Original Article
A Genetic Risk Factor for Periodic Limb Movements in Sleep
N Engl J Med 2007; 357:639-647August 16, 2007
- Abstract
Background
The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric.
Methods
To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS.
Results
In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2×10–9). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4×10–4) and a U.S. sample (odds ratio, 1.5; P=4×10–3). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1×10–17). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002).
Conclusions
We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.
Media in This Article
Figure 1
Linkage Disequilibrium at the BTBD9 Locus.Figure 2
Correlation between the Frequency of Periodic Limb Movements in Sleep with the Presence of Allele A of Marker rs3923809 and of Homozygosity for the AA Genotype.Article Activity
- Article
The restless legs syndrome (RLS) is a common neurologic disorder involving both sensory and motor elements. The combination of symptoms is manifested clinically as an uncomfortable and distressing sensory urge during rest or inactivity in the evening and at night that delays the onset of sleep. Sleep is often interrupted by involuntary, highly stereotypical, and regularly occurring limb movements, called periodic limb movements in sleep. Despite a high prevalence of RLS in North America and Europe (5 to 15%), its pathogenesis remains unclear. RLS has a negative impact on quality of life and chronic medical conditions.1-11
Iron deficiency and iron excess have been associated with the pathophysiology of various brain disorders. A deficiency of iron affects brain development, and iron accumulation has been related to neurodegeneration. Forty-seven years ago, Ekbom reported that 25% of people with RLS have low serum iron levels and that 24% of those with iron-deficiency anemia have RLS.12
A genetic contribution to RLS has been well documented and is substantial.13,14 There is striking ethnic disparity in reported prevalence of the condition: 5 to 15% in the populations of western European ancestry, as compared with 0.1% of people in Singapore,15 2% in native Ecuadorans,15 3.2% of people in Turkey,15 and 4.6% in elderly Japanese.16 The prevalence in African populations is unknown.17
Identification of the genetic underpinnings of RLS has been challenging because of age-dependent expressivity; the influences of anemia, uremia, diabetes, and peripheral neuropathy; and possibly the modulation of phenotype by body iron stores.18 At the onset of disease, sensory symptoms are mild and punctuated by asymptomatic periods of variable duration. Although one third of patients are affected before the age of 20 years, clinical presentation typically occurs between the fourth and sixth decades of life, when sensory symptoms occur nearly nightly.19-22 Periodic limb movements in sleep, the motor component of RLS, are increasingly recognized as integral to the phenotypic spectrum. Limb movements, which are present in most patients with RLS,2,23 can predate the RLS sensory disturbance13,21,24,25 and are more common in otherwise asymptomatic family members of patients with RLS than in the general population.19,21
Methods
Subjects
We obtained approval for the study protocol from the National Bioethics Committee and the Data Protection Authority (DPA) of Iceland. We contacted 451 persons who had answered a newspaper advertisement describing the clinical signs and symptoms of RLS. We then contacted 514 of their first-degree relatives. We surveyed 943 of the 965 subjects, using RLS questionnaires, and measured periodic limb movements; we obtained serum ferritin measurements for all 965 subjects. Written informed consent was obtained from all subjects. A nurse practitioner administered the questionnaire, which asked about the presence and severity of RLS symptoms26 (according to the International Restless Legs Syndrome Study Group [IRLSSG] rating scale27), clinical features, and coexisting conditions and collected venous blood for serum iron measurements and genotyping. The DPA encrypted all personal identifiers associated with information or blood samples with the use of the third-party encryption system developed by deCODE Genetics in collaboration with the DPA.28 The Icelandic controls were chosen from persons who have participated in other genetic studies at deCODE Genetics (see the Supplementary Appendix, available with the full text of this article at www.nejm.org).
Subjects for the U.S. replication sample were recruited through the Program in Sleep at Emory University in Atlanta. An institutional review board at Emory approved the protocol, and all subjects provided written informed consent for inclusion in the study and for the collection of blood samples. Patients presenting to other general and subspecialty neurology clinics and their spouses were chosen as control subjects (as described in the Supplementary Appendix).
Ascertainment
The Icelandic portion of the study, which began in 2002, was designed to ask subjects questions regarding the four diagnostic criteria for RLS that were adopted in 1995.26 These criteria were a desire to move the extremities, often associated with paresthesias or dysesthesias; motor restlessness; worsening of symptoms at rest with at least temporary relief during activity; and worsening of symptoms in the evening or at bedtime. In line with a 2003 revision of the criteria, we removed the criterion of motor restlessness from the survey (Fig. 1 in the Supplementary Appendix). Thus, we considered subjects to be affected by RLS if they reported that at least two to four times per month, while at rest, they had an uncomfortable desire to move their legs that was relieved by movement and that predominated in the evening or at bedtime.
Under the best of circumstances, the sensitivities and specificities of subjective assessments regarding RLS do not exceed 0.80 to 0.90.1 We therefore sought to enhance our discriminative abilities by measuring periodic limb movements in sleep and assessed the limitations intrinsic to our ascertainment strategy in Iceland by direct clinical examination of a subgroup of 123 Icelanders whose questionnaire responses conformed to the RLS consensus criteria (see data regarding phenotypic considerations in the Supplementary Appendix).
For detection of periodic limb movements, subjects wore a small (65-g), wristwatch-size triaxial accelerometer with 10-Hz sampling (PAM-RL detector, IM Systems) that was affixed by a hook-and-loop strap to their more affected ankle (or, as a default position, the nondominant ankle) for five consecutive nights. The PAM-RL provides an accurate assessment of polysomnographically derived frequencies (Pearson's correlation coefficient, 0.87; P<0.001),29 discriminates between periodic limb movements and normal nocturnal motor activity,30 and is sensitive to treatment effects in subjects with RLS.7,31 The PAM-RL cannot discriminate between periodic limb movements that occur while subjects are awake and those that occur during sleep, but it can discriminate between movements that occur while the subject is recumbent and those that occur while the subject is upright. Thus, subjects who had more than five movements per hour for at least one night while recumbent during their major rest period (including sleep) were classified as having periodic limb movements in sleep (Fig. 2 of the Supplementary Appendix). Quantification of the frequency of movement was performed with the use of a software algorithm that accompanied PAM-RL version 7.5.7032 (see the Demographics section of the Supplementary Appendix). A diagram showing the overlap between the group with RLS and the group with periodic limb movements in sleep is shown in Fig. 3 of the Supplementary Appendix.
Ascertainment of RLS in the U.S. sample was based on the clinical judgment of an RLS specialist. All 188 genotyped subjects had periodic limb movements in sleep, according to ambulatory assessment with PAM-RL or polysomnographic measurements.
Serum Iron Levels
Serum levels of soluble transferrin receptor and ferritin were assayed in 362 men and 603 women (subjects with RLS or their relatives) with the use of a clinical chemical analyzer and a ferritin reagents kit (Hitachi 912 Chemical Analyzer and Tina-quant kit, Roche Diagnostics). These measurements were used to derive the ferritin index (the ratio of soluble transferrin receptor to log10 ferritin), which is inversely related to total-body iron stores.33
Association Analysis
For the discovery phase, samples were genotyped with the use of genotyping systems and software (Human Hap300 and Human Hap300-duo+ Bead Arrays, Illumina).34 In total, 311,388 single-nucleotide–polymorphism (SNP) markers, distributed across the human genome, were common to both platforms. For the association analysis, we used 306,937 of the SNP markers; the other 4451 were deemed unusable because of low yield, deviations from Hardy–Weinberg expectations, or discrepancies in genotype frequencies between the two arrays. A total of 306 case subjects and 15,664 control subjects from Iceland were tested for an association with the 306,937 SNP markers. The genomewide significance threshold, after the Bonferroni correction for the number of SNPs tested, was set at 2×10−7 (approximately 0.05 of 306,937). Samples with a yield below 98% were excluded from the analysis.
