Mapping the gene for autosomal dominant restless legs syndrome in an Irish family

Restless Legs Syndrome (RLS) is a common neurological disorder affecting nearly 15% of the general population. Ironically, RLS can be described as the most common condition one has never heard of. It is usually characterised by uncomfortable, unpleasant sensations in the lower limbs inducing an uncontrollable desire to move the legs. RLS exhibits a circadian pattern with symptoms present predominantly in the evening or at night, thus leading to sleep disruption and daytime somnolence. RLS is generally classified into primary (idiopathic) and secondary (symptomatic) forms. Primary RLS includes sporadic and familial cases of which the age of onset is usually less than 45 years and progresses slowly with a female to male ratio of 2:1. Secondary forms often occur as a complication of another health condition, such as iron deficiency or thyroid dysfunction. The age of onset is usually over 45 years, with an equal male to female ratio and more rapid progression. Ekbom described the familial component of the disorder in 1945 and since then many studies have been published on the familial forms of the disorder. Molecular genetic studies have so far identified ten loci (5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p). No specific gene within these loci has been identified thus far. Association mapping has highlighted a further five areas of interest. RLS6 has been found to be associated with SNPs in the BTBD9 gene. Four other variants were found within intronic and intergenic regions of MEIS1, MAP2K5/LBXCOR1, PTPRD and NOS1. The pathophysiology of RLS is complex and remains to be fully elucidated. Conditions associated with secondary RLS, such as pregnancy or end-stage renal disease, are characterised by iron deficiency, which suggests that disturbed iron homeostasis plays a role. Dopaminergic dysfunction in subcortical systems also appears to play a central role. An ongoing study within the Department of Pathology (University College Cork) is investigating the genetic characteristics of RLS in Irish families. A three generation RLS pedigree RLS3002 consisting of 11 affected and 7 unaffected living family members was recruited. The family had been examined for four of the known loci (5q, 12q, 14p and 9p) (Abdulrahim 2008). The aim of this study was to continue examining this Irish RLS pedigree for possible linkage to the previously described loci and associated regions. Using informative microsatellite markers linkage was excluded to the loci on 5q, 12q, 14p, 9p, 20p, 16p, 19p, 4q, 17p and also within the regions reported to be associated with RLS. This suggested the presence of a new unidentified locus. A genome-wide scan was performed using two microsatellite marker screening sets (Research Genetics Inc. Mapping set and the Applied Biosystems Linkage mapping set version 2.5). Linkage analysis was conducted under an autosomal dominant model with a penetrance of 95% and an allele frequency of 0.01. A maximum LOD score of 3.59 at θ=0.00 for marker D19S878 indicated significant linkage on chromosome 19p. Haplotype analysis defined a genetic region of 6.57 cM on chromosome 19p13.3, corresponding to 2.5 Mb. There are approximately 100 genes annotated within the critical region. Sequencing of two candidate genes, KLF16 and GAMT, selected on the assumed pathophysiology of RLS, did not identify any sequence variant. This study provides evidence of a novel RLS locus in an Irish pedigree, thus supporting the picture of RLS as a genetically heterogeneous trait.

Variations circadiennes du syndrome d’impatiences musculaires de l’éveil (SIME ou RLS – restless legs syndrome)

La sécrétion de mélatonine chez des patients atteints du syndrome d’impatience musculaire de l’éveil (SIME) débute approximativement 2 heures avant l’aggravation des symptômes en soirée (Michaud et al., 2004). Le but de ce projet était de préciser le rôle de la mélatonine dans l’augmentation de la sévérité des symptômes en soirée. Huit sujets atteints de SIME primaire ont été étudiés dans trois conditions : contrôle, avec administration de mélatonine, avec exposition à la lumière vive. La sévérité des symptômes a été évaluée par l’administration de tests d’immobilisation suggérée (TIS). Les résultats ont démontré une augmentation significative des mouvements périodiques des jambes durant l’éveil (MPJE) lorsque de la mélatonine avait été administrée comparativement à la condition contrôle et celle où les sujets étaient exposés à la lumière vive. La lumière vive n’a pas eu d’effet significatif sur les symptômes moteurs comparativement à la condition contrôle mais elle a amélioré significativement les symptômes sensoriels comparativement à la condition contrôle. Ainsi, bien que la mélatonine exogène ait un effet aggravant sur les symptômes moteurs du SIME, l’augmentation de la sécrétion endogène au cours de la soirée ne saurait expliquer à elle seule les variations de la sévérité des symptômes du SIME.

