Restless Legs Syndrome Families Research Articles

SNCA-Rep1 polymorphism correlates with susceptibility and iron deficiency in restless legs syndrome

BackgroundBrain iron disequilibrium and dopaminergic dysfunction are key pathophysiological features of Restless Legs Syndrome (RLS). Rep1 polymorphism in the promotor region of SNCA is associated with risk of Parkinson's disease, however its association with RLS and iron status is unclear. ObjectiveTo investigate SNCA-Rep1 polymorphism in RLS and its phenotypes. MethodsWe recruited RLS patients as well as age and gender matched healthy controls. Demographic information and clinical features of RLS were recorded. Laboratory examinations were performed to exclude possible secondary causes. Results215 RLS patients and 369 healthy controls were included. We found that the Rep1 allele 0 homozygosity significantly decreased RLS risk (OR: 0.345; P < 0.0001, and remained significant after the Bonferroni correction). Phenotypic analysis demonstrated that longer Rep1 alleles were associated with increased susceptibility to iron deficiency (53.0% vs 36.1%, P = 0.017), however had no phenotypic significant effects on age, gender, onset age, duration, RLS family history, severity, laterality, extra body involvement and seasonal fluctuation. Multivariate logistic regression analyses confirmed long Rep1 allele was associated with higher risk of iron deficiency in RLS after adjusting for potential confounding factors. In detail, Rep1 allele 2 homozygosity was prone to a higher risk of peripheral iron deficiency in RLS (OR: 4.550, P = 0.006, remained significant after the Bonferroni correction). ConclusionThe SNCA-Rep1 variability modified RLS risk and influenced peripheral iron deficiency in this group of Chinese RLS patients. Rep1 allele 0 homozygosity decreased the risk of RLS, while homozygous allele 2 increased the risk of nonanemic iron deficiency in RLS.

Clinical features and subtypes of restless legs syndrome in Chinese population: a study of 359 patients

BackgroundThe clinical spectrum of restless legs syndrome (RLS) has not been described in a Chinese population. We aim to evaluate the detailed clinical profile in a cohort of unselected RLS patients in China. MethodsWe enrolled RLS patients continuously according to the diagnostic criteria. Laboratory examinations were performed to exclude mimics and notable comorbidities. ResultsA total of 359 patients with RLS were enrolled. RLS symptoms were mostly symmetrical (65.2%), and purely unilateral RLS was not common (5.6%); however, unilateral dominant RLS was relatively more common. Only 1.1% of RLS patients reported no unpleasant sensations in the legs. The largest proportion of RLS patients described their uncomfortable sensation as indescribable (43.5%) and reported soreness (40.4%). In all, 8.9% of RLS patients described their abnormal sensation as painful, and 34.5% of RLS patients reported their symptoms fluctuated with seasonal trends. This population had a higher likelihood of an RLS family history. RLS patients with summer exacerbation had a younger age at RLS onset and longer disease duration (p < 0.01). Iron deficiency without anemia was common in Chinese RLS patients. Early-onset RLS patients were more likely to have a positive family history (p < 0.01), more summer worsening of symptoms (p < 0.01) and more severely disturbed peripheral iron status (p < 0.01) when compared to late-onset RLS patients. ConclusionThe subjective description is somewhat different, with Chinese RLS patients reporting less pain and more soreness than patients from Western countries. Seasonal fluctuation and iron deficiency without anemia are frequently seen in Chinese RLS patients and predict some other features. Differentiating these various subtypes can facilitate optimal management.

