Thursday, November 30, 2023
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Restless legs syndrome (RLS) is a prevalent disorder that has a significant impact on patient quality of life. Recent studies have identified gene variants that confer a significant amount of risk for developing the disorder. Some patients may have a family history of RLS, suggesting that it may be inherited. There is also a growing amount of information related to the pathophysiology of RLS, specifically regarding the roles of iron and dopamine. A better understanding of the genetics and pathophysiology of RLS will help in the development of better screening techniques and management strategies. In this expert interview, Dr. David Rye provides an overview of the genetics and pathophysiology of RLS and discusses how healthcare professionals can apply this information to clinical practice.
Medscape: Dr. Rye, thank you for joining us today to discuss issues pertaining to the genetics and pathogenesis of the sensory motor disorder known as restless legs syndrome (RLS). Let's begin by discussing the 2 recently published studies that were the first studies to identify gene variants associated with RLS. One was published by Winkelmann and colleagues in Nature Genetics[1] and the other by Stefansson and colleagues in The New England Journal of Medicine.[2] Can you please discuss the objectives and methodologies of these 2 studies?
Dr. Rye: Certainly. These studies are very complementary. To start, the New England Journal article, which was spearheaded by a group I worked with in Iceland, used genome-wide association techniques to look for gene variants within the human genome that were overrepresented or more likely to occur in patients identified as suffering from RLS.[2] We had additional clinical data regarding these patients, which are not part of the essential clinical criteria for RLS, such as their serum iron parameters, as well as periodic limb movements of sleep.
This study identified 1 gene variant that was overrepresented in the RLS patient group compared with a population control group. This variant was located on chromosome 6 in an intron of a gene known as BTBD9. Presence of this gene variant conferred a significant amount of risk for RLS. One way to assess or communicate that risk is through an odds ratio (the ratio of the number of people having the event to the number not having the event). The odds ratio for having RLS in patients who carry 1 copy of this genetic variant was about 1.5 to 1.8, and maybe a little bit higher depending on how you defined restless legs. It was even higher for those with 2 copies of this gene variant. This gene variant is very common and is present in about 65% of people, but it's present at a much higher rate in patients with RLS, approaching about 80%.
The second study by Winkelmann and colleagues, in Nature Genetics,[1] which focused primarily on familial cases of RLS in Germany, utilized a very similar analysis using similar techniques. These patients were identified from families, whereas the Icelandic study was drawn from a newspaper advertisement, a little bit more naturalistic. The Nature Genetics study identified not only the BTBD9 variant associated with RLS, but also common variants in 2 other gene regions, one on chromosome 2 and another on chromosome 15.[1]
Medscape: What are some of the similarities in the key findings from the studies?
Dr. Rye: Taken together, these gene variants explain quite a bit of what we've known for some time as the genetic risk or heritability of RLS -- for example, we have known for quite some time that this disorder is very heritable. These studies together are significant because they identify, for the first time, specific genes and variants of those genes that are associated with a risk for RLS. Both studies identified the same variant on chromosome 6 in the BTBD9 gene. The BTBD9 gene accounts for about 50% of the entire population risk for RLS and is significant in terms of the size of the effect.
Also, the Icelandic study in The New England Journal of Medicine is significant because the frequency of this gene variant was correlated with many things that we know about RLS.[2] For example, it correlated in a dose-dependent fashion to periodic limb movements of sleep, which are present in nearly all patients with restless legs (but common in other disorders as well). The gene variant also correlated in an inverse manner with serum iron status, and we know from clinical epidemiology, for example, that lower iron is associated with RLS.
Finally, the frequencies of these at-risk variants also correlated in a dose-dependent fashion to the different prevalence rates for RLS noted across different population groups. For example, in Northern Europe, such as Scandinavia, the frequencies of RLS are noted to be in the 10% range or higher; whereas in the Far East they are noted to be 2% to 4% and may be lower. Of note, these gene variants that we know from the HapMap data -- the human genome project, essentially -- are much less common in the Far East than they are in Northern Europeans. It is very likely that these gene variants, particularly the BTBD9 variant, although we don't know the function of that gene per se as of yet, are biologically plausible causes because they are related so intimately to some of the clinical features we know about RLS.