In subsequent replication studies, the SNP rs3923809 was genotyped in an additional 123 case subjects and 1233 control subjects in Iceland and in 188 case subjects and 662 controls in the United States.
Statistical Analysis
For the association analyses, we used a likelihood procedure described previously35 (see the Supplementary Appendix). Evaluation of statistical significance took the relatedness of the subjects into account by applying a correction factor to the distribution of the chi-square test statistic. On the basis of the method of genomic control36 and a simulation procedure using the known genealogy, which we had previous used (see the Supplementary Appendix), this correction factor was 1.117 for subjects in Iceland and 1.216 for subjects in the United States. We used the Mantel–Haenszel model37 to combine results from the Icelandic and U.S. samples.
Results
Genomic Markers
To minimize phenotypic heterogeneity, we focused our initial genomewide association analysis on 306 subjects with RLS who also had periodic limb movements in sleep. Two markers, rs3923809 and rs6923737, in an intron of the BTB (POZ) domain–containing 9 (BTBD9) gene on chromosome 6p21.2 (Figure 1Figure 1
Linkage Disequilibrium at the BTBD9 Locus.) showed genomewide associations that were significant (for rs3923809: odds ratio, 1.8; P=2×10–9; for rs6923737: odds ratio, 1.7; P=1×10–7) (Table 1Table 1
Association between Allele A of SNP rs3923809 and RLS with Periodic Leg Movements in Sleep among Subjects in Iceland and the United States., and Fig. 1 and Table 2 of the Supplementary Appendix). After adjustment for rs3923809, the association with rs6923737 was no longer significant (P=0.16), whereas the association with rs3923809 remained significant after adjustment for rs6923737 (P=0.001). None of the other 70 SNPs in a 600-kb region around rs3923809 remained significant after adjustments for rs3923809 and for multiple testing. The association with rs3923809 remained significant after adjustment for each of the SNPs individually (Table 2 of the Supplementary Appendix).To validate these results, we analyzed a second Icelandic sample of 123 subjects with RLS and periodic limb movements in sleep and 1233 controls. The results with the second sample significantly replicated the original results for rs3923809 (odds ratio, 1.8; P=4×10–4) (Table 1, and Table 2 of the Supplementary Appendix). Extending the replication effort to a third sample of 188 subjects with RLS and periodic limb movements in sleep and 662 controls from the United States further confirmed the initial result for rs3923809 (odds ratio, 1.5; P=0.004) (Table 1). With all three samples combined, the association between the A allele of rs3923809 and RLS and periodic limb movements in sleep was highly significant (odds ratio, 1.7; P=3×10–14). There was no significant deviation from the multiplicative model, which assumed that the ratio of risk for homozygous carriers (AA) to heterozygous carriers (AG) was the same as the ratio of risk for heterozygous carriers to homozygous noncarriers (GG) in both the Icelandic subjects and the U.S. subjects (Table 3 of the Supplementary Appendix). The odds ratio for homozygous carriers was estimated at 3.2 for the Icelandic subjects and 2.3 for the U.S. subjects under the multiplicative model and at 4.3 for the Icelandic subjects and 2.0 for the U.S. subjects under the full model.
Among the 229 subjects who reported having RLS symptoms in the absence of periodic limb movements (35%), there was no association with the A allele of rs3923809 (odds ratio, 1.0; P=0.81) (Table 2Table 2
Association between Allele A of SNP rs3923809 and RLS with or without Periodic Leg Movements in Sleep among Subjects in Iceland.). Conversely, among the 105 subjects who had periodic limb movements in sleep but who did not meet the RLS consensus criteria, there was an association with the A allele of marker rs3923809 (odds ratio, 2.3; P=2×10–6) (Table 2). The odds ratio for this group did not differ significantly from that for the group that had RLS plus periodic limb movements in sleep (P=0.19). With the combined data from all the Icelandic subjects who had periodic limb movements in sleep (i.e., those with and those without RLS), the strength of the association (odds ratio, 1.9; P=1×10–17) was greater than that for the group with RLS plus periodic limb movements in sleep alone.We found that the frequency of periodic limb movements in sleep correlated with the presence of allele A of marker rs3923809 (Figure 2AFigure 2
Correlation between the Frequency of Periodic Limb Movements in Sleep with the Presence of Allele A of Marker rs3923809 and of Homozygosity for the AA Genotype.) and that AA homozygotes had almost twice as many limb movements per hour of sleep as did noncarriers (P<0.001) (Figure 2B). The odds ratio for the group of subjects with the most severe symptoms (>20 movements per hour of sleep) was 2.0, whereas it was 1.0 for the group with the least severe symptoms (≤5 movements per hour of sleep) (Figure 2A). No significant correlation was observed between allele A and the severity of RLS symptoms, as assessed on the basis of the IRLSSG rating scale (P=0.35) or the self-reported age at the onset of RLS symptoms (P=0.73).Other Risk Factors
Female sex, advanced age, depletion of body iron stores, and western European ancestry were risk factors for RLS.38,39 To determine whether these factors interact with the at-risk variant, we analyzed them as covariates in conferring a risk of RLS. The risk of RLS and periodic limb movements in sleep conferred by allele A of rs3923809 in men was greater than that for women (odds ratio, 2.0 vs. 1.7), although the difference was not significant (P=0.28). A similarly insignificant trend was observed for the combined groups with periodic limb movements in sleep (odds ratio for men, 2.3; odds ratio for women, 1.7; P=0.09). The number of periodic limb movements in sleep was significantly higher after the age of 50 years than at a younger age (P<0.001 for both sexes), a finding that is consistent with a previous study.23 The difference was significantly less in women (P=0.04).
The principal clinical measures of iron availability are serum iron, transferrin iron-binding capacity, and ferritin. Serum soluble transferrin receptor, ferritin, total iron-binding capacity, and iron were assayed in 965 Icelandic subjects (subjects with RLS and their relatives). The ferritin index, a measure inversely related to body iron stores, was increased by 5.5% per A allele of marker rs3923809 (95% confidence interval [CI], 1 to 10; P=0.02). In line with this observation, serum ferritin levels were decreased by 13% per A allele (95% CI, 5 to 20; P=0.002) (Figure 3Figure 3
Serum Ferritin Levels in Subjects with RLS and Their Relatives.).Discussion
The association between a sequence variant and subjects who have periodic limb movements without RLS — and the absence of such an association in subjects with RLS without periodic limb movements — suggest that we have identified a genetic determinant of periodic limb movements in sleep. Among the minority of subjects with periodic limb movements who did not fulfill the subjective criteria for RLS, sensory discomfort might have been absent — or the subjective RLS questionnaire for assessing the sensory component might have lacked sensitivity (see the Supplementary Appendix). Further study is required to determine whether the A allele of marker rs3923809 is associated with periodic limb movements outside the context of RLS. It also remains to be determined whether a sequence variant for RLS without periodic limb movements can be found.
The association between allele A of rs3923809 and RLS with periodic limb movements is evident in different populations of subjects with RLS: two population-based groups of mostly untreated Icelandic subjects, whose disease status was determined by self-report and ambulatory assessment, and U.S. subjects drawn from a sleep center, where the diagnosis rested on clinical judgment and ambulatory and laboratory assessment.