Restless legs syndrome - en beskrivning av dess inverkan på individens sömn, livskvalitet samt olika behandlingsformer : En systematisk litteraturstudie

Syftet med denna systematiska litteraturstudie var att beskriva hur restless legs inverkar på individens sömn och livskvalitet. Syftet var även att granska vilka olika former av behandlingar som finns att tillgå vid restless legs. För att finna information om detta ämne har endast vetenskapliga artiklar använts. Datainsamlingen har skett via databaser, internet samt Högskolans bibliotek, och artiklar från år 1995 och framåt har valts ut. Inklusionskriterier för denna studie var att de valda artiklarna skulle vara internationella vetenskapliga artiklar i fulltext. De funna artiklarna granskades med avseende på vetenskaplig kvalitet och poängsattes utifrån för ändamålet avsedda granskningsmallar. Denna bedömning resulterade i 21 artiklar. Resultatet visade att restless legs patienter upplever sömnbristen som det största problemet. För flertalet individer som drabbas av restless legs försämrades livskvaliteten och patienterna drabbades vanligtvis av psykologiska och fysiologiska besvär. Det vanligaste sättet att behandla restless legs var att använda dopaminerga läkemedel samt bensodiazepiner, antiepileptika och opioider. Andra former av behandlingar var järn, homeopatiska läkemedel, hypnos samt fysisk aktivitet. Det förekom även att restless legs patienter på eget initiativ använde hasch eftersom det ansågs lindra symtomen.

Severity of restless legs syndrome is inversely correlated with echogenicity of the substantia nigra in different neurodegenerative movement disorders. A preliminary observation

Objective: Hyperechogenicity of the substantia nigra is a frequent observation on transcranial sonography in Parkinson's disease and Machado-Joseph disease patients. Additionally, restless legs syndrome is a sleep disorder that is also frequently found in both diseases. Autopsy studies have demonstrated increased SN iron content in hyperechogenic substantia nigra. Iron storage is also known to be involved in restless legs syndrome. We formally compared echogenicity of the substantia nigra with restless legs syndrome in Parkinson's disease and Machado-Joseph disease patients. Methods: Transcranial brain sonography was performed in a sample of Parkinson's disease and Machado-Joseph disease patients, and findings then correlated with the presence and severity of restless legs syndrome. Results: There was a continuum of substantia nigra echogenicity among groups (Parkinson's disease versus Machado-Joseph disease versus controls) and sub-groups (Parkinson's disease with and without restless legs syndrome versus Machado-Joseph disease with and without restless legs syndrome) as well as a statistically significant negative correlation between restless legs syndrome severity and substantia nigra echogenicity (p<0.001). Conclusions: These preliminary observations demonstrate that the severity of RLS may be influenced by nigral iron load reflected by substantia nigra echogenicity in different neurodegenerative movement disorders. (C) 2012 Elsevier B.V. All rights reserved.

La Restless Legs Syndrome aumenta il rischio cardiovascolare e la mortalità a breve termine nei pazienti emodializzati

Abstract Restless legs syndrome (RLS) is a sensori-motor neurological disorder characterzed by paraesthesia, dysaesthesia and irresistibile urge to move the legs especially at night. Its prevalence is much higher among dialysis patients at 12 to 62% compared to 3 to 9% in the general population. In our study we investigated the association between RLS and cardiovascular events risk and laboratory parameters in End-stage kidney disease (ESKD) patients on dialysis. We studied 100 ESKD patients undergoing hemodialysis that were enrolled in an 18-months prospective observational study. The main outcomes were the association of RLS with new cardiovascular events and cardiovascular mortality. RLS affected 31% of the study population. It was associated with female gender, gradual reduction in residual dieresis, lower albumin (P=0.039) and inflammation, but not the dialysis parameters spKt/V and URR. During observation, 47% of patients experienced new cardiovascular events (64.5% with and 39.1% without RLS; P=0.019). Mortality was 20.0% in all patients, 32.3% in those with and 14.5% in patients without RLS (P=0.04). This study confirmed the high prevalence of RLS among dialysis patients and the associations between the severity of RLS and the risk of new cardiovascular events and higher short-term mortality. Abstract Restless legs syndrome (RLS) is a sensori-motor neurological disorder characterzed by paraesthesia, dysaesthesia and irresistibile urge to move the legs especially at night. Its prevalence is much higher among dialysis patients at 12 to 62% compared to 3 to 9% in the general population. In our study we investigated the association between RLS and cardiovascular events risk and laboratory parameters in End-stage kidney disease (ESKD) patients on dialysis. We studied 100 ESKD patients undergoing hemodialysis that were enrolled in an 18-months prospective observational study. The main outcomes were the association of RLS with new cardiovascular events and cardiovascular mortality. RLS affected 31% of the study population. It was associated with female gender, gradual reduction in residual dieresis, lower albumin (P=0.039) and inflammation, but not the dialysis parameters spKt/V and URR. During observation, 47% of patients experienced new cardiovascular events (64.5% with and 39.1% without RLS; P=0.019). Mortality was 20.0% in all patients, 32.3% in those with and 14.5% in patients without RLS (P=0.04). This study confirmed the high prevalence of RLS among dialysis patients and the associations between the severity of RLS and the risk of new cardiovascular events and higher short-term mortality.

