Risk Of Restless Legs Syndrome Research Articles

Restless legs syndrome induced by quetiapine: report of seven cases and review of the literature

We report on seven cases of restless legs syndrome (RLS) in patients treated with quetiapine. Small doses (50-250mg at bedtime) provoked RLS in a dose-dependent way. Most patients suffered from an affective disorder and all were treated concomitantly with antidepressants. A search of the literature revealed a further nine cases of RLS concerning quetiapine, also afflicting only patients with affective disorders. Quetiapine seems to carry a special risk for RLS in this sort of patient. Possible causes for this concurrence are discussed.

Prospective study of restless legs syndrome and mortality among men

To prospectively examine whether men with restless legs syndrome (RLS) had an increased risk of mortality. This was a prospective cohort study of 18,425 US men free of diabetes, arthritis, and renal failure in the Health Professionals Follow-up Study (HPFS). In 2002, RLS was assessed using a set of standardized questions. Deaths were identified from state vital statistics records, the National Death Index, family reports, and the postal system. During 8 years of follow-up (2002-2010), we documented 2,765 deaths. In an age-adjusted model, RLS was associated with a 39% increased risk of mortality (hazard ratio [HR] = 1.39; 95% confidence interval [CI] 1.19-1.62; p < 0.0001). The association between RLS and mortality was slightly attenuated after further adjustment for body mass index, lifestyle factors, chronic conditions, sleep duration, and other sleep-related disorders (adjusted HR = 1.30; 95% CI 1.11-1.52; p = 0.003). When we further excluded those with major chronic conditions (e.g., cancer, high blood pressure, cardiovascular disease, and other comorbidities), the adjusted HR was 1.92 (95% CI 1.03-3.56; p = 0.04). The interactions between RLS and other risk factors (older age, overweight, short sleep duration, smoking, low physical activity, and unhealthy diet) in relation to total mortality risk were not significant (p for interaction >0.2 for all). We observed that men with RLS had a higher overall mortality and this association was independent of known risk factors. The increased mortality in RLS was more frequently associated with respiratory disease, endocrine disease, nutritional/metabolic disease, and immunologic disorders. Future research exploring the pathophysiologic relationship between these disorders and RLS is warranted.

Dopamine receptor D3 (DRD3) gene rs6280 variant and risk for restless legs syndrome

Dopamine receptor D3 (DRD3) gene rs6280 variant and risk for restless legs syndrome

Latest Perspectives in Genetic Risk Factors for Restless Legs Syndrome

The high frequency of positive family history of restless legs syndrome (RLS) in patients with this disease and the observed high concordance rates in monozygotic compared with dizygotic twins support a major role of genetic factors in the development of RLS. Although a number of variants for several genes may increase the risk of RLS, no definitive causative genes have been identified to date. In this review, we summarise the studies performed on families with RLS, twin studies, linkage studies, genome-wide association studies, case-control association studies and exome sequencing in RLS. The strongest candidate genes are ofPTPRD, BTBD9andMEIS.

MAPT1 gene rs1052553 variant is unrelated with the risk for restless legs syndrome

Mutations in the microtubule-associated protein tau gene (MAPT) can cause frontotemporal dementia with Parkinsonism linked to the chromosome 17, and are associated with the risk for progressive supranuclear palsy, Parkinson's disease, corticobasal degeneration, and multiple system atrophy. We tried to establish, whether MAPT H1 discriminating haplotype single nucleotide polymorphisms (SNP) (rs1052553) is associated with the risk for restless legs syndrome (RLS). We studied the allelic and genotype frequencies of the SNP rs1052553 in 205 patients with RLS and 324 healthy controls using TaqMan genotyping. rs1052553 genotype and allelic frequencies did not differ significantly between patients with RLS and controls, and were unrelated with the age at onset of RLS, gender, family history of RLS, and severity of RLS. The results of the present study suggest that the SNP rs1052553 is not related with the risk for RLS.

