Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal ... Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (Bonati et al., 2003). - Genetic Heterogeneity of Restless Legs Syndrome RLS1 has been mapped to chromosome 12q. Other susceptibility loci for RLS include RLS2 (608831) on chromosome 14q13-q31; RLS3 (610438) on chromosome 9p24-p22; RLS4 (610439) on chromosome 2q33; RLS5 (611242) on chromosome 20p13; RLS6 (611185) on chromosome 6p21; RLS7 (612853) on chromosome 2p14; and RLS8 (615197) on chromosome 5q31.
Ekbom (1945) first described restless legs syndrome. Affected persons experience paresthesias in the legs when first going to bed or sitting still for a time and cannot resist fidgeting with their feet. Huizinga (1957) described a family with ... Ekbom (1945) first described restless legs syndrome. Affected persons experience paresthesias in the legs when first going to bed or sitting still for a time and cannot resist fidgeting with their feet. Huizinga (1957) described a family with affected persons in 5 generations. The condition, which began in adolescence, was relieved by cold. Ekbom (1960) and Bornstein (1961) also described familial aggregation. Autosomal dominant inheritance was particularly well documented by Boghen and Peyronnard (1976), who furthermore described myoclonic jerks in 10 of 18 affected persons. The jerks occurred at night before sleep and severely interfered with it. The authors referred to the 'painful-legs--moving-toes syndrome' in a patient whose relatives had the restless legs syndrome and proposed that the disorders are the same. Sudden bodily jerking on falling asleep is a frequent finding in normal persons (Oswald, 1959). Ondo et al. (2000) noted the phenotypic variation in genetic RLS. They reported 12 pairs of monozygotic twins in which both members of 10 pairs had definite restless legs syndrome based on criteria proposed by the International Restless Legs Syndrome Study Group (IRLSSG) including the desire to move the extremities associated with paresthesia/dysesthesia; motor restlessness; worsening of symptoms at rest with temporary relief by activity; and worsening of symptoms in the evening or night. Despite the high concordance rate and high penetrance, the symptom descriptions and age at onset varied markedly. Earley (2003) gave a clinical review of the restless legs syndrome and its management. Earley (2003) stated that a familial association seems to be most obvious in the family members of female patients whose symptoms start early in life. Manconi et al. (2004) found that 161 (26.6%) of 606 Italian pregnant women had symptoms of RLS during pregnancy. Sixty (9.9%) of these women experienced symptoms before pregnancy. Of those with preexisting RLS, 11% reported an improvement of RLS during pregnancy, 28% observed no change, and 61% had a significant worsening of symptoms after pregnancy began, particularly during the third trimester. RLS symptoms dramatically decreased around the time of delivery and were present in only 8 women (5%) 6 months after delivery. Despite similar amounts of iron and folate supplements, women with RLS had evidence of decreased plasma iron stores, as indicated by decreased hemoglobin and decreased mean corpuscular volume (MCV) compared to the women without RLS. Manconi et al. (2004) suggested that hormonal changes contribute to the pathogenesis of RLS during pregnancy. In a follow-up study involving 207 previously pregnant women, including 74 who experienced RLS during pregnancy and 133 who did not, Cesnik et al. (2010) found that patients with transient RLS during pregnancy were at increased risk of having recurrence of RLS during pregnancy and at 4-fold increased risk of developing the chronic form of RLS compared to women who did not have RLS during pregnancy. Kotagal and Silber (2004) reported that 32 (5.9%) of 538 patients under the age of 18 years with sleep disorders in their clinic had features consistent with RLS. Sleep onset or sleep maintenance insomnia was the most common symptom (87.5%). Serum ferritin (see 134770) levels were decreased in 20 (83%) of 24 patients tested, suggesting that iron deficiency is a characteristic of the disorder. A family history of RLS was present in 72%, with mothers almost 3 times more likely to be affected than fathers. Kotagal and Silber (2004) concluded that RLS in childhood is similar to that seen in adults. Konofal and Cortese (2005) commented on the observed association between RLS and attention deficit-hyperactivity disorder (ADHD; 143465) in some children, and postulated a common alteration in dopaminergic function. In a cross-sectional community-based study of 701 individuals aged 50 to 89 years in Northern Italy, Hogl et al. (2005) found that 10.6% of individuals had symptoms consistent with RLS. The prevalence was over twice as high in women (14.2%) than in men (6.6%). Although two-thirds of patients reported moderate to severe disease, none had received dopaminergic therapy. Free serum iron, transferrin (TF; 190000), and ferritin concentrations were similar in individuals with and without RLS, but those with RLS had higher serum concentrations of soluble transferrin receptor (TFRC; 190010).
Pichler et al. (2008) provided a detailed review of the genetics of RLS.
- Modifier Genes
Pharmacotherapy and brain imaging studies have suggested that the dopaminergic system plays a role in the pathogenesis of ... Pichler et al. (2008) provided a detailed review of the genetics of RLS. - Modifier Genes Pharmacotherapy and brain imaging studies have suggested that the dopaminergic system plays a role in the pathogenesis of RLS. In 96 unrelated patients, Desautels et al. (2002) found that females with the high activity alleles of the MAOA gene (309850) promoter polymorphism (3.5, 4, and 5 repeats), which resulted in lower levels of synaptic dopamine, had a greater risk (odds ratio = 2.0) of being affected with RLS than females carrying the low activity allele (3 repeats). The affected females showed longer sleep latency and a higher movement index. The association was not observed in males, and there were no differences for either group regarding the MAOB gene (309860). Desautels et al. (2002) suggested that the MAOA gene may modulate the pathogenesis of RLS and that estrogen may interact with specific MAOA alleles.