Although the authenticity of RLS has recently been questioned,40 our study provides evidence that periodic limb movements in sleep is a genuine syndrome with an ascertainable phenotype and a genetic basis. In fact, our study provides insight into the manner in which common medical conditions are, and might come to be, defined in the genomics era. Given the prevalence of the “risk” SNP, the population attributable risk — the fraction of cases that would be eliminated from the population if the risk among carriers were to be reduced to that among noncarriers — is approximately 50% for RLS with periodic limb movements on the basis of combined data from Iceland and the United States. However, the high population attributable risk does not eliminate the possibility that additional major susceptibility variants for the syndrome exist.
The results of the genomewide association analysis point to three genes: BTBD9, GLO1 (encoding glyoxalase I), and DNAH8 (encoding axonemal dynein heavy chain). BTBD9 is widely expressed in parts of the brain, such as the amygdala, cerebellum, hippocampus, and caudate and subthalamic nuclei, and in other organs, such as the heart, kidneys, pancreas, and liver. The BTBD9 protein is not well characterized, and its function has not been determined. It contains a BTB domain, also called POZ, which is known to be a protein–protein interaction motif. GLO1 is a glutathione-binding protein involved in the detoxification of methylglyoxal, a by-product of glycolysis. Dyneins, on the other hand, are microtubule-associated motor protein complexes whose heavy chains are responsible for force production and ATPase activity. All three genes — BTBD9, GLO1 and DNAH8 — are candidates for affecting the risk of periodic limb movements in sleep. The SNPs that are most strongly associated with periodic limb movements and that also confer a risk of RLS are not in exons or known regulatory elements.
The discovery of sequence variants that are strongly associated with susceptibility to periodic limb movements in sleep, such as the one identified in our study, may lead to new approaches for preventing or alleviating the symptoms associated with this condition.
Supported in part by the Restless Legs Syndrome and Arthur L. Williams, Jr., Foundations and the Robert W. Woodruff Health Sciences Fund.
Dr. Rye reports receiving consulting fees from or serving on paid advisory boards for GlaxoSmithKline, Boehringer Ingelheim, Ortho-McNeill, and Sepracor and lecture fees from GlaxoSmithKline and Boehringer Ingelheim; Dr. Bliwise, receiving consulting fees from or serving on paid advisory boards for Takeda, Neurocrine, Sepracor, and Cephalon and lecture fees from Takeda and Boehringer Ingelheim. Dr. K. Stefansson is chief executive officer and Dr. Gulcher is chief scientific officer of deCODE Genetics, and both report having equity in the company. The company has a financial interest in the results of this study, including diagnostic products and patents. No other potential conflict of interest relevant to this article was reported.
Drs. H. Stefansson, Rye, and Hicks contributed equally to this article.
This article (10.1056/NEJMoa072743) was published at www.nejm.org on July 18, 2007.
We thank the subjects and their relatives and the staff at Nóatún Genetic Research Service Center, deCODE Genetics, and the Emory University Program in Sleep for their contributions to this study.
Source Information
From deCODE Genetics (H.S., A.H., H.P., A. Ingason, T.E.T., S.P., E.S., G.A.H., K.K., L.J.G., U.T., A.K., J.R.G., D.G., K.S.), Landspítalinn University Hospital (T.S., A.P.S.), and Clinical Research Center (I.E.) — all in Reykjavik, Iceland; the Department of Neurology and Program in Sleep, Emory University, Atlanta (D.B.R., D.B., J.M.B., A.R., S.W., L.M.T.); Neurology Service, Hospital Clinic de Barcelona, Barcelona (A. Iranzo); and Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King's College, London (M.T.).
Address reprint requests to Dr. K. Stefansson at 1 deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland, or at kstefans@decode.is.
- References
References
1
Hening WA . Subjective and objective criteria in the diagnosis of the restless legs syndrome. Sleep Med 2004;5:285-292
CrossRef | Web of Science | Medline2
Montplaisir J ,Boucher S ,Poirier G ,Lavigne G ,Lapierre O ,Lesperance P . Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997;12:61-65
CrossRef | Web of Science | Medline3
Rothdach AJ ,Trenkwalder C ,Haberstock J ,Keil U ,Berger K . Prevalence and risk factors of RLS in an elderly population: the MEMO study: Memory and Morbidity in Augsburg Elderly. Neurology 2000;54:1064-1068
Web of Science | Medline4
Phillips B ,Young T ,Finn L ,Asher K ,Hening WA ,Purvis C . Epidemiology of restless legs symptoms in adults. Arch Intern Med 2000;160:2137-2141
CrossRef | Web of Science | Medline5
Ulfberg J ,Nystrom B ,Carter N ,Edling C . Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001;16:1159-1163
CrossRef | Web of Science | Medline6
Ulfberg J ,Nystrom B ,Carter N ,Edling C . Restless legs syndrome among working-aged women. Eur Neurol 2001;46:17-19
CrossRef | Web of Science | Medline7
Rye DR ,Carson S ,Ritchie S . Ropinirole decreases bedtime periodic leg movements in patients with RLS: results of a 12-week US study. Sleep 2005;28:Suppl S:A270-A270
Web of Science8
Berger K ,Luedemann J ,Trenkwalder C ,John U ,Kessler C . Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004;164:196-202
CrossRef | Web of Science | Medline9
Winkelman JW ,Finn L ,Young T . Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med 2006;7:545-552
CrossRef | Web of Science | Medline10
Ohayon MM ,Roth T . Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002;53:547-554
CrossRef | Web of Science | Medline11
Phillips B ,Hening W ,Britz P ,Mannino D . Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll. Chest 2006;129:76-80
CrossRef | Web of Science | Medline12
Ekbom KA . Restless legs syndrome. Neurology 1960;10:868-873
Web of Science | Medline13
Walters AS ,Wagner M ,Hening WA . Periodic limb movements as the initial manifestation of restless legs syndrome triggered by lumbosacral radiculopathy. Sleep 1996;19:825-826
Web of Science | Medline14
Allen RP . Race, iron status and restless legs syndrome. Sleep Med 2002;3:467-468
CrossRef | Medline15
Merlino G ,Valente M ,Serafini A ,Gigli GL . Restless legs syndrome: diagnosis, epidemiology, classification and consequences. Neurol Sci 2007;28:Suppl 1:S37-S46
CrossRef | Web of Science16
Mizuno S ,Miyaoka T ,Inagaki T ,Horiguchi J . Prevalence of restless legs syndrome in non-institutionalized Japanese elderly. Psychiatry Clin Neurosci 2005;59:461-465
