Winkelmann, J., Schormair, B., Lichtner, P., Ripke, S., Xiong, L., Jalilzadeh, S. et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat. Genet. 39, 1000-1006

Institute of Human Genetics, GSF National Research Center of Environment and Health, D-85764 Neuherberg, Munich, Germany.
Nature Genetics (Impact Factor: 29.35). 09/2007; 39(8):1000-6. DOI: 10.1038/ng2099
Source: PubMed


Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

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    • "There is no definitive diagnostic test for RLS/WED and the pathophysiology is not fully understood. Mechanisms that are thought to play a role include genetic variants (Winkelmann et al., 2007), iron dysregulation (Connor et al., 2011; Dusek et al., 2012), reduced D 2 receptors in the putamen (Connor et al., 2009), and dopamine dysregulation (Trenkwalder and Paulus, 2010). Sensory disturbance (Stiasny-Kolster et al., 2004), altered neurochemistry in the thalamus (Allen et al., 2013; Rizzo et al., 2012), and reduced intracortical inhibition in the hand (Nardone et al., 2006; Tergau et al., 1999) and leg (Tergau et al., 1999) area of motor cortex have also been observed. "
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    ABSTRACT: Objective: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor amplitude but normal dexterity and movement speed and rhythmicity compared to healthy controls. Methods: RLS/WED patients (n=17, 59±7 yrs) with moderate disease and healthy controls (n=17, 58±6 yrs) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. Results: Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. Conclusions: Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. Significance: Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology.
    Full-text · Article · Apr 2015 · Clinical Neurophysiology
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    • "Enfin, l'hypothèse d'une liaison génétique entre ces deux pathologies a été étudiée. Ainsi, Schimmelmann et al. [33] ont trouvé chez 386 enfants une association significative entre le risque de développer un TDA/H et un polymorphisme nucléotidique (SNP) du gène BTBD9, gène déjà connu pour son implication en tant que gène de susceptibilité du SJSR et de carence martiale [34] [35]. Dans la même perspective, Gao et al. ont mis en évidence un risque accru de SJSR chez les mères d'enfants présentant un TDA/H [36]. "
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    ABSTRACT: Le trouble déficit de l’attention/hyperactivité (TDA/H) est un trouble fréquent chez l’enfant qui persiste souvent à l’âge adulte. Des plaintes de sommeil sont fréquemment rapportées dans le TDA/H. Les liens entre sommeil et TDA/H ont fait l’objet de recherche depuis les années 1990 d’abord chez les enfants et plus récemment chez les adultes présentant un TDA/H. Des données se sont accumulées concernant une association entre le TDA/H et le syndrome des jambes sans repos (SJSR), le syndrome d’apnées obstructives du sommeil (SAOS), les hypersomnies et les troubles du rythme circadien. L’objectif de cet article est de faire une revue de ces associations et de leurs conséquences afin d’explorer de futures perspectives de prise en charge thérapeutique et de recherche scientifique.
    Full-text · Article · Nov 2014 · Médecine du Sommeil
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    • "This approach compares 100s of 1000s or more polymorphic genomic markers in large samples humans with variable phenotypes. This approach has been particularly useful for identifying genetic underpinnings of complex diseases such as restless leg syndrome, (Winkelmann et al., 2007) and familial PD (Soto-Ortolaza et al., 2013). Application of GWAS to toxicology can be illustrated by the work of Pierce et al. (2012). "
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    ABSTRACT: Heavy metals, various pesticide and herbicides are implicated as risk factors for human health. Paraquat, maneb, and rotenone, carbamate, and organophosphorous insecticides are examples of toxicants for which acute and chronic exposure are associated with multiple neurological disorders including Parkinson's disease. Nevertheless, the role of pesticide exposure in neurodegenerative diseases is not clear-cut, as there are inconsistencies in both the epidemiological and preclinical research. The aim of this short review is to show that at least, some of the inconsistencies are related to individual differences in susceptibility to the effects of neurotoxicants, individual differences that can be traced to the genetic constitution of the individuals and animals studies, i.e., host-based susceptibility.
    Full-text · Article · Sep 2014 · Frontiers in Genetics
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