Risk of restless legs syndrome in low socioeconomic rheumatoid arthritis patients

Our aim was to determine the frequency of restless leg syndrome (RLS) in rheumatoid arthritis (RA) patients from a low socioeconomic area of Pakistan and compare results with a control group to evaluate the effect of variables on RLS patients. A clinical observational study was carried out on 240 RA patients form low socioeconomic group. Controls (n = 210) were frequency-matched by age group to the RA patients. We evaluated the presence of RLS and collected information on characteristics believed to be correlated with RLS in the general population. Multiple logistic regression models were used to study the association between RLS and other risk factors such as age, smoking status, and obesity. Among all rheumatic patients seen at our rheumatology clinic, 70.8% were women. Our study shows that 20% of RA patients were suffering from RLS compared with 10% of the control group with other rheumatic diseases. Multivariate logistic regression adjusted for age, obesity, and smoking also showed that women with RA were more likely to have RLS than control patients. RLS was also significantly associated with increasing age, high body mass index, and smoking status. Approximately 20% of RA patients were suffering from RLS. Hence, there is need of increase awareness of RLS among rheumatologists to enhance early RLS diagnosis and appropriate management of this treatable condition.

Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensory-motor neurological disorder with a circadian component. RLS is characterized by uncomfortable sensations in the extremities, generally at night or during sleep, which often leads to an uncontrollable urge to move them for relief. Recently, genomic studies identified single-nucleotide polymorphisms in BTBD9, along with three other genes, as being associated with a higher risk of RLS. Little is known about the function of BTBD9 or its potential role in the pathophysiology of RLS. We therefore examined a line of Btbd9 mutant mice we recently generated for phenotypes similar to symptoms found in RLS patients. We observed that the Btbd9 mutant mice had motor restlessness, sensory alterations likely limited to the rest phase, and decreased sleep and increased wake times during the rest phase. Additionally, the Btbd9 mutant mice had altered serum iron levels and monoamine neurotransmitter systems. Furthermore, the sensory alterations in the Btbd9 mutant mice were relieved using ropinirole, a dopaminergic agonist widely used for RLS treatment. These results, taken together, suggest that the Btbd9 mutant mice model several characteristics similar to RLS and would therefore be the first genotypic mouse model of RLS. Furthermore, our data provide further evidence that BTBD9 is involved in RLS, and future studies of the Btbd9 mutant mice will help shine light on its role in the pathophysiology of RLS. Finally, our data argue for the utility of Btbd9 mutant mice to discover and screen novel therapeutics for RLS.

Sleep Fragmentation and Motor Restlessness in a Drosophila Model of Restless Legs Syndrome

Restless Legs Syndrome (RLS), first chronicled by Willis in 1672 and described in more detail by Ekbom in 1945, is a prevalent sensorimotor neurological disorder (5%-10% in the population) with a circadian predilection for the evening and night. Characteristic clinical features also include a compelling urge to move during periods of rest, relief with movement, involuntary movements in sleep (viz., periodic leg movements of sleep), and fragmented sleep. Although the pathophysiology of RLS is unknown, dopaminergic neurotransmission and deficits in iron availability modulate expressivity. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS. Here, we report that loss of the Drosophila homolog CG1826 (dBTBD9) appreciably disrupts sleep with concomitant increases in waking and motor activity. We further show that BTBD9 regulates brain dopamine levels in flies and controls iron homeostasis through the iron regulatory protein-2 in human cell lines. To our knowledge, this represents the first reverse genetic analysis of a "novel" or heretofore poorly understood gene implicated in an exceedingly common and complex sleep disorder and the development of an RLS animal model that closely recapitulates all disease phenotypes.

Association of multiple sclerosis with restless legs syndrome and other sleep disorders in women.

To assess the association of multiple sclerosis (MS) with concurrent restless legs syndrome (RLS) and daytime sleepiness. We also prospectively examined whether women with MS had an increased risk of developing RLS during 4 years of follow-up. The main analysis was based on a cross-sectional study of 65,544 women (aged 41-58 years) free of diabetes, arthritis, and pregnancy, who were participating in the Nurses' Health Study II cohort. Participants were considered to have RLS if they met 4 RLS diagnostic criteria recommended by the International Restless Leg Syndrome Study Group and had restless legs ≥ 5 times/month. MS was self-reported and confirmed by medical record review. Among women with MS, the prevalence of RLS and severe RLS (15+ times/month) were 15.5% and 9.9% in 2005, respectively, relative to 6.4% and 2.6% among women without MS. After adjustment for potential confounders and the presence of other sleep disorders, women with MS had a higher likelihood of having RLS (odds ratio [OR] = 2.72, 95% confidence interval [CI] 1.89-3.93), severe RLS (OR = 4.12, 95% CI 2.65-6.42), and daily daytime sleepiness (OR = 2.11, 95% CI 1.31-3.42) compared with women without MS. Among the 172 women who had MS and were free of RLS in 2005, 9 developed RLS (5.2%) during a 4-year period and all had severe RLS. The adjusted relative risk of severe RLS was 3.58 (95% CI 1.53-8.35), comparing women with MS at baseline with those without MS. Women with MS had a significantly higher prevalence of RLS and daytime sleepiness and an increased risk of developing RLS in the future.

