Vanderbilt University Medical Center has been selected as one of three sites to share a three-year, $1.3 million grant from the National Institutes of Health (NIH) to explore the potential therapeutic properties of manganese, a chemical element and biologically essential trace mineral, in treating Restless Legs Syndrome (RLS).
“The overarching goal of this work is to determine if changes in brain manganese levels affect Restless Legs Syndrome,” said Aaron Bowman, Ph.D., assistant professor of Neurology and co-principal investigator of the study.
“If our hypothesis is correct, it will provide a new therapeutic target for treatment. In fact, we have already begun screening certain drugs for small molecules that have the potential to correct the changes in the brain that we hope to find.”
“The study has been designed to evaluate the relationship between a patient’s genetics and brain manganese levels, so that if successful we could make individualized decisions about diagnoses and create treatment plans tailored to the biology of each patient,” Bowman said.
There are four major criteria used to establish a diagnosis of RLS: a strong, overwhelming urge to move the affected limb; symptoms that are worse at night compared to the daytime; symptoms becoming worse by lying down or resting; and a feeling of at least some relief in the limb with movement.
“The type of sensation patients feel in their legs varies widely. I’ve had patients describe everything from mild tingling to severe burning pain that interrupts their ability to sleep,” said Arthur Walters, M.D., professor of Neurology and co-investigator. “It has been estimated that approximately one-third of cases involve some degree of pain for the patient.”
According to the NIH, RLS affects up to 10 percent of the population, both adults and children.
Annually, more women are diagnosed with RLS than men and diagnoses of RLS become more common as patients age. Approximately a quarter of these cases are serious enough to warrant treatment.
Walters said that although the primary cause of RLS has not been determined, iron deficiency is the most well-documented and widely accepted cause.
He notes that there is also evidence that RLS can be genetic, can be affected by the level of dopamine and other neurotransmitters in the brain and is frequently associated with autoimmune disorders.
“Changes in iron and dopamine levels in the brain have long been associated with Restless Legs Syndrome and we know from basic biology that there is a link between both the levels of iron and manganese in the brain and dopamine and manganese in the brain,” added Bowman. “Because we know these correlations exist, it was a natural progression for us to look into the effects of manganese.”
Bowman said that the Vanderbilt portion of the study will be two-pronged:
• Walters’ group will explore whether there is an association between having genetic risk factors and alterations in blood and brain iron levels and exhibiting elevated manganese blood and brain levels.
• Bowman’s team will use dopaminergic neurons created from skin cell samples of patients with RLS for their portion of the study. Specifically, they will examine two prevalent genetic variants with known links to RLS to determine if RLS is associated with altered manganese transport in these cells.
The Vanderbilt researchers will work with Einstein College of Medicine’s Michael Aschner, Ph.D., and James Connor, Ph.D., from Penn State’s Milton S. Hershey Medical Center.
The project is supported by NIH grant number 3R01ES010563-13S1.