CrossRef | Web of Science | Medline17
Lee HB ,Hening WA ,Allen RP ,Earley CJ ,Eaton WW ,Lyketsos CG . Race and restless legs syndrome symptoms in an adult community sample in east Baltimore. Sleep Med 2006;7:642-645
CrossRef | Web of Science | Medline18
Parker KP ,Rye DB . Restless legs syndrome and periodic limb movement disorder. Nurs Clin North Am 2002;37:655-673
CrossRef | Web of Science | Medline19
Lazzarini A ,Walters AS ,Hickey K , et al. Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord 1999;14:111-116
CrossRef | Web of Science | Medline20
Trenkwalder C ,Seidel VC ,Gasser T ,Oertel WH . Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996;11:389-394
CrossRef | Web of Science | Medline21
Walters AS ,Picchietti D ,Hening W ,Lazzarini A . Variable expressivity in familial restless legs syndrome. Arch Neurol 1990;47:1219-1220
CrossRef | Web of Science | Medline22
Ondo WG ,Vuong KD ,Wang Q . Restless legs syndrome in monozygotic twins: clinical correlates. Neurology 2000;55:1404-1406
Web of Science | Medline23
Hornyak M ,Feige B ,Riemann D ,Voderholzer U . Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006;10:169-177
CrossRef | Web of Science | Medline24
Santamaria J ,Iranzo A ,Tolosa E . Development of restless legs syndrome after dopaminergic treatment in a patient with periodic leg movements in sleep. Sleep Med 2003;4:153-155
CrossRef | Web of Science | Medline25
Allen RP ,Earley CJ . Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19:205-213
Web of Science | Medline26
Walters AS . Toward a better definition of the restless legs syndrome. Mov Disord 1995;10:634-642
CrossRef | Web of Science | Medline27
Walters AS ,LeBrocq C ,Dhar A , et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121-132
CrossRef | Web of Science | Medline28
Gulcher JR ,Kristjansson K ,Gudbjartsson H ,Stefansson K . Protection of privacy by third-party encryption in genetic research in Iceland. Eur J Hum Genet 2000;8:739-742
CrossRef | Web of Science | Medline29
Sforza E ,Johannes M ,Claudio B . The PAM-RL ambulatory device for detection of periodic leg movements: a validation study. Sleep Med 2005;6:407-413
CrossRef | Web of Science | Medline30
Tuisku K ,Holi MM ,Wahlbeck K ,Ahlgren AJ ,Lauerma H . Quantitative rest activity in ambulatory monitoring as a physiological marker of restless legs syndrome: a controlled study. Mov Disord 2003;18:442-448
CrossRef | Web of Science | Medline31
Tuisku K ,Holi MM ,Wahlbeck K ,Ahlgren AJ ,Lauerma H . Actometry in measuring the symptom severity of restless legs syndrome. Eur J Neurol 2005;12:385-387
CrossRef | Web of Science | Medline32
The Atlas Task Force
Web of Science | Medline33
Suominen P ,Punnonen K ,Rajamaki A ,Irjala K . Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits. Blood 1998;92:2934-2939
Web of Science | Medline34
Barrett JC ,Cardon LR . Evaluating coverage of genome-wide association studies. Nat Genet 2006;38:659-662
CrossRef | Web of Science | Medline35
Gretarsdottir S ,Thorleifsson G ,Reynisdottir ST , et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 2003;35:131-138[Erratum, Nat Genet 2005;37:555.]
CrossRef | Web of Science | Medline36
Devlin B ,Bacanu SA ,Roeder K . Genomic control to the extreme. Nat Genet 2004;36:1129-1131
CrossRef | Web of Science | Medline37
Mantel N ,Haenszel W . Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-748
Web of Science | Medline38
Allen R . Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5:385-391
CrossRef | Web of Science | Medline39
Trenkwalder C ,Paulus W ,Walters AS . The restless legs syndrome. Lancet Neurol 2005;4:465-475
CrossRef | Web of Science | Medline40
Woloshin S ,Schwartz LM . Giving legs to restless legs: a case study of how the media helps make people sick. PLoS Med 2006;3:e170-e170
CrossRef | Web of Science | Medline
- Citing Articles (136)
Citing Articles
1
Lynn M Trotti, Srinivas Bhadriraju, Lorne A Becker, Lynn M Trotti. 2012. Iron for restless legs syndrome. .
CrossRef2
Margaret G. Distler, Leigh D. Plant, Greta Sokoloff, Andrew J. Hawk, Ivy Aneas, Gerald E. Wuenschell, John Termini, Stephen C. Meredith, Marcelo A. Nobrega, Abraham A. Palmer. (2012) Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal. Journal of Clinical Investigation
CrossRef3
Erik Sørensen, Katrine Grau, Trine Berg, Anne Catrine Simonsen, Karin Magnussen, Christian Erikstrup, Morten Bagge Hansen, Henrik Ullum. (2012) A genetic risk factor for low serum ferritin levels in Danish blood donors. Transfusionno-no
CrossRef4
J. Vávrová, D. Kemlink, K. Šonka, E. Havrdová, D. Horáková, B. Pardini, B. Müller-Myhsok, J. Winkelmann. (2012) Restless legs syndrome in Czech patients with multiple sclerosis: An epidemiological and genetic study. Sleep Medicine
CrossRef5
Helen O’Brien, Shaun T O’Keeffe. (2012) Restless legs syndrome (Willis–Ekbom disease) in the older person. Aging Health 8:2, 137-146
CrossRef6
Raffaele Ferri. (2012) The time structure of leg movement activity during sleep: The theory behind the practice. Sleep Medicine 13:4, 433-441
CrossRef7
Leslie C. Jellen, Erica L. Unger, Lu Lu, Robert W. Williams, Sarah Rousseau, Xusheng Wang, Christopher J. Earley, Richard P. Allen, Michael F. Miles, Byron C. Jones. (2012) Systems genetic analysis of the effects of iron deficiency in mouse brain. neurogenetics
CrossRef8
Evelyn B. Skehan, Manal M. A. Abdulrahim, Nollaig A. Parfrey, Collette K. Hand. (2012) A novel locus for restless legs syndrome maps to chromosome 19p in an Irish pedigree. neurogenetics
CrossRef9
J. Rémi. (2012) Unruhe statt Schlafen. Somnologie - Schlafforschung und Schlafmedizin 16:1, 20-23
CrossRef10
Nancy G. Kutner, Rebecca Zhang, Yijian Huang, Donald L. Bliwise. (2012) Racial differences in restless legs symptoms and serum ferritin in an incident dialysis patient cohort. International Urology and Nephrology
CrossRef11
Richard B. Berry. 2012. The Restless Leg Syndrome, Periodic Limb Movements in Sleep, and the Periodic Limb Movement Disorder. , 429-449.
CrossRef12
Leonard B. Weinstock, Arthur S. Walters, Paisit Paueksakon. (2012) Restless legs syndrome – Theoretical roles of inflammatory and immune mechanisms. Sleep Medicine Reviews
CrossRef13
David B. Rye, Lynn Marie. Trotti. 2012. Restless Legs Syndrome and Periodic Limb Movement Disorders. , 307-323.
CrossRef14
Grace W. Pien, Barbara A. Phillips, Nancy A. Collop. 2012. Sleep in Women. , 717-734.
CrossRef15
Suresh. Kotagal. 2012. Parasomnias, Periodic Limb Movements, and Restless Legs in Children. , 475-484.
CrossRef16
Stuart F. Quan. 2012. History of Sleep in Society, Sleep Science, and Sleep Medicine. , 3-9.