Medscape: Do these findings provide any insight as to why progression of RLS symptoms may be slower in patients with early onset of RLS symptoms when compared with late onset? Does any other evidence provide insight as to why that occurs?
Dr. Rye: From the studies that were published regarding the genetic component influencing RLS, we have yet to provide any definitive insights as to what distinguishes early-onset vs late-onset RLS. There was no relationship to age of onset or age, but more information in larger groups of patients is needed to tease this out. Progression of early onset is typically slower. One could envision, for example, that it's more probable or likely that patients suffering from early onset of symptoms may carry a heavier genetic load and are more likely to carry 2 copies or to be homozygous for the at-risk variants across multiple genes, as compared with the late-onset patients. This is yet far from clear.
Medscape: The New England Journal of Medicine study by Stefansson and colleagues reported an inverse correlation of the identified genetic variant with iron stores.[2] Is there any particular significance to this finding and the potential role of iron in the pathogenesis of RLS?
Dr. Rye: The findings of this study are consistent with what we know about the disorder clinically. Investigators found that patient iron stores, as reflected in ferritin levels, were 13% lower per copy of the at-risk variant of the BTBD9 gene. Therefore, patients who had 2 copies of that at-risk variant (ie, homozygous patients) would have predictably lower iron stores, by about 26%. It is very common to see patients with RLS who exhibit low absolute or storage forms of iron in the clinic.
What these data do not answer is the cause-effect relationship. Do we, for example, know from this study that the gene variant directly causes or contributes to iron deficiency, which in turn contributes to symptoms of RLS? Or is it more likely that when the gene variant is present, the patients with lower iron are more likely to express symptoms? This has not been looked at in the normal population of patients with low iron, compared with people suffering from RLS. It's attractive to think about the gene variant providing some risk that you're born with and that various environmental or medical insults represent so-called "second hits," one example of which would be low iron. The "second hit" is something that causes the symptoms to appear in the presence of an underlying genetic tendency or diathesis to having RLS, but we are not at the point that we can make that conclusion as of yet.
Medscape: I'd like to elaborate on our discussion of the pathogenesis of RLS. For example, what specifically are the roles of dopamine and iron in the pathogenesis of RLS?
Dr. Rye: There is a lot of information on both dopamine and iron and their involvement, or potential involvement, in the pathogenesis of RLS.[3,4] Because patients are so exquisitely responsive to agents that increase dopamine, it has always been assumed that patients have a lower availability of dopamine that essentially leads to the expression of RLS. It has been very difficult, however, to confirm that hypothesis with any data that suggest specific deficits in dopamine, and there are arguments on both sides of the fence.
The largest amount of the collective data suggests that in the evening, we have a normal nadir or drop in how much dopamine is available in the brain. Therefore, the difference between a person not suffering from restless legs and one suffering from restless legs is that the drop is much more accentuated in patients suffering from RLS compared with the drop in patients not suffering from RLS. Replacing dopamine in the evening possibly corrects for that abnormality.
With respect to iron, it also varies across time of day. Of note, this variation occurs in a similar pattern as dopamine. We know from numerous studies that patients with RLS have depressed iron. These studies have evaluated cerebrospinal fluid, utilized brain imaging, and examined autopsy material from the brains of patients with RLS. It's thought that iron may somehow interact with dopamine to cause a dopamine-deficient state, or at least exacerbate a dopamine-deficient state.[4] This theory is based on evidence from animal experiments where animals by dietary means are made deficient in iron, and one observes alterations in the availability of dopamine in the central nervous system. This is almost a complete picture and model that makes sense, but it is not quite comprehensively established yet.
Medscape: The potential role of dopamine in the pathogenesis of RLS suggests why some classes of medication, such as dopamine antagonists, may worsen symptoms. What other classes of medications may worsen RLS symptoms and why?
Dr. Rye: There are certainly medicines that can interact with the effects of dopamine or antagonize the effects of dopamine that clearly make RLS worse in many patients. These are medicines that are commonly used for other medical indications and something that patients may be inadvertently exposed to either by an unknowing healthcare provider or over the counter.
