Restless Legs Syndrome, Susceptibility To, 1

Description

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.

Clinical Features

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).

Other Features

Earley et al. (2000) found that 16 patients with RLS had significantly lower CSF ferritin and higher CSF transferrin levels compared to controls. There was no difference in serum ferritin and transferrin levels between the 2 groups. The findings suggested that RLS patients have low stores of iron in the brain.

Using a special MRI measurement to assess regional brain iron concentrations, Allen et al. (2001) found that 5 patients with RLS had decreased iron levels in the substantia nigra and putamen compared to 5 controls. The iron decreases were more pronounced in those patients with more severe RLS.

By postmortem examination and immunohistochemical analysis, Connor et al. (2003) found a dramatic decrease in iron and ferritin heavy chain and an increase in transferrin in the substantia nigra of 7 RLS brains compared to controls. Staining for transferrin receptors was not increased, as would be expected with iron deficiency. In addition, RLS brains had decreased staining for the divalent metal transporter-1 (DMT1; 600523), which is important for iron uptake into cells, and the iron transport protein MTP1 (156360). Tyrosine hydroxylase (TH; 191290) staining of dopaminergic neurons was normal in RLS brains. Connor et al. (2003) hypothesized that the defect in RLS involves a defect in iron acquisition in neuromelanin cells, which could lead to other changes, including impaired dopaminergic activity.

Connor et al. (2004) isolated neuromelanin cells from the substantia nigra of 4 patients with RLS using laser capture microdissection. Protein isolation and immunoblotting techniques showed that cells from the RLS patients had a 40% decrease in ferritin heavy chain, whereas ferritin light chain was similar to controls. The 2 iron transport proteins DMT1 and ferroportin (604653) and the transferrin receptor were also decreased in RLS neuromelanin cells. Transferrin was increased by 72% compared to controls. Iron regulatory protein-1 (IRP1; 100880) was decreased and IRP2 (147582) was increased in RLS brains compared to controls. Connor et al. (2004) suggested that a decrease in IRP1 in neuromelanin cells in RLS may result in instability of the transferrin receptor mRNA, leading to cellular iron deficiency.

Approximately 80% of RLS patients experience periodic limb movements in sleep (PLMS), which are rhythmic extensions of the big toe and dorsiflexion of the ankle, with occasional flexion at the knee and hip. Although PLMS is more common in RLS patients, it can occur in other sleep disorders as well. In a polysomnographic study of 10 patients with RLS who also had PLMS, Pennestri et al. (2007) found that blood pressure increased significantly with all periodic limb movements in sleep, particularly those associated with microarousals. Changes in blood pressure increased with age and duration of the illness. Transient tachycardia was also observed in association with PLMS. Pennestri et al. (2007) suggested that these changes could contribute to increased risk for cardiovascular events and disease in RLS patients.

Della Marca et al. (2009) reported 7 patients with myalgia in the lower limbs and increased serum creatine kinase (hyperCKemia; 123320) who were found to have severe restless legs syndrome with severe periodic limb movements in sleep. Treatment of RLS resulted in improved serum creatine kinase levels in 6 patient who underwent treatment. The authors concluded that some severe cases of RLS can result in increased serum CK, and discussed the possible overlap of the 2 disorders.

Diagnosis

Allen et al. (2003) reported the revised diagnostic criteria developed by the International Restless Legs Syndrome Study Group. Patients must have (1) an urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs; (2) the urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting; (3) the urge to move or unpleasant sensations are partially or totally relieved by movement; (4) the urge to move or unpleasant sensations are worse in the evening or at night than during the day. Most patients experience sleep disturbances. Allen et al. (2003) noted that the diagnosis may be difficult to determine in elderly patients with cognitive impairment and in children and suggested additional methods of evaluating these patients.

Clinical Management

Most patients with RLS have a favorable response to dopaminergic drugs (Allen et al., 2003).

Allen and Earley (1996) reported that 82% of 30 RLS patients treated with dopaminergic agents experienced 'augmentation' of their symptoms in the afternoon and evening prior to taking the next nightly dose. This phenomenon was distinct from 'rebound,' in which RLS symptoms worsen in the early morning. Augmentation was greater for those with more severe symptoms and for patients on higher doses, but was unrelated to age or gender.

Allen et al. (2003) defined augmentation as a shift of RLS symptoms to a time period that is 2 or more hours earlier than was typical of the time of symptom onset before starting treatment. Augmentation typically presents within 6 months after treatment begins.

In a prospective randomized clinical trial of 85 patients with RLS, Stiasny-Kolster et al. (2004) found that the dopamine agonist cabergoline was an effective treatment. The beneficial effects lasted for 1 year, with 6 patients experiencing mild augmentation.