CrossRef17
Valérie Cochen De Cock, Sophie Bayard, Huan Yu, Magda Grini, Bertrand Carlander, Ron Postuma, Mahmoud Charif, Yves Dauvilliers. (2012) Suggested immobilization test for diagnosis of restless legs syndrome in Parkinson's disease. Movement Disordersn/a-n/a
CrossRef18
J. Rémi. (2011) Unruhe statt Schlafen. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 54:12, 1332-1336
CrossRef19
Anke Hinney, André Scherag, Ivonne Jarick, Özgür Albayrak, Carolin Pütter, Sonali Pechlivanis, Maria R. Dauvermann, Sebastian Beck, Heike Weber, Susann Scherag, Trang T. Nguyen, Anna-Lena Volckmar, Nadja Knoll, Stephen V. Faraone, Benjamin M. Neale, Barbara Franke, Sven Cichon, Per Hoffmann, Markus M. Nöthen, Stefan Schreiber, Karl-Heinz Jöckel, H.-Erich Wichmann, Christine Freitag, Thomas Lempp, Jobst Meyer, Susanne Gilsbach, Beate Herpertz-Dahlmann, Judith Sinzig, Gerd Lehmkuhl, Tobias J. Renner, Andreas Warnke, Marcel Romanos, Klaus-Peter Lesch, Andreas Reif, Benno G. Schimmelmann, Johannes Hebebrand, . (2011) Genome-wide association study in German patients with attention deficit/hyperactivity disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 156:8, 888-897
CrossRef20
Mauro Manconi, Jan Ulfberg, Klaus Berger, Imad Ghorayeb, Jan Wesström, Stephany Fulda, Richard P. Allen, Thomas Pollmächer. (2011) When gender matters: Restless legs syndrome. Report of the “RLS and woman” workshop endorsed by the European RLS Study Group. Sleep Medicine Reviews
CrossRef21
Sarah von Spiczak, Katrin Finsterwalder, Hiltrud Muhle, Andre Franke, Markus Schilhabel, Ulrich Stephani, Ingo Helbig. (2011) Comprehensive analysis of candidate genes for photosensitivity using a complementary bioinformatic and experimental approach. Epilepsia 52:10, e143-e147
CrossRef22
Qinbo Yang, Lin Li, Qiuyun Chen, Nancy Foldvary-Schaefer, William G. Ondo, Qing Kenneth Wang. (2011) Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. Sleep Medicine 12:8, 800-804
CrossRef23
Lan Xiong. (2011) What’s next after the exciting discovery and reassuring replications of genome-wide association studies of restless legs syndrome?. Sleep Medicine 12:8, 733-734
CrossRef24
Alex Iranzo, Cynthia L. Comella. 2011. Restless Legs Syndrome and Akathisia in Parkinson's Disease. , 333-345.
CrossRef25
Amita Sehgal, Emmanuel Mignot. (2011) Genetics of Sleep and Sleep Disorders. Cell 146:2, 194-207
CrossRef26
Jeffrey S. Durmer, Ghazala H. Quraishi. (2011) Restless Legs Syndrome, Periodic Leg Movements, and Periodic Limb Movement Disorder in Children. Pediatric Clinics of North America 58:3, 591-620
CrossRef27
Barbara Schormair, Juliane Winkelmann. (2011) Genetics of Restless Legs Syndrome: Mendelian, Complex, and Everything in Between. Sleep Medicine Clinics 6:2, 203-215
CrossRef28
Eva C. Schulte, Juliane Winkelmann. (2011) When Parkinson’s disease patients go to sleep: specific sleep disturbances related to Parkinson’s disease. Journal of Neurology 258:S2, 328-335
CrossRef29
Ye-Ming J. Sun, Theresa Hoang, Judith A. Neubauer, Arthur S. Walters. (2011) Opioids protect against substantia nigra cell degeneration under conditions of iron deprivation: A mechanism of possible relevance to the Restless Legs Syndrome (RLS) and Parkinson's Disease. Journal of the Neurological Sciences 304:1-2, 93-101
CrossRef30
Jorge L. Juncos, Joash T. Lazarus, Emily Graves-Allen, Lisa Shubeck, Michelle Rusin, Gloria Novak, Deborah Hamilton, Julia Rohr, Stephanie L. Sherman. (2011) New clinical findings in the fragile X-associated tremor ataxia syndrome (FXTAS). neurogenetics 12:2, 123-135
CrossRef31
Pamela Hamilton-Stubbs, Arthur S. Walters. 2011. Restless Legs Syndrome. , 311-330.
CrossRef32
C. M. Morris. (2011) Any old iron?. Brain 134:4, 924-927
CrossRef33
Hanna Scholz, Claudia Trenkwalder, Ralf Kohnen, Levente Kriston, Dieter Riemann, Magdolna Hornyak, Magdolna Hornyak. 2011. Dopamine agonists for the treatment of restless legs syndrome. .
CrossRef34
Allan I. Pack, Grace W. Pien. (2011) Update on Sleep and Its Disorders. Annual Review of Medicine 62:1, 447-460
CrossRef35
Stanley Fahn, Joseph Jankovic, Mark Hallett. 2011. Restless legs and peripheral movement disorders. , 496-506.
CrossRef36
Juliette Faraco, Emmanuel Mignot. 2011. Genetics of Sleep and Sleep Disorders in Humans. , 184-198.
CrossRef37
Lynn marie Trotti, David B. Rye. 2011. Restless legs syndrome. , 661-673.
CrossRef38
Claire LeBlanc, Kristin Houghton. 2011. NONINFLAMMATORY MUSCULOSKELETAL PAIN CONDITIONS. , 697-717.
CrossRef39
Xiang Gao, Kristen Lyall, Natalia Palacios, Arthur S. Walters, Alberto Ascherio. (2011) RLS in middle aged women and attention deficit/hyperactivity disorder in their offspring. Sleep Medicine 12:1, 89-91
CrossRef40
Jacques Montplaisir, Richard P. Allen, Walters Arthur, Luigi Ferini-Strambi. 2011. Restless Legs Syndrome and Periodic Limb Movements during Sleep. , 1026-1037.
CrossRef41
M. Rizzi, M. Barrella, G. D. Kotzalidis, M. Bevilacqua. (2011) Periodic Limbic Movement Disorder during Sleep as Diabetes-Related Syndrome? A Polysomnographic Study. ISRN Endocrinology 2011, 1-5
CrossRef42
Stanley Fahn, Joseph Jankovic, Mark Hallett. 2011. Clinical overview and phenomenology of movement disorders. , 1-35.
CrossRef43
Jeanne F. Duffy, Alex S.W. Lowe, Edward J. Silva, John W. Winkelman. (2011) Periodic limb movements in sleep exhibit a circadian rhythm that is maximal in the late evening/early night. Sleep Medicine 12:1, 83-88
CrossRef44
Natalya Shneyder, Meghan K. Harris, Alireza Minagar. 2011. Movement disorders in patients with multiple sclerosis. , 307-314.