Dopaminergic antagonists such as metoclopramide, which is commonly used to enhance gastric motility, can certainly exacerbate RLS symptoms. Over-the-counter antivomiting or antinausea medications also have somewhat of a dopaminergic antagonist effect.
Antihistamines like diphenhydramine may aggravate RLS, and it's a little bit ironic, as some of these medicines are advertised as sleep aids. No one has actually categorized or catalogued how frequently this happens, but it is fairly commonly seen in the clinical setting that antihistamines worsen symptoms. In fact, many RLS patients will list this as an allergy or an adverse drug reaction. Another group of medications are over-the-counter cold medicines that contain ephedrine or pseudoephedrine, which can exacerbate symptoms.
Many prescribed antidepressant medications that act as inhibitors of serotonin or norepinephrine reuptake, particularly the latter, exacerbate RLS symptoms. The norepinephrine inhibitors seem to exacerbate symptoms in a large number of patients. We do not have good data on the frequency of patients that can have symptoms exacerbated with these agents. As to why these medications exacerbate symptoms, I think that dopaminergic antagonist medications are counteracting or worsening this hypothetical low dopamine situation; whereas with the others, such as the antihistamines, the cold medicines and the antidepressants, it's less than clear exactly where in the nervous system they interact with dopamine or other neural brain circuits to exacerbate symptoms.
Medscape: Among other things that could potentially exacerbate RLS symptoms, are there any aspects of a patient's diet that should be altered to help modify their symptoms? Are there any food or beverages that are known to exacerbate symptoms?
Dr. Rye: The major foods or beverages that exacerbate RLS symptoms are red wines and dark-colored liquors. Alcohol-containing beverages that contain amines or tannins seem to be much more likely to exacerbate symptoms than other sources of alcohol. We don't know precisely why it is, but I suspect it's related to the amine content and/or tannin content. We also have limited data that caffeine or caffeinated beverages such as colas or teas can worsen restless legs as well. It should also be noted that tannins (which bring the color to liquors or tea and coffee, for example) over a longer term interfere with iron absorption in the gut, so that may also have some longer-term ill-effects with respect to controlling restless leg symptomatology.
As to foods, it is even less clear. Many patients note that a very high carbohydrate load can bring on symptoms, and I've heard many patients talk about ice cream, for example, in the clinical setting. I suffer from RLS myself and on several occasions within the first 3 spoonfuls of ice cream I've had a pretty rapid and sudden acute restless legs attack, but it's not always and not in every patient.
Medscape: What are the 4 essential criteria that are required to confirm a diagnosis of RLS?
Dr. Rye: The criteria for identifying a patient who's suffering from restless legs are essentially 4, the primary of which is a compelling, almost insatiable urge to move. This may or may not be accompanied by some other sensory experience or symptom, such as tugging, pulling, ants crawling in the legs, etc. That's number one. Number two is that this urge or compelling need to move comes on with rest or inactivity. Number three is that these urges or compelling needs to move get better with movement. Four is this proclivity of symptoms to be more likely and/or more severe in the early evening or late at night. It's really a clinical diagnosis. There's no particular blood test, for example, for restless legs.
Medscape: If a healthcare provider is screening a patient, would it be important to ask the patient about a possible family history of RLS?
Dr. Rye: Having a positive family history of RLS -- and that would be in a first-degree relative, so a parent or a sibling or a child -- is very supportive. In fact, it's included in the NIH and International Restless Legs Study Group criteria as a secondary criterion for diagnosing restless legs. In 50% to 60% of the cases, clinicians are able to elicit a history in a first-degree relative of a patient with RLS. That can be certainly supportive of a diagnosis when one encounters a patient whose diagnosis of RLS is ambiguous. The 4 essential criteria are really the key ones in terms of whether someone has restless legs or not. You can certainly make a diagnosis without a family history. In fact, coming back to me, neither of my parents have restless legs, but I do. That would tell you that asking me about them and getting a negative response does not preclude me, or someone that might be encountered in the clinic, from having restless legs.
Medscape: What is the significance of the family history in RLS diagnosis?
