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.
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.
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=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-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=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002).
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.
"Enfin, l'hypothèse d'une liaison génétique entre ces deux pathologies a été étudiée. Ainsi, Schimmelmann et al.  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  . 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 . "
[Show abstract][Hide abstract] 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.
Médecine du Sommeil 11/2014; 11(4). DOI:10.1016/j.msom.2014.10.002
"GWAS studies and forward genetics studies in animals can be complementary and informative . For example, Winkelmann et al. (2007) and Stefansson et al. (2007) each reported GWAS studies of individuals with restless legs syndrome and periodic limb movements that identified associated genetic markers near BTBD9 gene in humans. Restless legs syndrome and periodic limb movements are associated with low iron in the substantia nigra and related DA dysfunction. "
[Show abstract][Hide abstract] 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.
Frontiers in Genetics 09/2014; 5:327. DOI:10.3389/fgene.2014.00327
"Three patients with a family history of idiopathic RLS developed olanzapine induced-RLS, indicating that family history may be a risk factor for the condition; however, the underlying mechanisms are not known. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS  . Furthermore, one study found that loss of BTBD9 significantly disrupted sleep with concomitant increases in waking and motor activity in a Drosophila model . "
[Show abstract][Hide abstract] ABSTRACT: Only nine patients with olanzapine-induced restless legs syndrome (RLS) have been reported in the literature to our knowledge. We describe two patients with olanzapine-induced RLS treated at our hospital and review the nine reported patients. There were five women and six men aged between 28 and 62years in the overall group. RLS symptoms emerged at olanzapine doses between 2.5 and 20mg. The symptoms improved in all patients when the dose was reduced and immediately disappeared when the medication was stopped. International Restless Legs Scale (IRLS) scores ranged from 10 to 35. Three patients had a family history of idiopathic RLS. Supplemental drugs were administered to control RLS symptoms in five patients. Ropinirole was effective in one patient, while two patients did not respond to the drug. Propoxyphene effectively relieved symptoms in one patient who did not respond to ropinirole or clonazepam. RLS symptoms did not recur following substitution of other antipsychotic drugs for olanzapine. In conclusion, olanzapine can induce RLS, particularly in patients with a family history of idiopathic RLS. More than half of the patients experienced severe to very severe symptoms. A dose-dependent relationship was observed between olanzapine and RLS symptoms. A gradual increase in dose may prevent olanzapine-induced RLS. The optimal treatment for olanzapine-induced RLS is discontinuation of olanzapine.
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