CrossRef45
Bryndis Benediktsdottir, Christer Janson, Eva Lindberg, Erna Sif Arnardóttir, Isleifur Olafsson, Elizabeth Cook, Elin Helga Thorarinsdottir, Thorarinn Gislason. (2010) Prevalence of restless legs syndrome among adults in Iceland and Sweden: Lung function, comorbidity, ferritin, biomarkers and quality of life. Sleep Medicine 11:10, 1043-1048
CrossRef46
Daniel Moreno-De-Luca, Jennifer G. Mulle, Erin B. Kaminsky, Stephan J. Sanders, Scott M. Myers, Margaret P. Adam, Amy T. Pakula, Nancy J. Eisenhauer, Kim Uhas, LuAnn Weik, Lisa Guy, Melanie E. Care, Chantal F. Morel, Charlotte Boni, Bonnie Anne Salbert, Ashadeep Chandrareddy, Laurie A. Demmer, Eva W.C. Chow, Urvashi Surti, Swaroop Aradhya, Diane L. Pickering, Denae M. Golden, Warren G. Sanger, Emily Aston, Arthur R. Brothman, Troy J. Gliem, Erik C. Thorland, Todd Ackley, Ram Iyer, Shuwen Huang, John C. Barber, John A. Crolla, Stephen T. Warren, Christa L. Martin, David H. Ledbetter. (2010) Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia. The American Journal of Human Genetics 87:5, 618-630
CrossRef47
Umakanth Khatwa, Sanjeev V Kothare. (2010) Restless legs syndrome and periodic limb movements disorder in the pediatric population. Current Opinion in Pulmonary Medicine 16:6, 559-567
CrossRef48
Robert Arbuckle, Linda Abetz, Jeffrey S. Durmer, Anna Ivanenko, Judith A. Owens, Jens Croenlein, Kate Bolton, Adam Moore, Richard P. Allen, Arthur S. Walters, Daniel L. Picchietti. (2010) Development of the Pediatric Restless Legs Syndrome Severity Scale (P-RLS-SS)©: A patient-reported outcome measure of pediatric RLS symptoms and impact. Sleep Medicine 11:9, 897-906
CrossRef49
Hubert E. Blum. (2010) Individualized medicine 2010. Journal of Cellular and Molecular Medicine 14:9, 2257-2263
CrossRef50
Sarah Spiczak, Hiltrud Muhle, Ingo Helbig, Carolien G. F. Kovel, Jochen Hampe, Verena Gaus, Bobby P. C. Koeleman, Dick Lindhout, Stefan Schreiber, Thomas Sander, Ulrich Stephani. (2010) Association Study of TRPC4 as a Candidate Gene for Generalized Epilepsy with Photosensitivity. NeuroMolecular Medicine 12:3, 292-299
CrossRef51
Antonetta M.G. Sas, Alessio Di Fonzo, Stef L.M. Bakker, Erik J. Simons, Ben A. Oostra, Anneke J. Maat-Kievit, Agnita J.W. Boon, Vincenzo Bonifati. (2010) Autosomal dominant restless legs syndrome maps to chromosome 20p13 (RLS-5) in a Dutch kindred. Movement Disorders 25:11, 1715-1722
CrossRef52
Matthew A. Picchietti, Daniel L. Picchietti. (2010) Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment. Sleep Medicine 11:7, 643-651
CrossRef53
Claudia Trenkwalder, Walter Paulus. (2010) Restless legs syndrome: pathophysiology, clinical presentation and management. Nature Reviews Neurology 6:6, 337-346
CrossRef54
Rachel E. Salas, Russell Rasquinha, Charlene E. Gamaldo. (2010) All the Wrong Moves: A Clinical Review of Restless Legs Syndrome, Periodic Limb Movements of Sleep and Wake, and Periodic Limb Movement Disorder. Clinics in Chest Medicine 31:2, 383-395
CrossRef55
Mathieu Raux, Elias G. Karroum, Isabelle Arnulf. (2010) Case Scenario: Anesthetic Implications of Restless Legs Syndrome. Anesthesiology 112:6, 1511-1517
CrossRef56
Michael H Silber. 2010. Insomnia in Other Sleep Disorders: Movement Disorders. , 199-209.
CrossRef57
Johannes Hebebrand, Andre Scherag, Benno G. Schimmelmann, Anke Hinney. (2010) Child and adolescent psychiatric genetics. European Child & Adolescent Psychiatry 19:3, 259-279
CrossRef58
Nicholas P. Pantaleo, Wayne A. Hening, Richard P. Allen, Christopher J. Earley. (2010) Pregnancy accounts for most of the gender difference in prevalence of familial RLS. Sleep Medicine 11:3, 310-313
CrossRef59
Magdolna Hornyak. (2010) Depressive Disorders in Restless Legs Syndrome. CNS Drugs 24:2, 89-98
CrossRef60
P. Hamilton-Stubbs, A.S. Walters. 2010. Restless Legs Syndrome. , 32-37.
CrossRef61
Daniel F. Kripke, Farhad F. Shadan, Arthur Dawson, John W. Cronin, Shazia M. Jamil, Alexandra P. Grizas, James A. Koziol, Lawrence E. Kline. (2010) Genotyping Sleep Disorders Patients. Psychiatry Investigation 7:1, 36
CrossRef62
P. Hamilton-Stubbs, A.S. Walters. 2010. Periodic Limb Movements. , 444-449.
CrossRef63
Grace W. Pien, Allan I. Pack. 2010. Sleep-Disordered Breathing. , 1881-1913.
CrossRef64
Wayne Hening, Claudia Trenkwalder. 2010. Restless Legs Syndrome. , 587-621.
CrossRef65
Luigi Ferini-Strambi, Mauro Manconi. (2009) Treatment of restless legs syndrome. Parkinsonism & Related Disorders 15, S65-S70
CrossRef66
K. Ekbom, J. Ulfberg. (2009) Restless legs syndrome. Journal of Internal Medicine 266:5, 419-431
CrossRef67
Franco Gemignani, Francesca Brindani, Francesca Vitetta, Adriana Marbini. (2009) Restless Legs Syndrome and Painful NeuropathyâRetrospective Study. A Role for Nociceptive Deafferentation?. Pain Medicine 10:8, 1481-1486
CrossRef68
Emrah Caylak. (2009) The genetics of sleep disorders in humans: Narcolepsy, restless legs syndrome, and obstructive sleep apnea syndrome. American Journal of Medical Genetics Part A 149A:11, 2612-2626
CrossRef69
L. I. Varga, N. Ako-Agugua, J. Colasante, L. Hertweck, T. Houser, J. Smith, A. A. Watty, S. Nagar, R. B. Raffa. (2009) Critical review of ropinirole and pramipexole - putative dopamine D 3 -receptor selective agonists - for the treatment of RLS. Journal of Clinical Pharmacy and Therapeutics 34:5, 493-505
CrossRef70
Daniel L. Picchietti, Ramji R. Rajendran, Michael P. Wilson, Matthew A. Picchietti. (2009) Pediatric restless legs syndrome and periodic limb movement disorder: Parent–child pairs. Sleep Medicine 10:8, 925-931
CrossRef71
An FAN, Shao-Qi RAO. (2009) Advances in genetics of restless legs syndrome. Hereditas (Beijing) 31:7, 675-682
CrossRef72
William G. Ondo. (2009) Restless Legs Syndrome. Neurologic Clinics 27:3, 779-799
CrossRef73
Chiara Cirelli. (2009) The genetic and molecular regulation of sleep: from fruit flies to humans. Nature Reviews Neuroscience 10:8, 549-560
CrossRef74
Ludger Grote, Lena Leissner, Jan Hedner, Jan Ulfberg. (2009) A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Movement Disorders 24:10, 1445-1452
CrossRef75
B.G. Schimmelmann, S. Friedel, T.T. Nguyen, S. Sauer, C.I. Ganz Vogel, K. Konrad, C. Wilhelm, J. Sinzig, T.J. Renner, M. Romanos, H. Palmason, A. Dempfle, S. Walitza, C. Freitag, J. Meyer, M. Linder, H. Schäfer, A. Warnke, K.P. Lesch, B. Herpertz-Dahlman, A. Hinney, J. Hebebrand. (2009) Exploring the genetic link between RLS and ADHD. Journal of Psychiatric Research 43:10, 941-945
CrossRef76
Birgit Frauscher, Viola Gschliesser, Elisabeth Brandauer, Essam El-Demerdash, Matthias Kaneider, Lukas Rücker, Werner Poewe, Birgit Högl. (2009) The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: Association with ferritin levels. Sleep Medicine 10:6, 611-615
CrossRef77
Lynn Marie Trotti, Donald L. Bliwise, Sophia A. Greer, Albert P. Sigurdsson, Gudbjörg Birna Gudmundsdóttir, Thomas Wessel, Lisa M. Organisak, Thor Sigthorsson, Kristleifur Kristjansson, Thordur Sigmundsson, David B. Rye. (2009) Correlates of PLMs variability over multiple nights and impact upon RLS diagnosis. Sleep Medicine 10:6, 668-671
CrossRef78
V. Cochen, C. Arbus, M. -E. Soto, R. Debs, H. Villars, M. Tiberge, T. Montemayor, C. Hein, M. -F. Veccherini, S. -H. Onen, I. Ghorayeb, M. Verny, L. Jaime Fitten, J. Yesavage, Y. Dauvilliers, B. Vellas. (2009) Les troubles du sommeil et leurs répercussions chez les sujets âgés, en bonne santé, dépendants et fragiles. Les cahiers de l'année gérontologique 1:2, 87-97
CrossRef79
Harrison G. Bloom, Imran Ahmed, Cathy A. Alessi, Sonia Ancoli-Israel, Daniel J. Buysse, Meir H. Kryger, Barbara A. Phillips, Michael J. Thorpy, Michael V. Vitiello, Phyllis C. Zee. (2009) Evidence-Based Recommendations for the Assessment and Management of Sleep Disorders in Older Persons. Journal of the American Geriatrics Society 57:5, 761-789
CrossRef80
Lynn M Trotti, Srinvas Bhadriraju, Lorne A Becker, Lynn M Trotti. 2009. Iron for restless legs syndrome. .