Enhanced Hippocampal Long-Term Potentiation and Fear Memory in Btbd9 Mutant Mice

Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.

Migraine and restless legs syndrome in women

Few clinic-based studies report an association between migraine and restless legs syndrome (RLS); however, population-based data are unavailable. Cohort study among 31,370 women participating in the Women's Health Study. We had detailed self-reported information on migraine, including aura status, and RLS. RLS was ascertained at the 9-year follow-up. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between migraine and RLS. We investigated any indication of migraine until RLS ascertainment as well as migraine with and without aura at baseline, prior migraine before baseline, and new reports of migraine during follow-up. At baseline or during follow-up 6857 (21.9%) women reported any migraine. These women had an increased risk for RLS (multivariable-adjusted OR = 1.22; 95%CI 1.13-1.32). Further analyses indicated a similar association for migraine with aura (multivariable-adjusted OR = 1.27; 95%CI 1.10-1.48) and migraine without aura (multivariable-adjusted OR = 1.24; 95%CI 1.09-1.40) as well as for new reports of migraine during follow-up (multivariable-adjusted OR = 1.30; 95%CI 1.10-1.54). Prior migraine did not appear to be associated with RLS. Our data suggest an association between migraine and RLS at the population level. The association is similar for migraine with and without aura and for new reports of migraine during follow-up.

Socio‐economic risk factors for incident restless legs syndrome in the general population

Few and controversial data exist about the relationship between socio-economic status and restless legs syndrome, and prospective analyses are lacking. We aimed to explore the associations between socio-economic factors and incident restless legs syndrome in the general population. Two prospective population-based cohort studies were conducted: the Dortmund Health Study with a mean follow-up of 2.2 years; and the Study of Health in Pomerania with a mean follow-up of 5.2 years. The studies included 1312 subjects and 4308 subjects, respectively. Restless legs syndrome was assessed twice according to the standard minimal criteria. The modified Winkler Index of social class, education, job status, partnership and income were assessed by interviews at baseline. The risk of restless legs syndrome associated with each socio-economic factor was estimated by multivariable logistic regression adjusted for behavioural factors and co-morbidities. Female gender, being retired and unemployment were independent risk factors of incident restless legs syndrome in both studies. Low level of education and income were independently associated with incident restless legs syndrome only in the Dortmund Health Study, but not in the other study. Migrational background and shiftwork were further independent risk factors of restless legs syndrome that were only assessed in the Dortmund Health Study. People with less favourable socio-economic situation are at an increased risk of developing restless legs syndrome. Behavioural variables and co-morbidities did not explain this association, thus further studies are required to reveal the mechanism behind the proposed relationship.

Increased risk of leg motor restlessness but not RLS in early Parkinson disease

This study explores the risk and correlates of leg restlessness in drug-naive patients with Parkinson disease (PD) as compared to control subjects matched for age and gender. A total of 200 drug-naive patients with early, unmedicated PD derived from a population-based incident cohort and 173 age- and gender-matched control subjects were assessed for leg restlessness by structured interviews, clinical examination, and blood samples. All subjects were Caucasian. Restless legs syndrome (RLS) was diagnosed according to the essential diagnostic criteria. More patients (81 of 200, 40.5%) than controls (31 of 173, 17.9%) reported leg restlessness (p < 0.001). Thirty-one (15.5%) of these patients with PD and 16 (9.2%) control subjects met RLS criteria (p = 0.07). A total of 21 (12.5%) patients and 12 (6.9%) controls with RLS remained after the exclusion of potential RLS mimics and 26 patients vs 10 control subjects with leg motor restlessness (LMR), leading to a relative risk for RLS of 1.76 (95% confidence interval [CI] 0.90-3.43, p = 0.089) and 2.84 for LMR (95% CI 1.43-5.61, p = 0.001) in PD. Except for increased sleep disturbances in patients with RLS and increased Montgomery and Åsberg Depression Rating Scale scores for patients with RLS or LMR there were no other major differences in relevant blood tests, motor or cognitive function between PD with and without RLS or LMR. LMR and not RLS occurs with a near 3-fold higher risk as compared to controls in early PD. The findings underline a need for more accurate assessments of RLS in PD and support the notion that RLS and PD are different entities.

