A Genetic Risk Factor for Periodic Limb Movements in Sleep

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Abstract

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. Copyright 2007 Massachusetts Medical Society.

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Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome.

(2003)

There is a need for an easily administered instrument which can be applied to all patients with restless legs syndrome (RLS) to measure disease severity for clinical assessment, research, or therapeutic trials. The pathophysiology of RLS is not clear and no objective measure so far devised can apply to all patients or accurately reflect severity. Moreover, RLS is primarily a subjective disorder. Therefore, a subjective scale is at present the optimal instrument to meet this need. Twenty centers from six countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). A ten-question scale was developed on the basis of repeated expert evaluation of potential items. This scale, the IRLSSG rating scale (IRLS), was administered to 196 RLS patients, most on some medication, and 209 control subjects. The IRLS was found to have high levels of internal consistency, inter-examiner reliability, test-retest reliability over a 2-4 week period, and convergent validity. It also demonstrated criterion validity when tested against the current criterion of a clinical global impression and readily discriminated patient from control groups. The scale was dominated by a single severity factor that explained at least 59% of the pooled item variance. This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials. It supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patient's life. In future studies, the IRLS should be tested against objective measures of RLS severity and its sensitivity should be studied as RLS severity is systematically manipulated by therapeutic interventions.

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Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria.

J. Montplaisir, S Boucher, G. Poirier … (1997)

One hundred thirty-three cases of restless legs syndrome (RLS), diagnosed with criteria recently formulated by an international study group, were studied by questionnaire and with all-night polysomnographic recordings. Results show that RLS starts at a mean age of 27.2 years and before age 20 in 38.3% of patients. Symptoms often appear in one leg only and also involve upper limbs in about half of all cases. Most patients (94%) report sleep-onset insomnia or numerous nocturnal awakenings due to RLS symptoms. A strong relationship was found between these complaints and polysomnographic findings; increasing sleep latency and number of awakenings and decreasing sleep efficiency were associated with worsening symptoms. Periodic leg movements in sleep (index > 5 movements/h sleep) were found in 80.2% of patients. This study shows that this percentage is increased when 2 recording nights are considered (most severe score). Eighty patients of 127 (63%) reported the presence of RLS in at least one of their first-degree relatives. In these families, 221 of 568 first-degree relatives (39%) were reported by the patients to be affected with RLS.

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Prevalence of restless legs syndrome and periodic limb movement disorder in the general population.

Maurice M Ohayon, Thomas Roth (2002)

Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS) are two sleep disorders characterized by abnormal leg movements and are responsible for deterioration in sleep quality. However, the prevalence of these disorders is not well known in the general population. This study aims to document the prevalence of RLS and PLMD in the general population and to identify factors associated with these conditions. Cross-sectional studies were performed in the UK, Germany, Italy, Portugal and Spain. Overall, 18,980 subjects aged 15 to 100 years old representative of the general population of these five European countries underwent telephone interviews with the Sleep-EVAL system. A section of the questionnaire assessed leg symptoms during sleep. The diagnoses of PLMD and RLS were based on the minimal criteria provided by the International Classification of Sleep Disorders. The prevalence of PLMD was 3.9% and RLS was 5.5%. RLS and PLMD were higher in women than in men. The prevalence of RLS significantly increased with age. In multivariate models, being a woman, the presence of musculoskeletal disease, heart disease, obstructive sleep apnea syndrome, cataplexy, doing physical activities close to bedtime and the presence of a mental disorder were significantly associated with both disorders. Factors specific to PLMD were: being a shift or night worker, snoring, daily coffee intake, use of hypnotics and stress. Factors solely associated with RLS were: advanced age, obesity, hypertension, loud snoring, drinking at least three alcoholic beverages per day, smoking more than 20 cigarettes per day and use of SSRI. PLMD and RLS are prevalent in the general population. Both conditions are associated with several physical and mental disorders and may negatively impact sleep. Greater recognition of these sleep disorders is needed.