Prevalence of Restless Legs Syndrome in a Georgian Primary Healthcare Setting: A Pilot Study

Background: The prevalence of restless legs syndrome (RLS) is approximately 10% in Western Europe, but unknown in Georgia. This pilot study aimed to assess RLS prevalence in a focused Georgian population. Methods: An RLS epidemiological questionnaire [Allen et al.: Sleep Med 2003;4:101–119] was filled out by patients in five primary healthcare centers in two Georgian cities between March and September 2006. Additionally, questions related to RLS symptom onset, family history, treatment, sleep disturbance and history of iron deficiency were included. RLS diagnosis was based on an expert interview and an epidemiological questionnaire for RLS. Results: The total number of respondents was 115 (75% women/25% men); mean age was 47 years (range 18–85). Thirteen subjects (11.3%) reported RLS symptoms (9 women/4 men); mean age was 52 years (range 32–83). Eleven (85%) had a positive family history of RLS. All subjects had sleep disturbance and none had a history of known iron deficiency. Conclusion: The prevalence of RLS in a focused Georgian population is in line with other RLS epidemiologic studies performed in clinical settings. However, the prevalence rate of RLS in a studied group might not be representative for the general Georgian population. Further population-based epidemiological studies are required.

A Novel Locus for Restless Legs Syndrome on Chromosome 13q

Background: Restless legs syndrome (RLS) is a sensorimotor disorder in which affected individuals suffer from uncomfortable sensations and an urge to move their lower limbs; it occurs mainly in resting situations during the evening or at night. Multiple chromosomal loci have been mapped for RLS through family-based linkage analysis, and genome-wide association studies but causative mutations have not been identified yet. Method: We identified an RLS family from the eastern part of central Turkey which has 10 patients suffering from this syndrome. Whole genome linkage analysis was performed in family members who consented for study (9 affected and 2 unaffected). Results: A theoretical maximum logarithm of the odds score of 3.29 was identified at chromosome 13q32.3–33.2. This result shows strong genetic linkage to this locus. Conclusions: We demonstrated a genetic linkage at chromosome 13 in a RLS family. Further investigation in this linkage area may reveal a causative gene leading to RLS phenotype and may illuminate the pathogenesis of this disease. This study supports the genetic heterogeneity in the pathogenesis of this syndrome.

Phenocopies in families with essential tremor and restless legs syndrome challenge Mendelian laws. Epigenetics might provide answers

Essential Tremor (ET) and Restless Legs Syndrome (RLS) are both highly heritable neurological disorders. The frequent occurrence of multi-incident families suggests the existence of highly penetrant alleles. However, linkage analyses and positional cloning approaches performed within the last 10 years essentially failed to identify responsible mutations. Several loci were found, but their relevance was questioned given the occurrence of suspected phenocopies in many of those families. Remarkably, in some ET and RLS families with an apparent autosomal dominant mode of transmission, the proportion of affected individuals was higher than the expected 50% and therefore suggests a non-mendelian inheritance in some cases. In fact, there is increasing evidence that epigenetic modifications, which refer to changes in gene expression without changes in DNA sequence, can be transmitted to the next generation. Moreover, epigenetic information can be transferred from one allele of a gene to the other allele of the same gene; if then inherited to the next generation, the offspring consequently presents phenotypic properties related to the untransmitted allele. This phenomenon known as paramutation is well documented in plants and has recently been shown to occur also in mammals. Here, I explore the possibility that it is the epigenetic and not only the genetic state which confers disease risk in families. Inheritance of epigenetic mutations along with paramutational events have the potential to explain the non-mendelian features in the genetics of both diseases.

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.

Evaluation of contributing factors to restless legs syndrome in migraine patients

Recent studies have provided evidence for a positive association between migraine and restless legs syndrome (RLS), although the exact mechanisms and contributing factors remain unclear. A cross-sectional, case-control study was conducted, including patients with migraine (n = 262) and headache-free control subjects (n = 163). Migraine was diagnosed according to International Classification of Headache Disorders II criteria. RLS diagnosis was made based on four essential criteria as described by the International Restless Legs Syndrome Study Group. All patients completed the Migraine Disability Assessment (MIDAS) questionnaire, Beck Depression Inventory (BDI)-II scores, Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). A total of 210 blood samples were collected to correlate various parameters with RLS. RLS frequency was significantly greater in patients with migraine than in controls (13.7 vs. 1.8%). Migraine patients with RLS had high scores for MIDAS, BDI-II, PSQI, and ESS compared with those without RLS. In addition, migraine patients with RLS had a high rate of smoking and RLS family history, as well as increased levels of serum phosphorus and urea nitrogen compared with those without RLS. However, there was no difference in serum iron and ferritin levels between the groups. In migraine patients, logistic regression analysis revealed that positive RLS family history, BDI-II, ESS, and serum phosphorus levels were significant RLS predictors. Our study confirmed a positive association between RLS and migraine. RLS comorbidity in migraine patients was associated with insomnia, daytime sleepiness, depressive symptoms, headache-related disability, and increased serum phosphorus levels. These findings may provide a better understanding of RLS pathogenesis in migraine.