Psychiatric comorbidity, Restless Legs Syndrome and Nocturnal Eating Disorder: a case-control study

Objective: to evaluate the psychopathological profile in primary Restless Legs Syndrome (p-RLS) patients with and without nocturnal eating disorder (NED), analysing obsessive-compulsive traits, mood and anxiety disorder, and the two domains of personality proposed by Cloninger, temperament and character. Methods: we tested ten p-RLS patients without NED, ten p-RLS patients with NED and ten healthy control subjects, age and sex-matched, using Hamilton Depression and Anxiety Rating Scales, State-Trait Anxiety Inventory, Maudsley Obsessive Compulsive Inventory (MOCI) and Temperament and Character Inventory - revised (TCI). Results: p-RLS patients, particularly those with NED, had increased anxiety factor scores. MOCI-total, doubting and checking compulsion, and TCI-harm avoidance scores were significantly higher in p-RLS patients with NED. p-RLS patients without NED had significantly higher MOCI-doubting scores and a trend toward higher checking compulsion and harm avoidance scores with an apparent grading from controls to p-RLS patients without NED to p-RLS with NED. Conclusions: higher harm avoidance might predispose to display obsessive-compulsive symptoms, RLS and then, with increasing severity, compulsive nocturnal eating. RLS and NED could represent a pathological continuum in which a dysfunction in the limbic system, possibly driven by a dopaminergic dysfunction, could be the underlying pathophysiological mechanism.

Dopaminergic treatment in idiopathic restless legs syndrome: effects on subjective sleepiness

To assess frequency and characteristics of excessive daytime sleepiness (EDS) in restless legs syndrome (RLS) and the evolution of EDS under different RLS therapies.

Dissociation of periodic leg movements from arousals in restless legs syndrome

The purpose of this study was to characterize the nature of the relation between periodic leg movements during sleep (PLMS) and cortical arousals to contribute to the debate on the clinical significance and treatment of PLMS.

Pramipexole versus dual release levodopa in restless legs syndrome: a double blind, randomised, cross-over trial

To compare efficacy and safety of the dopamine agonist pramipexole (PPX) versus reference treatment with dual release levodopa/benserazide (L/B) in de novo patients with restless legs syndrome (RLS).

European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society

Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society.

Characteristics and determinants of restless legs syndrome in pregnancy: a prospective study

The aim of this cohort study was to prospectively assess frequency, characteristics, and determinants of restless legs syndrome (RLS) in pregnancy and its impact on sleep.

Cerebral correlates of muscle tone fluctuations in restless legs syndrome: A pilot study with combined functional magnetic resonance imaging and anterior tibial muscle electromyography

BACKGROUND: The pathology of restless legs syndrome (RLS) is still not understood. To investigate the pathomechanism of the disorder further we recorded a surface electromyogram (EMG) of the anterior tibial muscle during functional magnetic resonance imaging (fMRI) in patients with idiopathic RLS. METHODS: Seven subjects with moderate to severe RLS were investigated in the present pilot study. Patients were lying supine in the scanner for over 50min and were instructed not to move voluntarily. Sensory leg discomfort (SLD) was evaluated on a 10-point Likert scale. For brain image analysis, an algorithm for the calculation of tonic EMG values was developed. RESULTS: We found a negative correlation of tonic EMG and SLD (p <0.01). This finding provides evidence for the clinical experience that RLS-related subjective leg discomfort increases during muscle relaxation at rest. In the fMRI analysis, the tonic EMG was associated with activation in motor and somatosensory pathways and also in some regions that are not primarily related to motor or somatosensory functions. CONCLUSIONS: By using a newly developed algorithm for the investigation of muscle tone-related changes in cerebral activity, we identified structures that are potentially involved in RLS pathology. Our method, with some modification, may also be suitable for the investigation of phasic muscle activity that occurs during periodic leg movements.