CrossRef81
Narong Simakajornboon, Leila Kheirandish-Gozal, David Gozal. (2009) Diagnosis and management of restless legs syndrome in children. Sleep Medicine Reviews 13:2, 149-156
CrossRef82
Claudia Trenkwalder, Birgit Högl, Juliane Winkelmann. (2009) Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. Journal of Neurology 256:4, 539-553
CrossRef83
Valérie Cochen, C. Arbus, M. E. Soto, H. Villars, M. Tiberge, T. Montemayor, C. Hein, M. F. Veccherini, S. -H. Onen, I. Ghorayeb, M. Verny, L. J. Fitten, J. Savage, Y. Dauvilliers, B. Vellas. (2009) Sleep disorders and their impacts on healthy, dependent, and frail older adults. The Journal of Nutrition, Health and Aging 13:4, 322-329
CrossRef84
Domenico Paci, Bartolo Lanuzza, Filomena I.I. Cosentino, Antonella Belfiore, Maurizio Papotto, Anna Cocilovo, Ivan Iero, Mariangela Tripodi, Raffaele Ferri. (2009) Subclinical abnormal EMG activation of the gastrocnemii during gait analysis in restless legs syndrome: A preliminary report in 13 patients. Sleep Medicine 10:3, 312-316
CrossRef85
J. E. Young, C. Vilarino-Guell, S.-C. Lin, Z. K. Wszolek, M. J. Farrer. (2009) Clinical and Genetic Description of a Family With a High Prevalence of Autosomal Dominant Restless Legs Syndrome. Mayo Clinic Proceedings 84:2, 134-138
CrossRef86
Anastasia Levchenko, Jacques-Yves Montplaisir, Géraldine Asselin, Sylvie Provost, Simon L. Girard, Lan Xiong, Emmanuelle Lemyre, Judith St-Onge, Pascale Thibodeau, Alex Desautels, Gustavo Turecki, Claudia Gaspar, Marie-Pierre Dubé, Guy A. Rouleau. (2009) Autosomal-dominant locus for restless legs syndrome in French-Canadians on chromosome 16p12.1. Movement Disorders 24:1, 40-50
CrossRef87
L. Xiong, H. Catoire, P. Dion, C. Gaspar, R. G. Lafreniere, S. L. Girard, A. Levchenko, J.-B. Riviere, L. Fiori, J. St-Onge, I. Bachand, P. Thibodeau, R. Allen, C. Earley, G. Turecki, J. Montplaisir, G. A. Rouleau. (2009) MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels. Human Molecular Genetics 18:6, 1065-1074
CrossRef88
Stéphanie Maret, Yves Dauvilliers, Mehdi Tafti. 2009. Human and Animal Genetics of Sleep and Sleep Disorders. , 295-306.
CrossRef89
Yusuke Nakamura. (2009) DNA variations in human and medical genetics: 25 years of my experience. Journal of Human Genetics 54:1, 1-8
CrossRef90
Wayne A. Hening, Richard P. Allen, Arthur S. Walters, Sudhansu Chokroverty. 2009. Motor Functions and Dysfunctions of Sleep. , 397-435.
CrossRef91
Sudhansu Chokroverty. 2009. Sleep Disorders in the Elderly. , 606-620.
CrossRef92
Irene Pichler, Fabio Marroni, Cristian Pattaro, Katja Lohmann, Alessandro de Grandi, Christine Klein, Andrew A. Hicks, Peter P. Pramstaller. (2009) Parkin gene modifies the effect of RLS4 on the age at onset of restless legs syndrome (RLS). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 9999B, n/a-n/a
CrossRef93
Mauro Manconi, Luigi Ferini-Strambi. 2009. Restless Legs Syndrome and Pregnancy. , 173-177.
CrossRef94
Lan Xiong, Gustavo Turecki, Anastasia Levchenko, Claudia Gaspar, Wayne A Hening, Jacques Montplaisir, Guy A Rouleau. 2009. Genetics of Restless Legs Syndrome. , 31-49.