Tippmann-Peikert et al. (2007) reported 3 patients with RLS who developed pathologic gambling (see 606349) after treatment with dopamine agonists. The behavior was dose-dependent, and there were no other compulsive behaviors. Pathologic gambling resolved in all 3 patients after discontinuation of the medication. In 1 patient, treatment with gabapentin led to resolution of RLS symptoms without side effects.

Inheritance

Pedigree analysis in families of 12 pairs of monozygotic twins suggested autosomal dominant inheritance (Ondo et al., 2000). Trenkwalder et al. (1996) found evidence of anticipation in restless legs syndrome in 1 large German pedigree. The disorder had a 30-year age-at-onset difference between generations.

Winkelmann et al. (2002) performed a complex segregation analysis of RLS in 2 groups of families: those with mean age at onset up to 30 years, and those older than 30 years. In the former, they demonstrated the action of a single major gene behaving as an autosomal dominant with a multifactorial component, and found no evidence for a major gene in the latter.

In a review of several studies, Allen et al. (2003) found that more than 50% of patients with RLS had a positive family history of RLS and that a person with RLS is 3 to 6 times more likely to have a family history of RLS than is a person who does not have RLS.

A family history of RLS was described in 40 to 90% of patients (Winkelmann and Ferini-Strambi, 2006), and the high concordance rate of 83.3% between identical twins (Ondo et al., 2000) supports a genetic basis.

Xiong et al. (2007) reported the results of an RLS questionnaire completed by 272 twin pairs in Canada, including 140 monozygotic (MZ)and 132 dizygotic (DZ) pairs. Eleven MZ twins pairs were concordant for RLS, compared to only 2 DZ pairs. Heritability was estimated at 69.4%. There was a high correlation of age at onset and severity scores among the affected twin pairs. There was also a strong associations between RLS and arthritis and between RLS and anemia. The findings confirmed a significant genetic component in RLS.

Among 249 Canadian probands with RLS, Xiong et al. (2010) reported that 192 (77.1%) had a family history of the disorder and 57 (22.9%) had sporadic disease. Among the familial cases, the relative risk was 3.6 for sibs and 1.8 for offspring. Most inheritance patterns were consistent with autosomal dominant, although autosomal recessive and bilineal inheritance were also observed. RLS was more common in women, and was associated with iron-deficiency anemia, arthritis, and pregnancy. The mean age of onset was 28 years, and there was some evidence for genetic anticipation within families. Overall, the findings indicated a significant familial component to RLS.

Mapping

To map genes that may play a role in the vulnerability to restless legs syndrome, Desautels et al. (2001) conducted a genomewide scan in a large French Canadian family. Significant linkage was established on chromosome 12q for a series of adjacent microsatellite markers with a maximum 2-point lod score of 3.42 at recombination fraction 0.05, assuming an autosomal recessive mode of inheritance, whereas multipoint linkage calculations yielded a lod score of 3.59. Haplotype analysis refined the genetic interval, positioning the RLS-predisposing gene in a 14.71-cM region between D12S1044 and D12S78. Several plausible candidate genes map to this region, including the homolog of timeless (TIM1; 603887), which maps to 12q12-q13, and neurotensin (NTS; 162650), which maps to 12q21. Kock et al. (2002) could not confirm the susceptibility locus for RLS on chromosome 12q in either of the families they studied. They questioned certain parameters used in the recessive model by Desautels et al. (2001). Winkelmann et al. (2002) noted that the study of the single French Canadian family by Desautels et al. (2001) used an autosomal recessive model with very high allele frequency (q = 0.75).

Desautels et al. (2005) performed linkage analysis using an autosomal recessive model on the family reported by Desautels et al. (2001) and 5 additional families with RLS; all of the families were of French Canadian origin. A maximum 2-point lod score of 5.67 was obtained at marker D12S1636; a maximum multipoint lod score of 8.84 was obtained between D12S326 and D12S304, thus confirming the presence of an RLS susceptibility locus on chromosome 12q. Desautels et al. (2005) noted that autosomal dominant inheritance is suggested clinically in RLS but stated that their lod scores were higher under a recessive model. Possible reasons included pseudodominant inheritance, particularly for a disorder with features of a founder effect in the French Canadian population, or ascertainment bias. Clinically, probands from the families linked to 12q showed increased periodic leg movements during sleep compared to those from families not linked to 12q.

Winkelmann et al. (2006) confirmed the assignment of RLS1 to chromosome 12q.

Heterogeneity

In a genomewide association study of 393 patients with restless legs syndrome and 1,602 controls, Winkelmann et al. (2007) found evidence for an association with several SNPs within a region on chromosome 15q that contains the LBXCOR1 (611273) and MAP2K5 (602520) genes.

In a study including 649 RLS patients and 1,230 controls from the Czech Republic, Austria, and Finland, Kemlink et al. (2009) identified an association between RLS and rs6494696 at chromosome 15q near the MAP2K5 and LBXCOR1 genes (p = 0.04; OR of 1.27). The association was found only in familial and not sporadic cases.

Molecular Genetics

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.