Restless Leg and Periodic Limb Movement Disorder: Genetics and Solutions

Twitchy legs, restless sleep…  That urge to move your legs at night or being woken up with your leg moving rhythmically — both take a toll on sleep quality. And good sleep is foundational for overall health and wellbeing.

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 the treatment options.  No magic bullet cures here… but perhaps some options that you haven’t yet tried.

RLS and PLMD

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 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 or Periodic Limb Movements in Sleep (PLMS).

RLS and PLMD overlap for a lot of 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 RLS genetic?

Twin studies show that there is a strong genetic element to RLS, but there are also some 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 Assocation 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 the studies agree that BTBD9 and MEIS1 are important in restless leg and periodic limb movement disorder, 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 susbstantia 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) as 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 (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…

Human brain imaging studies:

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.

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 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 really 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 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]


Genetic variants linked to RLS and PLMD:

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: normal risk of RLS

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: normal risk of RLS, PLMD

 

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: normal risk of RLS

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: normal risk of RLS; increase PLMD risk[ref]

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: normal risk of RLS

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]

GABA Receptors:

A study of patients with restless leg 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: normal
  • G/T: earlier age of onset for RLS
  • T/T: earlier age of onset for RLS[ref]  (also, faster motor reaction times [ref])

Lifehacks:

Iron: There is a statistical link between low iron (in the brain) and restless leg syndrome. And a subset of RLS patients improved with additional iron. Before you start supplementing with iron, you really need to do a blood test to see what your iron levels are. Iron is definitely one mineral you don’t want to go overboard with!  Talk with your doctor about getting an iron panel run – or order one yourself through UltaLab Tests or another online lab test ordering service.  If you do order your own lab tests, check around for coupon codes and specials. For example, on UltaLab Tests, if you wait a minute on the page they usually pop up a coupon.

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).

Acupuncture: A randomized-controlled trial of acupuncture plus gabapentin vs gabapentin alon 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]

l-dopa: A small trial of l-dopa for RLS/PLMD in children with ADHD, l-dopa was found to improve restless leg syndrome. [ref] It also has been shown to help with RLS in people with chronic kidney disease. [ref]

You can get l-dopa in an herbal form by taking mucuna pruriens, which is an herbal supplement high in l-dopa. It is available on Amazon or at your local health food store. There aren’t any studies that I can find on using mucuna pruriens for RLS.  Here is the Examine.com article on mucuna pruriens, if you want to read more about it.

Magnesium: A small study found that magnesium supplement before bed cut the incidence of PLMD in half.  [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 altitude. [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]

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