CrossRef95
Claudia Trenkwalder, Wayne A. Hening, Pasquale Montagna, Wolfgang H. Oertel, Richard P. Allen, Arthur S. Walters, Joao Costa, Karin Stiasny-Kolster, Cristina Sampaio. (2008) Treatment of restless legs syndrome: An evidence-based review and implications for clinical practice. Movement Disorders 23:16, 2267-2302
CrossRef96
Jonathan Lipton, Ronald E Becker, Sanjeev V Kothare. (2008) Insomnia of childhood. Current Opinion in Pediatrics 20:6, 641-649
CrossRef97
Rozi Andretic, Paul Franken, Mehdi Tafti. (2008) Genetics of Sleep. Annual Review of Genetics 42:1, 361-388
CrossRef98
Janna E. Hutz, Aldi T. Kraja, Howard L. McLeod,, Michael A. Province. (2008) CANDID: a flexible method for prioritizing candidate genes for complex human traits. Genetic Epidemiology 32:8, 779-790
CrossRef99
Javier Simón-Sánchez, Andrew Singleton. (2008) Genome-wide association studies in neurological disorders. The Lancet Neurology 7:11, 1067-1072
CrossRef100
John P.A. Ioannidis. (2008) Calibration of credibility of agnostic genome-wide associations. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 147B:6, 964-972
CrossRef101
Pasquale Montagna. (2008) Migraine genetics. Expert Review of Neurotherapeutics 8:9, 1321-1330
CrossRef102
Wayne A. Hening, Christine K. Caivano. (2008) Restless Legs Syndrome: A Common Disorder in Patients with Rheumatologic Conditions. Seminars in Arthritis and Rheumatism 38:1, 55-62
CrossRef103
Barbara Schormair, David Kemlink, Darina Roeske, Gertrud Eckstein, Lan Xiong, Peter Lichtner, Stephan Ripke, Claudia Trenkwalder, Alexander Zimprich, Karin Stiasny-Kolster, Wolfgang Oertel, Cornelius G Bachmann, Walter Paulus, Birgit Högl, Birgit Frauscher, Viola Gschliesser, Werner Poewe, Ines Peglau, Pavel Vodicka, Jana Vávrová, Karel Sonka, Sona Nevsimalova, Jacques Montplaisir, Gustavo Turecki, Guy Rouleau, Christian Gieger, Thomas Illig, H-Erich Wichmann, Florian Holsboer, Bertram Müller-Myhsok, Thomas Meitinger, Juliane Winkelmann. (2008) PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nature Genetics 40:8, 946-948
CrossRef104
K
ri Stef
CrossRef105
Lynn Marie Trotti, Srinivas Bhadriraju, David B. Rye. (2008) An update on the pathophysiology and genetics of restless legs syndrome. Current Neurology and Neuroscience Reports 8:4, 281-287
CrossRef106
Patrice Bourgin, Jamie M Zeitzer, Emmanuel Mignot. (2008) CSF hypocretin-1 assessment in sleep and neurological disorders. The Lancet Neurology 7:7, 649-662
CrossRef107
L. C. Jones, C. J. Earley, R. P. Allen, B. C. Jones. (2008) Of mice and men, periodic limb movements and iron: how the human genome informs the mouse genome. Genes, Brain and Behavior 7:5, 513-514
CrossRef108
Kapil D Sethi. (2008) Restless legs syndrome sees the light of day. The Lancet Neurology 7:7, 564-565
CrossRef109
Claudia Trenkwalder, Heike Beneš, Werner Poewe, Wolfgang H Oertel, Diego Garcia-Borreguero, Al W de Weerd, Luigi Ferini-Strambi, Pasquale Montagna, Per Odin, Karin Stiasny-Kolster, Birgit Högl, K Ray Chaudhuri, Markku Partinen, Erwin Schollmayer, Ralf Kohnen. (2008) Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. The Lancet Neurology 7:7, 595-604
CrossRef110
Hiltrud Muhle, Anja Neumann, Katja Lohmann-Hedrich, Thora Lohnau, Yang Lu, Susen Winkler, Stephan Waltz, Anke Fischenbeck, Patricia L. Kramer, Christine Klein, Ulrich Stephani. (2008) Childhood-onset restless legs syndrome: Clinical and genetic features of 22 families. Movement Disorders 23:8, 1113-1121
CrossRef111
Karen Thomas, Carolyn B. Watson. (2008) Restless Legs Syndrome in Women: A Review. Journal of Women's Health 17:5, 859-868
CrossRef112
Eric Ball, Christine K. Caivano. (2008) Internal Medicine: Guidance to the Diagnosis and Management of Restless Legs Syndrome. Southern Medical Journal 101:6, 631-634
CrossRef113
Shilpa Chitnis. (2008) Ropinirole treatment for restless legs syndrome. Expert Opinion on Drug Metabolism & Toxicology 4:5, 655-664
CrossRef114
Juliane Winkelmann. (2008) Genetics of restless legs syndrome. Current Neurology and Neuroscience Reports 8:3, 211-216
CrossRef115
Ku Chee Seng, Chia Kee Seng. (2008) The success of the genome-wide association approach: a brief story of a long struggle. European Journal of Human Genetics 16:5, 554-564
CrossRef116
Teri A. Manolio, Lisa D. Brooks, Francis S. Collins. (2008) A HapMap harvest of insights into the genetics of common disease. Journal of Clinical Investigation 118:5, 1590-1605
CrossRef117
David Kemlink, Giuseppe Plazzi, Roberto Vetrugno, Federica Provini, Olli Polo, Karin Stiasny-Kolster, Wolfgang Oertel, Sona Nevsimalova, Karel Sonka, Birgit Högl, Birgit Frauscher, Georgios M. Hadjigeorgiou, Peter P. Pramstaller, Peter Lichtner, Thomas Meitinger, Bertram Müller-Myshok, Juliane Winkelmann, Pasquale Montagna. (2008) Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13. Neurogenetics 9:2, 75-82
CrossRef118
I Pichler, AA Hicks, PP Pramstaller. (2008) Restless legs syndrome: an update on genetics and future perspectives. Clinical Genetics 73:4, 297-305
CrossRef119
Emmanuel Mignot. (2008) Excessive daytime sleepiness: Population and etiology versus nosology. Sleep Medicine Reviews 12:2, 87-94
CrossRef120
Giuseppe Plazzi, Leonardo Serra, Raffaele Ferri. (2008) Nocturnal aspects of narcolepsy with cataplexy. Sleep Medicine Reviews 12:2, 109-128
CrossRef121
James R. Connor. (2008) Pathophysiology of restless legs syndrome: Evidence for iron involvement. Current Neurology and Neuroscience Reports 8:2, 162-166
CrossRef122
H-Y Tan, J H Callicott, D R Weinberger. (2008) Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer?. Molecular Psychiatry 13:3, 233-238
CrossRef123
Richard K Bogan. (2008) Ropinirole treatment for restless legs syndrome. Expert Opinion on Pharmacotherapy 9:4, 611-623
CrossRef124
Stephen F. Kingsmore, Ingrid E. Lindquist, Joann Mudge, Damian D. Gessler, William D. Beavis. (2008) Genome-wide association studies: progress and potential for drug discovery and development. Nature Reviews Drug Discovery 7:3, 221-230
CrossRef125
(2008) A Genetic Risk Factor for Periodic Limb Movements in Sleep. New England Journal of Medicine 358:4, 425-428
Full Text126
Dong Soon Kim, Hong Beom Shin, Young Min Ahn. (2008) A case of restless legs syndrome in a child presenting with growing pains. Korean Journal of Pediatrics 51:11, 1222
CrossRef127
Joseph Jankovic. (2008) Parkinson's disease and movement disorders: moving forward. The Lancet Neurology 7:1, 9-11
CrossRef128
Sudhansu Chokroverty. 2008. Sleep and Its Disorders. , 1947-2009.
CrossRef129
A. Verma. (2008) A Genetic Risk Factor for Periodic Limb Movements in Sleep. Yearbook of Neurology and Neurosurgery 2008, 183-184
CrossRef130
C. R. Baumann, I. Marti, C. L. Bassetti. (2007) Restless legs symptoms without periodic limb movements in sleep and without response to dopaminergic agents: a restless legs-like syndrome?. European Journal of Neurology 14:12, 1369-1372
CrossRef131
Caren McHenry Martin. (2007) The Mysteries of Restless Legs Syndrome. The Consultant Pharmacist 22:11, 907-924
CrossRef132
Richard Robinson. (2007) Genes Discovered for Restless Leg Syndrome and Periodic Leg Movements. Neurology Today 7:17, 1,8
CrossRef133
Winkelman, John W., . (2007) Periodic Limb Movements in Sleep — Endophenotype for Restless Legs Syndrome?. New England Journal of Medicine 357:7, 703-705
Full Text134
Wayne A. Hening, Richard P. Allen, K. Ray Chaudhuri, Magdolna Hornyak, Hochang B. Lee, John Winkelman, Robert Yoakum. (2007) Clinical significance of RLS. Movement Disorders 22:S18, S395-S400
CrossRef135
Walter Paulus, Pascal Dowling, Roselyne Rijsman, Karin Stiasny-Kolster, Claudia Trenkwalder. (2007) Update of the pathophysiology of the Restless-Legs-Syndrome. Movement Disorders 22:S18, S431-S439
CrossRef136
M. Tafti, P. Franken. (2007) Molecular Analysis of Sleep. Cold Spring Harbor Symposia on Quantitative Biology 72:1, 573-578
CrossRef
- Letters
