Genetic Determined Iron Starvation Signature in Friedreich's Ataxia.

BACKGROUND: Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. OBJECTIVES: The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. METHODS: In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). RESULTS: We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. CONCLUSIONS: We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Revisiting brain iron deficiency in restless legs syndrome using magnetic resonance imaging.

STUDY OBJECTIVES: Studies on brain iron content in restless legs syndrome (RLS) using magnetic resonance imaging (MRI) are heterogeneous. In this study, we sought to leverage the availability of a large dataset including a range of iron-sensitive MRI techniques to reassess the association between brain iron content and RLS with added statistical power and to compare these results to previous studies. METHODS: The relaxation rates R2, R2', and R2* and quantitative susceptibility are MRI parameters strongly correlated to iron content. In general, these parameters are sensitive to magnetic field variations caused by iron particles. These parameters were quantified within iron-rich brain regions using a fully automatized approach in a cohort of 72 RLS patients and individually age and gender-matched healthy controls identified from an existing dataset acquired at the Sleep Laboratory of the Department of Neurology, Medical University of Innsbruck. 3 T-MRI measures were corrected for age and volume of the segmented brain nuclei and results were compared with previous findings in a meta-analysis. RESULTS: In our cohort, RLS patients had increased R2* signal in the caudate and increased quantitative susceptibility signal in the putamen and the red nucleus compared to controls, suggesting increased iron content in these areas. The meta-analysis revealed no significant pooled effect across all brain regions. Furthermore, potential publication bias was identified for the substantia nigra. CONCLUSIONS: Normal and increased iron content of subcortical brain areas detected in this study is not in line with the hypothesis of reduced brain iron storage, but favors CSF investigations and post mortem studies indicating alteration of brain iron mobilization and homeostasis in RLS.

Factors associated with augmentation in patients with restless legs syndrome.

BACKGROUND AND PURPOSE: Augmentation is a paradoxical reaction mainly to dopaminergic medication in patients with restless legs syndrome (RLS), but the exact pathomechanism remains unclear. The aim of this study was to identify factors associated with augmentation in RLS patients. METHODS: RLS patients with and without current or previous augmentation were recruited. Demographic characteristics, history of smoking, questionnaires for depression, alexithymia, and impulsivity, and RLS severity were obtained. RESULTS: We included 122 patients, of whom half had a history of augmentation. Patients with augmentation had a longer disease duration (p = 0.001), had higher RLS severity scores (p = 0.013), had higher levodopa equivalent doses (p < 0.001), had higher scores for alexithymia (p = 0.028), had higher prevalence of impulse control disorders (p < 0.001), more often had a history of smoking (p = 0.039), were more often currently smoking (p = 0.015), and had more average pack-years (p = 0.016). CONCLUSIONS: Here, we describe several factors commonly associated with augmentation in RLS. These may help clinicians to screen and treat patients carefully to avoid the challenging side effect of augmentation.

Signs of sympathetic and endothelial cell activation in the skin of patients with restless legs syndrome.

OBJECTIVES: To evaluate skin biopsies of patients with early- and late onset restless legs syndrome (RLS) for concomitant small fiber neuropathy (SFN) and to determine cutaneous sympathetic innervation and microvascularization in comparison to healthy individuals. METHODS: Density of intraepidermal nerve fibers (IENFD), adrenergic nerve fibers and dermal capillaries was analyzed by immunofluorescence for PGP9.5, tyrosine hydroxylase and endothelial markers CD31 and CD105 in skin biopsies of 11 individuals with RLS and 8 age- and sex-matched controls. RESULTS: IENFD did not differ between RLS and controls, but two RLS patients with comorbid impaired glucose metabolism fulfilled morphometric criteria of SFN according to published normative values. In contrast, dermal nerve bundles of RLS patients showed an increased density of tyrosine hydroxylase+ adrenergic nerve fibers (p < 0.005). Moreover, an increased ratio between immature CD105+ and mature CD31+ endothelial cells within dermal capillaries was observed in RLS (p < 0.02). CONCLUSIONS: SFN, as a potential contributing factor for RLS, should be considered in patients with predisposing comorbidities presenting with burning or shooting pain, dysesthesias and impaired sensory and temperature perception. Evidence of an increased adrenergic innervation of the skin in RLS patients is in accordance with sympathetic hyperactivity while signs of endothelial cell activation may reflect an adaptive response to tissue hypoxia.

Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder.

OBJECTIVE: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD). METHODS: We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex. RESULTS: We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in LAMP3 were also associated with iRBD (p = 0.0006 at >30×). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD. CONCLUSION: Our results suggest that rare coding variants in BST1 and rare noncoding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of BST1 could be a therapeutic target.

Prevalence and associated risk factors of periodic limb movement in sleep in two German population-based studies.

STUDY OBJECTIVES: Periodic limb movements in sleep (PLMS) are frequent motor phenomena; however, population-based data are scarce. We assessed the prevalence of PLMS and factors associated with PLMS within two German population-based cohorts, the SHIP-TREND and BiDirect. METHODS: Single-night polysomnography was performed on 1107 subjects recruited from the general population (mean age: 52.9 years, 54.1% men) in the SHIP-TREND and on 247 participants (mean age: 57.6 years, 50.6% men) in the BiDirect. PLMS were evaluated using the standard criteria of the American Academy of Sleep Medicine. Sociodemographic data, behavioral variables, medical history, current medication, and other sleep disorders were assessed. RESULTS: The prevalence of PLMS index (PLMSI) >15/hour was 32.4% (SHIP-TREND) and 36.4% (BiDirect). In multivariable models, age (odds ratio [OR] = 1.05 per +1 year), male gender (OR = 2.20), restless legs syndrome (OR = 2.32), physical inactivity (OR = 1.52), current smoking (OR = 1.49), diabetes (OR = 2.13), antidepressant use (OR = 2.27), lower serum magnesium (OR per -0.1 mmol/L = 1.27) showed a positive, and the intake of beta-blockers an inverse association with PLMSI >15/hour in SHIP-TREND. In BiDirect, age (OR = 1.13 per +1 year), body mass index (OR = 1.11 per +1 kg/m2), and restless legs syndrome (OR = 8.77) were significantly associated with PLMSI >15/hour. CONCLUSIONS: A high PLMSI is frequent in the German population. Age, male gender, restless legs syndrome, physical inactivity, current smoking, obesity, diabetes, antidepressant use, and lower magnesium were independently associated with PLMSI >15/hour in at least one of the cohorts.

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome.

BACKGROUND: Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level. METHODS: We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates. RESULTS: Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients. CONCLUSIONS: Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis. © 2018 International Parkinson and Movement Disorder Society.

Screening for idiopathic REM sleep behavior disorder: usefulness of actigraphy.

Study Objectives: To evaluate the utility of multimodal low-cost approaches including actigraphy, a wrist-worn device monitoring rest/activity cycles, in identifying patients with idiopathic REM sleep behavior disorder (iRBD). Methods: Seventy patients diagnosed with sleep disorders causing different motor manifestations during sleep (iRBD, sleep apnea, restless legs syndrome) and 20 subjects without any relevant motor manifestation during sleep, underwent video-polysomnography (vPSG) and 2 week actigraphy, completed six validated RBD screening questionnaires, and sleep apps use was assessed. Actigraphy was analyzed automatically, and visually by seven blinded sleep medicine experts who rated as "no," "possible," and "probable" RBD. Results: Quantitative actigraphy analysis distinguished patients from controls, but not between patients with different types of motor activity during sleep. Visual actigraphy rating by blinded experts in sleep medicine using pattern recognition identified vPSG confirmed iRBD with 85%-95% sensitivity, 79%-91% specificity, 81%-91% accuracy, 57.7% ± 11.3% positive predictive value, 95.1% ± 3.3% negative predictive value, 6.8 ± 2.2 positive likelihood ratio, 0.14 ± 0.05 negative likelihood ratio and 0.874-0.933 area under the ROC curve (AUC). AUC of the best performing questionnaire was 0.868. Few patients used sleep apps; therefore, their potential utility in the evaluated patients' groups is limited. Conclusions: Visual analysis of actigraphy using pattern recognition can identify subjects with iRBD, and is able to distinguish iRBD from other motor activities during sleep, even when patients are not aware of the disease in contrast to questionnaires. Therefore, actigraphy can be a reliable screening instrument for RBD potentially useful in the general population.

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder.