Dr. Rye: Many physicians and other healthcare providers, even experts, when they get to patients that may be more difficult to diagnose with respect to meeting the 4 essential RLS criteria, would then look for the secondary criteria, which would be a family history of a first-degree relative with similar symptoms. Also, a secondary supporting feature would be that they've gotten better with exposure to dopamine-containing agents, but that may not be a very common thing to encounter. It may be the healthcare provider who potentially tries an empiric trial of a dopamine agent to see if these symptoms that the patient is complaining about improve. What is much more likely is if RLS symptoms actually worsened when a patient has received an antidopaminergic medication. This is a much more likely scenario, given the number of medications out there that antagonize dopamine. The third supporting criteria would be the presence of periodic limb movements of sleep. Periodic limb movements of sleep are fairly sensitive for RLS and occur in 80% to 90% or more of patients that suffer from RLS, but because they also are noted to occur in other disorders, these are not very specific for restless legs.
Medscape: How is the information that we've obtained on genetics and the pathophysiology of RLS applicable to clinical practice?
Dr. Rye: The gene variants associated with RLS, particularly the BTBD9 variant, are common in the "normal" population, being present in 65% of white patients, and nearly 50% of the "normal" population is carrying 2 copies of the risk variant (ie, a homozygous state). It's important to emphasize that there is a very high likelihood then that someone will develop restless leg symptoms. What "second hit" or other exacerbating factor pushes one over a threshold to translate this genetic diathesis into the development of symptoms remains unknown. When RLS symptoms become present, the next threshold would be when they need to be recognized and treated. I think a very important point is that "if you look, you shall find."
In certain clinical situations, RLS occurs early, with slow or progressive development of symptoms, and is very likely to be familial, with a very high genetic component. In contrast, in cases where patients present with a sudden onset of symptoms at an older age as late-onset disease, or if the patient is African American or Asian, here the gene frequencies are much lower and a genetic component is less likely. It begs the healthcare provider to look much more aggressively for a factor that's causing the symptoms to occur. Iron deficiency, renal failure, or some other medical condition, or alternatively a new medicine that's been started may account for the sudden occurrence in populations one might consider as "low-risk." For example, a 60-year-old African-American or Asian male presenting with a 1-month history of restless legs should prompt you look hard for something that is contributing to RLS. African American and Asian individuals have a lower genetic risk for having restless legs, and sudden onset occurs at a later age; therefore, it is unlikely to have a familial component.
Medscape: Are there any currently ongoing studies, either in genetics or pathogenesis, that are new and exciting in the field of RLS right now, in terms of study results we should be looking out for?
Dr. Rye: Three major new, separate, and exciting issues related to the field of RLS are coming. The first is certainly the follow-up on the genetic observations and trying to understand specifically what these genes are and how they actually translate into symptoms. What is the real biology going on in the brain and what's happening specifically that make symptoms occur? Also again, since there's such a high frequency of these gene variants, what are the triggers that make symptoms occur by way of these genes?
Another issue is more epidemiologic and asks "are there other health-related issues other than the severity of symptoms interfering with sleep that make RLS important for the healthcare provider to diagnose and treat?" We're starting to see some converging lines of evidence suggesting that high blood pressure and the associated cardiovascular risk that comes with it are much more common in patients suffering from RLS. In fact, much of this may be attributable to the periodic limb movements of sleep that predominate during the night. The odds ratios for development of hypertension or cardiovascular disease in RLS patients are well over 2, and multiple studies have demonstrated some in the 2.3 to 2.4 range. This would essentially argue that the risk for high blood pressure and cardiovascular disease that occurs associated with restless legs is on par with the risk that is associated with obstructive sleep apnea, which has received so much attention from the medical community.
Finally, related to genetics but also related to epidemiology, is having genes in hand and realizing that one or several of those genes, but particularly the BTBD9 variant, are related to periodic limb movements of sleep in a dose-dependent fashion. This begs the question of whether periodic limb movements of sleep eventually will be recognized as part of a broader spectrum of RLS. We have certainly seen patients who have had periodic limb movements of sleep for years who essentially "grow" into having RLS. It is an issue of how a disorder is defined, identified, and diagnosed. There may be some significant insights coming for RLS from that sort of an angle.
Medscape: Thank you, Dr. Rye, for sharing your insights on the pathogenesis and genetic advances in RLS.
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