An update on the pathophysiology and genetics of restless legs syndrome

Abstract

This update on restless legs syndrome (RLS) focuses on its pathophysiology, genetics, health impact, and treatment. Although symptoms are exquisitely responsive to dopaminergics, clear delineation of dopaminergic pathology has not emerged. Rather, heuristic models of alterations in spinal sensorimotor circuits and central nervous system iron deficiency are gaining more attention. Genome-wide association studies have recently identified polymorphisms in three genes with no obvious relationship to dopamine that account for 70% of the population risk for RLS. A single variant in the BTBD9 gene on chromosome 6 contributes to 50% of the population risk. Although the functions of BTBD9 remain uncertain, its biological plausibility is evidenced by its dose-dependent relationship to periodic limb movements of sleep, decrements in iron stores, and ethnic differences in RLS prevalence. RLS is also implicated in cardiovascular morbidity. Despite these advances in our knowledge, there remain unanswered questions about the pathophysiology of RLS as well as its genetics, health-related significance, and treatment.

Ethnic Differences in the Prevalence and Predictors of Restless Legs Syndrome between Hispanics of Mexican Descent and Non-Hispanic Whites in San Diego County: A Population-Based Study

“…1,4 Restless legs syndrome is a clinical diagnosis that is determined by applying the four diagnostic questions of the International Restless Legs Syndrome Study Group, 2,3 either by a face-to-face interview or a telephone interview. 5 The etiology of RLS is unclear; however, disturbances of dopamine and iron metabolism and genetic predisposition have been implicated, 6,7 and RLS has been associated with peripheral neuropathy, diabetes, iron defi ciency, smoking, spinal cord injuries, pregnancy, Parkinson disease, older age, end-stage renal disease, and the use of some antidepressants. [8][9][10][11][12][13][14] The prevalence of RLS reported in international epidemiological studies has varied widely from as low as 0.4% to 15% among the general population; however, the most often quoted range is from 5% to 15%.…”

Efficacy of an Eight-Week Yoga Intervention on Symptoms of Restless Legs Syndrome (RLS): A Pilot Study

“…[9][10][11] While defects in dopamine function and iron metabolism have long been considered key factors in RLS pathogenesis, [12][13][14][15] evidence remains inconclusive. 9,[16][17][18] An emerging body of research suggests that autonomic and metabolic dysfunction may also play an important role. 2,19 Recent communitybased studies suggest that RLS may also be linked, in a bidirectional manner, to cardiovascular disease (CVD), stroke, and key components of the metabolic syndrome, 2,9,10,20 associations that may be mediated in part by the adverse effects of RLS on sleep and mood.…”

Prevalence and clinical correlates of restless legs syndrome among psychogeriatric patients

“…Diagnosis of RLS is purely clinical, based on history alone, and relies on the fulfillment of these four diagnostic criteria. Despite advances in our knowledge of RLS (Trotti et al, 2008), a number of critical questions remain unknown concerning its overall prevalence, its psychological impact, and its treatment. RLS patients have a higher incidence of psychological discomfort, depression, anxiety, and are more frequently under hypnotic or antidepressant treatment than non-RLS subjects (Gorman et al, 1965;Phillips et al, 2000;Rothdach et al, 2000;Saletu et al, 2002;Sevim et al, 2004;Celle et al, 2010).…”