Prevalence and clinical characteristics of restless legs syndrome in chronic kidney disease patients

To clarify the prevalence of restless legs syndrome (RLS) in the chronic kidney disease (CKD) population and determine the relationship between severity of renal dysfunction and risk of RLS as well as the impact of the disorder on mood and sleep disturbance, we conducted a questionnaire survey followed by face-to-face interviews with Japanese CKD patients. We sent a questionnaire battery including demographics items, the National Institutes of Health/International RLS Study Group (IRLSSG) consensus questionnaire, the Center for Epidemiological Studies Depression Scale, and the Pittsburgh Sleep Quality Index to eligible CKD patients (n=514) and age- and sex-matched controls (n=535). Structured interviews were performed for the diagnosis of RLS. The prevalence of positive RLS in the CKD subjects was significantly higher than that in the controls (3.5% vs. 1.5%, p=0.029). The proportion of renal failure (RF) in CKD subjects with RLS was significantly higher than in those without RLS, and multiple logistic regression analysis revealed that the presence of RLS symptoms was associated only with the existence of RF. In addition, the presence of both RLS and CKD was significantly associated with the presence of depression and sleep disturbance. The risk of RLS in the CKD population was higher than that in the general population and increased with the progression of renal dysfunction. Additionally, the existence of RLS might play a role in an increased risk for developing depression and sleep disturbance in the CKD population.

Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population.

A genome-wide association study (GWAS) identified significant association between variants in MEIS1, BTBD9, and MAP2K5/SKOR1 and restless legs syndrome (RLS). However, many independent replication studies are needed to unequivocally establish a valid genotype-phenotype association across various populations. To further validate the GWAS findings, we investigated three variants, rs2300478 in MEIS1, rs9357271 in BTBD9, and rs1026732 in MAP2K5/SKOR1 in 38 RLS families and 189 RLS patients/560 controls from the US for their association with RLS. Both family-based and population-based case-control association studies were carried out. The family-based study showed that SNP rs1026732 in MAP2K5/SKOR1 was significantly associated with RLS (P=0.01). Case-control association studies showed significant association between all three variants and RLS (P=0.0001/OR=1.65, P=0.0021/OR=1.59, and P=0.0011/OR=1.55 for rs2300478, rs9357271, and rs1026732, respectively). Variants in MEIS1, BTBD9, and MAP2K5/SKOR1 confer a significant risk of RLS in a US population.

Family recurrence and oligo-anuria predict uremic restless legs syndrome

To determine clinical and laboratory predictors of restless legs syndrome (RLS) in patients with end-stage kidney disease (ESKD) undergoing long-term hemodialysis (HD). One hundred and sixty-two consecutive patients were assessed. History of sleep disturbances, neurological examination, clinical, and laboratory data were collected. Patients with and without RLS were compared, and a logistic regression model described the relations between independent predictors and RLS. Fifty-one patients (32%) currently had RLS (RLS+). RLS+ vs RLS- patients were more frequently women (49% vs 29%, P = 0.012), had first-degree relative with RLS (22% vs 6%, P = 0.004), insomnia (59% vs 36%, P = 0.007), peripheral neuropathy (41% vs 21%, P = 0.006), and low residual diuresis (92% vs 68% with below 500 ml/24 h, P = 0.001). Low (OR = 8.71, CI = 2.27-33.41; P = 0.002) and absent (OR = 4.96, CI = 1.52-16.20; P = 0.008) residual diuresis, peripheral neuropathy (OR = 4.00, CI = 1.44-11.14; P = 0.008), and first-degree relative with RLS (OR = 3.82, CI = 1.21-12.13; P = 0.023) significantly predicted RLS in ESKD patients undergoing HD. Positive family history for RLS together with reduced/absent residual renal function and peripheral neuropathy predicts the risk for RLS in ESKD patients undergoing HD. Longitudinal studies are warranted to correlate RLS occurrence with genetic and environmental factors.