The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n = 539) and controls (n = 265) from New York, and PD patients (n = 551), rapid eye movement sleep behavior disorder (RBD) patients (n = 351), and controls (n = 956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency > 0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (odds ratio = 1.22, 95% confidence interval = 1.02-1.47, p = 0.03) but with significant heterogeneity (p = 0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant association (odds ratio = 1.11, 95% confidence interval, 0.92-1.35, p = 0.27, heterogeneity p = 0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p = 0.75), and no cumulative effect of carrying more than one MC1R variant was found. The present study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD.

Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: a multicenter study.

OBJECTIVE: To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD). METHODS: Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan-Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression. RESULTS: Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p < 0.001), with similar sex distribution. Neither caffeine, smoking, nor alcohol exposure predicted conversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide = 2.3% vs 9.0%). Convertors were more likely to report family history of dementia (odds ratio [OR] = 2.09), without significant differences in Parkinson disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR = 2.6). INTERPRETATION: Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and nonconvertors have both important commonalities and differences.

Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic condition characterized by nocturnal dysesthesias and an urge to move, affecting the legs. RLS is a complex trait, for which genome-wide association studies (GWASs) have identified common susceptibility alleles of modest (OR 1.2-1.7) risk at six genomic loci. Among these, variants in MEIS1 have emerged as the largest risk factors for RLS, suggesting that perturbations in this transcription factor might be causally related to RLS susceptibility. To establish this causality, direction of effect, and total genetic burden of MEIS1, we interrogated 188 case subjects and 182 control subjects for rare alleles not captured by previous GWASs, followed by genotyping of ∼3,000 case subjects and 3,000 control subjects, and concluded with systematic functionalization of all discovered variants using a previously established in vivo model of neurogenesis. We observed a significant excess of rare MEIS1 variants in individuals with RLS. Subsequent assessment of all nonsynonymous variants by in vivo complementation revealed an excess of loss-of-function alleles in individuals with RLS. Strikingly, these alleles compromised the function of the canonical MEIS1 splice isoform but were irrelevant to an isoform known to utilize an alternative 3' sequence. Our data link MEIS1 loss of function to the etiopathology of RLS, highlight how combined sequencing and systematic functional annotation of rare variation at GWAS loci can detect risk burden, and offer a plausible explanation for the specificity of phenotypic expressivity of loss-of-function alleles at a locus broadly necessary for neurogenesis and neurodevelopment.

Comorbidity and medication in REM sleep behavior disorder: a multicenter case-control study.

OBJECTIVE: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. METHODS: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. RESULTS: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3-2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4-3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8-7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95% CI 1.1-3.3; depression: OR 1.6, 95% CI 1.0-2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1-3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3-3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8-15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95% CI 2.0-118.8; nonsmoking: OR 2.4, 95% CI 0.4-13.2) and consequent pulmonary disease. CONCLUSIONS: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors.

ImmunoChip study implicates antigen presentation to T cells in narcolepsy.

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Dilution of candidates: the case of iron-related genes in restless legs syndrome.

Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n = 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P = 5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n = 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P = 0.00085) but not in the second replication step (joint nominal P-value = 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.

Transdermal rotigotine for the perioperative management of restless legs syndrome.

BACKGROUND: Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed. METHODS: The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period. RESULTS: During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study. CONCLUSIONS: Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms. TRIAL REGISTRATION: The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186.

A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study.

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinson's disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response. METHODS: Four hundred and eighty-four sleep-clinic-based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria. RESULTS: We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients with other sleep diagnoses. CONCLUSIONS: A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires.

Recent advances in the diagnosis, genetics and treatment of restless legs syndrome.

Knowledge of restless legs syndrome (RLS) has greatly increased in recent years due to the many advances that have been made in diagnosis, management and genetics. Tools have been developed that facilitate the diagnosis and treatment of RLS, in particular the essential diagnostic criteria for RLS have been refined, severity scales (IRLS, RLS-6, JHSS) have been developed, as have instruments that improve diagnostic accuracy and assess for specific aspects of RLS such as augmentation. These newly developed tools have been used in recent population-based studies, which have provided a greater understanding of the epidemiology of RLS, and also within patient-based trials. As far as the genetics of RLS is concerned, linkage studies in RLS families have revealed eight loci but no causally related sequence variant has yet been identified using this approach. Recent genome-wide association studies have identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBXCOR1, and PTPRD, raising new pathological hypotheses for RLS. An overview on therapeutic options and recent trials is given based on evidence-based management strategies for this common disorder.