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Causes of Restless Legs Syndrome

In the last 20 years, there has been a substantial amount of research into understanding the cause of RLS.  From that research there appears to be three factors which are pertinent to the disease:  brain concentrations of iron, brain dopamine concentrations and genes.

Role of Iron in RLS

The single most consistent finding and the strongest environmental risk factor associated with RLS is iron insufficiency. Professor Nordlander first recognized the association between iron deficiency and RLS, and reported that treatment of the iron deficiency markedly improved, if not eliminated, the RLS symptoms.   Despite this strong association between serum iron insufficiency and RLS, only about 15% of the RLS clinical population appears to have peripheral iron deficiency (serum ferritin < 50 mcg/l). To account for this, Professor Nordlander in proposing his “iron deficiency” hypothesis of RLS stated:  “it is possible…that there can exist an iron deficiency in the tissues in spite of normal serum iron”. This hypothesis has led investigators to examine whether the brain could be deficient in iron in the face of otherwise normal serum iron measures.

All studies to date support the concept of diminished brain iron in patients with RLS even when blood tests indicate that their iron stores are normal. Using “spinal tap” also called “lumbar puncture” techniques, which involves placing a needle deep into the lower part of the spine (similar to an epidural), one can obtain cerebrospinal fluid that contains proteins and chemicals that exist inside the brain. Using cerebrospinal fluid (CSF), studies have shown that the iron storage protein, ferritin, is low in RLS patients despite these patients not being anemic and having normal serum levels of iron and ferritin. Magnetic Resonant imaging, also called MRI, can also be used to measure brain iron. Studies using MRI have shown decreased iron concentrations in the substantia nigra, one of the primary brain regions where dopamine-producing cells reside. One study using MRI found a strong relation between iron concentrations in the substantia nigra and the severity of the RLS symptoms. Through the generous efforts of RLS Foundation, a Brain Bank has been set up to collect brains from RLS patients who wish to donate their brains after they die. Using tissues from those donated brains, studies have shown markedly diminished iron and iron storage protein in the substantia nigra consistent with iron insufficiency in the dopamine cells. Overall the studies support the concept of iron dysregulation in brains of patients with RLS, particularly in dopamine-producing cells.

Gaps in our knowledge.  Despite the substantial body of research on peripheral iron regulation, we still know very little about how iron is regulated by the blood-brain barrier or by the different cells within the brain. Also there is a relative lack of research on the effects of having iron insufficiency and on exactly how a brain region can be low in iron yet other organs in the body have normal levels?   

Role of Dopamine in RLS

Because of the marked improvement in RLS symptoms seen with drugs that stimulate the dopamine system and because of  the RLS-like symptoms produced with drug that block the dopamine system, the dopamine system has been implicated RLS.  CSF has also been used to evaluate dopamine system, and although this is a crude method for assessing the dopamine system in the brain, the data indicated possible increase in brain dopamine production.  Imaging studies using special radioactive chemicals have found reduced receptor and transporter function in the brain of more severely affected RLS patients.  Tissues from the Brain Bank have shown that the dopamine cells are normal in appearance and number and give no indication that the cells are damaged in anyway.  These studies also found that the dopamine receptors were decreased and the proteins associated with producing dopamine (tyrosine hydroxylase) were increased. The composite results suggest the presence of increased production and release of dopamine but the proteins, called receptors, that bind the dopamine and transmit the dopamine signal to other cells, may not be working normally.  The increase in dopamine may be the brain cells response to the poor signal. When you cannot hear the voices clearly on the TV, you turn up the volume. Cells interact with each other in the similar manner: if a cell cannot “hear” the message (i.e., dopamine) from another cell, it feedbacks to tell the other cell to increase the amount of message (i.e., dopamine).  Thus despite the increase in dopamine, the end result may be a decrease in the effect that dopamine has on certain brains cells at certain times of the day (i.e., evening and night time) leading to the develop of RLS symptoms. 

Gaps in our knowledge.  The mechanism by which iron influences dopamine function is still unclear.  Iron deficiency affects other systems in the brain, which potentially could affect the dopamine systems.  There is recent work done here at Johns Hopkins which suggests that another chemical in the brain, glutamate, may be equally important in causing some of the symptoms experienced by RLS patients.  Brain cells in culture and brains from animals show similar changes in the dopamine activity when the iron levels are made to go low.  Brain cells in culture and brains from animals are what is referred to as “models” of the disease.  We can uses these models to examine the connections between iron and dopamine or glutamate, which could potential be used to understand what is happening in the human brain and specifically what is happening in RLS.

Role of Genes in RLS

Understanding how genes can affect our lives is quite complex.  The simplest concept is when a specific gene is damaged, for example, hemophilia or sickle cell disease. In these diseases, the damaged gene results in an abnormal protein being made or in no protein at all being made.  When we talk about how genes are related to blood pressure, heart disease, Alzheimer’s disease, or RLS then the role of the gene is more difficult to understand because usually these common disorders do not result from one damaged gene but rather from interaction of several genes under certain environmental conditions. Most of us are born with normal hearts but over time, because of the interaction between environmental factors (aging, high cholesterol, smoking, increased blood pressure, diabetes, etc) and genes, some people will progress to having a bad heart.  RLS is also related to environmental factors and genes.  The single largest know environmental factors is low iron levels.  Low iron may occur before birth, during infancy, as a child, during pregnancy or later in adult life. The low iron may resolve long before one even develops RLS symptoms, but the low iron condition may set into motion set of conditions that eventually lead to getting RLS.    There are several genes (BTBD9, MEIS1, MAP2K5/LBXCOR1, PTPRD, TOX3,) in which a small natural variation in the genes structure is associated with an increased “risk” of developing RLS.  Having one of these natural genetic variations does not necessarily give you the disease, it only increases your risk of one day developing RLS.  For example, the change in the BTBD9 gene associated with increased risk of developing RLS is present in about 75% of patients who have RLS but also present in about 65% of patient who never had RLS.  We know from studies that there is some point of interaction between several of the genes and iron regulation, thus supporting the concept of an interaction between your iron levels at some point in your life and several genes that may trigger the onset of RLS.  

Gaps in our Knowledge.  The function of these genes in adult brain, let alone in RLS, remains unclear. The RLS-risk genes in relation to the primary iron management proteins may be upstream and may determine when and how iron is changed.  Alternatively, RLS susceptibility genes may be downstream from the iron changes and thus may act to modify the consequences of the changes in iron.    The more important question is: how does the cell metabolism-iron management proteins relation change or the iron-dopamine relation change when these RLS-risk genes are varied?

Next: RLS Symptoms

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