Restless legs syndrome‐associated MEIS1 risk variant influences iron homeostasis

Restless legs syndrome (RLS) is a frequent sleep disorder that is linked to disturbed iron homeostasis. Genetic studies identified MEIS1 as an RLS-predisposing gene, where the RLS risk haplotype is associated with decreased MEIS1 mRNA and protein expression. We show here that RNA interference treatment of the MEIS1 worm orthologue increases ferritin expression in Caenorhabditis elegans and that the RLS-associated haplotype leads to increased expression of ferritin and DMT1 in RLS brain tissues. Additionally, human cells cultured under iron-deficient conditions show reduced MEIS1 expression. Our data establish a link between the RLS MEIS1 gene and iron metabolism.

Restless Legs Syndrome in Behçet's Disease

The prevalence of restless legs syndrome (RLS) and its association with the clinical features of Behçet's disease (BD) has not previously been elucidated. The inflammatory character, central nervous system involvement and neuropathies of BD led to this investigation of RLS risk in BD patients. A total of 116 BD patients and 104 healthy control subjects were included; seven BD patients were excluded because of concurrent diseases, pregnancy or alcohol misuse that might cause RLS symptoms, and the remaining 109 BD patients were included in the analysis. The prevalence of RLS was significantly higher in patients with BD (32/109; 29.4%) than in controls (5/104; 4.8%). No significant differences were found between BD patients with and without RLS with regard to the clinical features of BD. RLS severity positively correlated with age in BD patients. In conclusion, BD-related RLS should be considered in symptomatic RLS secondary to rheumatological disorders and BD patients should be examined for RLS. Further studies are needed to clarify the pathogenetic mechanisms underlying BD-related RLS.

Variant screening of the coding regions of MEIS1 in patients with restless legs syndrome

Restless legs syndrome (RLS) is a common and genetically complex neurologic disease presenting with an urge to move the legs and dysesthesias in the evening and at times of rest. Genome-wide association studies have linked single nucleotide polymorphisms in MEIS1 and 3 other loci to an increased susceptibility to RLS.1,–,3 However, to date, only one potentially causal variant has been reported.4 Therefore, we screened the coding regions and exon-intron boundaries of MEIS1 for variants, which by exerting a strong phenotypic effect could provide a basis for assessing the function of the gene in RLS. ### Methods. Using Idaho LightScanner high-resolution melting curve analysis, we screened DNA of 188 patients with RLS of a first discovery sample (72.8% female, mean age 60.0 ± 11.2 years), all harboring RLS risk alleles of MEIS1 (G/T or G/G for rs2300478), for aberrant melting patterns (e-Methods on the Neurology ® Web site at www.neurology.org). Exons showing changes suggestive of variants were sequenced on an ABI Prism 3730 sequencer, and variants identified were subsequently genotyped in an independent German sample (henceforth termed “second sample”) consisting of 735 patients with RLS (70.8% female, mean age 61.5 ± 14.2 years) and 735 unrelated control subjects (74.5% female, mean age 59.8 ± 11.3 years) by matrix-assisted laser desorption ionization/time-of-flight mass spectrometry. Disease segregation was evaluated in one family with the p.R272H mutation of …

Systemic Lupus and Risk of Restless Legs Syndrome

To determine the prevalence of restless legs syndrome (RLS) in women with systemic lupus erythematosus (SLE), and to compare this to a rheumatic disease sample without SLE. Unselected consecutive female patients were SLE were recruited from a lupus clinic. A RLS questionnaire based on 4 criteria, validated by the International Restless Legs Syndrome Study Group, was administered during a face-to-face interview. Smoking history and height and weight data were collected. Similar methods were used to determine RLS prevalence in a comparator group of women with rheumatic diseases other than SLE. Controls were frequency-matched by age group (in 5-year age bands) to SLE subjects. Controls were otherwise unselected. We recruited 33 women with SLE and 32 controls. Twelve of 33 female SLE subjects scored positively for RLS (37.5%; 95% CI 22.9, 54.7) compared to 4 of 32 controls (12.5%; 95% CI 5.0, 28.1). Multivariate logistic regression showed that adjusted for age, obesity, and smoking, women with SLE were more likely to have RLS than the female controls (adjusted odds ratio 6.61, 95% CI 1.52, 28.77). In our multivariate analyses of all rheumatic patients, including SLE, the adjusted OR for obesity and RLS was 5.14 (95% CI 1.07, 24.6). These novel data indicate that RLS is more prevalent in women with SLE than in controls. Although obesity was a significant risk factor for RLS in our sample, the predictive covariates examined were limited.