Crohnʼs disease is associated with restless legs syndrome

Extraintestinal manifestations of Crohn's disease (CD) have not previously included the central nervous system (CNS). Restless legs syndrome (RLS) is a CNS disorder that is either idiopathic or secondary to a number of diseases. The aim of this study was to determine if RLS was associated with CD because both are associated with iron deficiency, inflammation, and bacterial overgrowth. Consecutive CD outpatients (N = 272) were prospectively surveyed at 4 centers for criteria for RLS. Incidence (having RLS at any point in time), prevalence (having RLS at time of survey), clinical characteristics, risk factors, and potential qualitative relationship between RLS and gastrointestinal symptoms were queried. The incidence of RLS in patients with CD was 42.7%. Prevalence was 30.2% compared with 9% of spouses. CD patients with and without RLS had a mean age of 46.8 versus 42.6 years, small intestine involvement in 77.9% versus 66.7%, colon involvement in 39.7% versus 63.2%, and prior iron deficiency anemia in 49.3% versus 33.1%. There was no difference between the CD groups with respect to current iron deficiency, RLS family history, or rare prevalence of concomitant RLS disorders. In 91.8% of patients with RLS and CD, RLS started during or after the onset of CD diagnosis. Among 73 patients with RLS, 67 (44.5%) stated there was a relationship between qualitative RLS symptom improvement with overall CD symptom improvement. These results demonstrate that RLS occurs frequently in CD and appears to be a possible extraintestinal manifestation. The potential relationship of RLS with CD activity warrants further investigation.

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.

Crohnʼs Disease Is Associated with Restless Legs Syndrome

Purpose: Extraintestinal manifestations of Crohn's disease (CD) rarely include the central nervous system (CNS). Restless legs syndrome (RLS) is a CNS disorder that is either idiopathic or secondary to a number of diseases. RLS is the strong urge to move the legs often with discomfort, occurs in 10% of the population, and causes poor sleep and reduced quality of life. The aim of this study was to determine if CD was associated with RLS since both are associated with iron deficiency. Inflammation and bacterial overgrowth are also associated with RLS and occur commonly in pts with CD. Methods: All consecutive CD outpatients (F-151, M-121; mean age 43.8 yrs) were prospectively surveyed by gastroenterologists at Specialists in Gastroenterology, a community GI practice (N = 135), Weill Cornell Medical Center (N = 71), Washington University School of Medicine (N = 54), and Johns Hopkins School of Medicine (N = 12). No patients were excluded or refused the survey. All four international criteria were required to be positive for RLS: 1) urge to move legs often with discomfort, 2) worse at rest, 3) worsening at night, and 4) relief with activity. Incidence (having RLS at any point in time), prevalence (having RLS at time of survey), clinical characteristics, RLS risk factors, and potential qualitative relationship to GI symptoms were queried. One IRB limited the RLS frequency question to prevalence and did not allow RLS risk factor questions (54 of 272 surveys). Results: RLS incidence was 42.7% (93/218). Prevalence of RLS was 30.2% (82/272; CI 29.9–30.3%) vs. 8.7% (17/194; CI 8.6–8.8%) of spouses (P < 0.0001; odds ratio = 4.5; CI 2.54–7.87%). In 91.8% pts, RLS started during or after onset of diagnosis of CD. Among 72 RLS (+) pts, 44.5% stated there was correlation of qualitative RLS symptom improvement with overall CD symptom improvement. RLS (+) pts and RLS (−) CD pts had: mean age of 46.8 vs. 42.6 yrs, small intestine involvement in 77.9% vs. 66.7%, colon involvement in 39.7% vs. 63.2%, and prior iron deficiency anemia in 49.3% vs. 33.1%. There was no difference between the CD groups with respect to: gender ratio, current iron deficiency (4.6%), RLS family history (12%), or the rare prevalence of concomitant RLS disorders. Conclusion: RLS occurs frequently in CD and appears to be a new extraintestinal manifestation. Factors other than iron deficiency play a role in RLS pathophysiology in CD. The potential relationship of RLS with CD activity needs further investigation. Determination of the effect of RLS on the quality of life in CD is warranted.

Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13

Five loci for restless legs syndrome (RLS) on chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1-RLS5) have been mapped in RLS families, with a recessive in the first and autosomal-dominant mode of inheritance in the latter cases. Investigations of further RLS families showed evidence for genetic locus heterogeneity. We have conducted a genome-wide linkage analysis in a large RLS family of Italian origin with 12 affected members in 3 generations using 5,861 single nucleotide polymorphisms (SNP, 6K Illumina). Linkage analysis was performed under an autosomal-dominant model with a complete penetrance, an allele frequency of 0.003 and a phenocopy rate of 0.005. The genome-wide scan resulted in suggestive evidence for linkage on chromosome 19p with maximum multipoint logarithm of the odds score of 2.61 between markers rs754292 and rs273265. The locus was replicated in a family-based association study in a set of 159 trios of European origin. This study provides evidence for a further RLS locus, thus supporting the picture of RLS as a genetically heterogenous complex trait.

Evidence for linkage of restless legs syndrome to chromosome 9p

Restless legs syndrome (RLS) is a common sensory-motor disorder characterized by paresthesias and an intense urge to move the legs with a considerable familial aggregation. To date, no gene mutation has been found, but five gene loci have been mapped in primary RLS to chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1 through 5). We identified a four-generational German RLS family with 37 family members including 15 affected cases. We performed linkage analysis using microsatellite markers at the five known loci. Prompted by the identification of a potentially shared haplotype near the RLS3 locus, we expanded the investigated linkage region on chromosome 9p using additional DNA markers. Mode of inheritance in our RLS family was compatible with an autosomal dominant pattern, and disease onset was mainly in childhood or adolescence. We excluded linkage to the RLS1, RLS2, RLS4, and RLS5 loci. However, we identified a likely new RLS gene locus (RLS3*) on chromosome 9p with a maximum lod score of 3.60 generated by model-based multipoint linkage analysis. A haplotype flanked by D9S974 and D9S1118 in a 9.9-Mb region, centromeric to RLS3, was shared by all 12 investigated patients. In addition, 11 of them carried a common haplotype extending telomeric to D9S2189 that is located within RLS3. We demonstrate linkage to a locus on chromosome 9p that is probably distinct from RLS3. Our family with a rather homogeneous phenotype and very early disease onset represents a unique opportunity to further elucidate the genetic causes of the frequent restless leg syndrome.

Molecular genetic studies ofDMT1on 12q in French‐Canadian restless legs syndrome patients and families

Converging evidence from clinical observations, brain imaging and pathological findings strongly indicate impaired brain iron regulation in restless legs syndrome (RLS). Animal models with mutation in (DMT1) divalent metal transporter 1 gene, an important brain iron transporter, demonstrate a similar iron deficiency profile as found in RLS brain. The human DMT1 gene, mapped to chromosome 12q near the RLS1 locus, qualifies as an excellent functional and possible positional candidate for RLS. DMT1 protein levels were assessed in lymphoblastoid cell lines from RLS patients and controls. Linkage analyses were carried out with markers flanking and within the DMT1 gene. Selected patient samples from RLS families with compatible linkage to the RLS1 locus on 12q were fully sequenced in both the coding regions and the long stretches of UTR sequences. Finally, selected sequence variants were further studied in case/control and family-based association tests. A clinical association of anemia and RLS was further confirmed in this study. There was no detectable difference in DMT1 protein levels between RLS patient lymphoblastoid cell lines and normal controls. Non-parametric linkage analyses failed to identify any significant linkage signals within the DMT1 gene region. Sequencing of selected patients did not detect any sequence variant(s) compatible with DMT1 harboring RLS causative mutation(s). Further studies did not find any association between ten SNPs, spanning the whole DMT1 gene region, and RLS affection status. Finally, two DMT1 intronic SNPs showed positive association with RLS in patients with a history of anemia, when compared to RLS patients without anemia.

