms are the natural biological rhythms that shape our biology.  Most people know about the master clock in our brain that keeps us on a wake-sleep cycle over 24 hours.  This is driven by our master ‘clock’ genes.

GABA: Genetic Variants that Impact this Inhibitory Neurotransmitter
GABA (gamma-Aminobuyteric acid) is a neurotransmitter that acts to block or inhibit a neuron from firing. It is an essential way that the brain regulates impulses, and low GABA levels are linked with several conditions including anxiety and PTSD.


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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.