Genetics of restless legs syndrome

Several studies on restless legs syndrome (RLS) have suggested a substantial genetic contribution in the etiology of this sleep disorder. Clinical surveys of idiopathic RLS patients have shown that 40-90% report a positive family history. The clinical features have been compared between familial and sporadic cases and the only difference found was a younger age-at-onset in familial RLS. Despite several reports suggesting a genetic contribution to the etiology of idiopathic RLS, few molecular genetic studies have been carried out attempting to identify genes that can predispose to this disorder. In particular, genes encoding for the GABA A receptor subunits, the gene for the alpha1 subunit of the glycine receptor, and genes involved in dopaminergic transmission and metabolism have been analyzed, however no significant findings have been reported. Genomewide linkage analysis studies using microsatellite markers have identified three loci for RLS: on chromosome 12q, on chromosome 14q and on chromosome 9p. It is important to investigate whether further RLS families show linkage to one of these loci to discuss the contribution of these loci and to provide a prerequisite of a mutational screening and identification of the RLS genes.

Family history study of the restless legs syndrome

Background: Although there is a relatively high rate of occurrence of sporadic cases of restless legs syndrome (RLS), the systematic study of family history of RLS in populations of RLS patients has been very limited. The objective of the present study was to determine the risk of RLS for first- and second-degree relatives of a population of primary RLS patients not selected for the number of affected relatives in their families and to obtain an estimate of the degree of genetic involvement in RLS. Methods: Consecutively consenting patients from two different sites who met the criteria for RLS completed a worksheet that asked them to indicate their current age, the date of their earliest RLS symptoms, and the names and RLS status of all of their first- and second-degree relatives. Controls with no clinical history of RLS also completed the worksheet. Results: First- and second-degree relatives of patients with RLS had a significantly greater risk of RLS than the first- ( P<0.001 ) and second-degree relatives ( P<0.003 ) of controls. The risk of RLS was found to be greater for first-degree relatives of early-onset, rather than late-onset, RLS probands ( P<0.001 ). Conclusions: This study provides a complete systematic examination of the risk of RLS among relatives of RLS probands and controls using the same assessment methodology. Although the results are consistent with a genetic etiology for RLS, they do not support the presence of one simple, Mendelian-inherited major gene in most RLS families.

Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families.

A strong familial component of restless legs syndrome (RLS) is known. The objective of this study therefore was to investigate the likely mode of inheritance of RLS. RLS patients and their first-degree relatives were investigated and classified in RLS affected and RLS nonaffected subjects. Assessments were based on direct, personal standardized diagnostic interviews. Complex segregation analysis was performed with the families stratified according to the mean age at onset of the disease within the families. Two hundred thirty-eight RLS patients, 537 first-degree relatives, and 133 spouses were interviewed. Two groups of families were stratified: mean age at onset up to 30 years of age (Group A) and older than 30 years (Group B; p < 0.005). In Group A, segregation analysis strongly favored a single major gene acting autosomal dominant with a multifactorial component. Parameter estimates were 0.003 for the allele frequency, 1.0 for the penetrance, and 0.005 for the phenocopy rate. In Group B, no evidence for a major gene could be elucidated. The segregation pattern found in our families argues for an autosomal allele acting dominantly in RLS families with an early age at onset of symptoms and suggests that RLS is a causative heterogeneous disease.