One of the challenges of evaluating the role of iron deficiency in RLS arises from the fact that serum iron levels are highly variable and can be impacted by a variety of confounding factors such as circadian rhythms, sleep disturbance (itself an RLS symptom), diet, and other lifestyle factors. It has, therefore, been hypothesized that serum ferritin (a protein that stores iron in tissue) might be a more clinically appropriate means of measuring and understanding the role of iron in RLS.²⁰ Mizuno et al conducted a study comparing sleep patterns, including periodic leg movement (PLM) index, in 10 subjects with diagnosed RLS and 10 matched subjects with psychophysiological insomnia but no RLS symptoms.²⁰ The 2 groups were compared for sleep patterns as well as disposition of iron, ferritin, and transferrin (a protein responsible for binding and transportation of iron) in both serum and cerebrospinal fluid (CSF). With regard to serum levels of iron, ferritin, and transferrin, no significant differences were observed between the groups. However, CSF iron and ferritin were both significantly lower in the RLS group, while transferrin was significantly higher. The higher transferrin levels indicate greater requirements for iron in the brain.²⁰ Subjects with RLS also experienced significantly longer sleep latency, less sleep efficiency, and a higher PLM index (all P <.01).²⁰

RLS in Pregnancy. Approximately one-fourth of pregnant women experience symptoms of RLS, with the most severe symptoms occurring in the third trimester. In most cases, women who experience RLS symptoms in pregnancy have not had symptoms of RLS previously.²¹ Typically, RLS symptoms resolve in most women within a few weeks to a few months after delivery.²¹ The transient restless legs syndrome during pregnancy is a significant risk factor for the development of a future chronic idiopathic restless legs syndrome.²² A variety of hypotheses have been offered to explain RLS in pregnancy. Several hormonal theories have been suggested, including the possibility that an increase in prolactin, which is associated with a lessening of dopamine activity, is responsible for RLS symptoms.²¹ The effects of pregnancy on increasing stress levels and promoting poor sleep have also been suggested as factors contributing to worsening of RLS symptoms.²¹ A metabolic hypothesis points to reductions in folate, iron, and ferritin, particularly in the later stages of pregnancy, which may increase RLS risk during pregnancy.²¹

Other Potential Associations. A wide spectrum of different diseases and pathologies has been associated with RLS, although the extent to which they have a causative relationship with the condition is poorly understood. End-stage renal disease is one of the most common comorbidities associated with RLS, and kidney transplants have been observed, in many cases, to resolve RLS symptoms.⁷ Other conditions linked with RLS include Parkinson’s disease, congestive heart failure, neuropathy, depression, and sleep apnea.¹ Certain lifestyle behaviors appear to be associated with increased risk for RLS, such as alcohol, tobacco, and caffeine consumption, although compelling data on these factors are lacking.⁷ Increased age, up until the age of approximately 79 years, has also been shown to be a risk factor for RLS.³ Several types of medications and medication classes known to aggravate RLS are shown in the Table.^6,7

Genetics of RLS. It is clear that, at least in some cases, RLS is inherited. However, the extent of the hereditary link remains difficult to precisely quantify. A hereditary link study by Winkelmann et al involved 300 RLS patients: 232 with idiopathic RLS and 68 patients with RLS secondary to uremia. The authors observed a definite family history of RLS, defined as at least 1 first-degree relative with verified RLS, in 42% of idiopathic RLS patients and 12% of patients with RLS secondary to uremia. An additional 13% of subjects with idiopathic RLS and 6% of those with secondary RLS were designated as having “possible positive” RLS inheritance; in these cases, examination of the first-degree relative was not possible.²³

Subjects with and without evidence of inherited RLS were similar in most respects, with the notable exception that those with a family history had a significantly earlier age of onset compared with those without a genetic connection (35 vs 47 years; P <.05). Subjects without a family history of RLS were significantly more likely to describe their symptoms as painful (85% versus 61%; P <.05), while those with a family history reported a greater influence of alcohol consumption on their symptoms. Finally, female subjects in the study with a family history of RLS had notably more frequent worsening of symptoms during pregnancy.²³

A study of 12 monozygotic twins, where at least 1 of the twins had an RLS diagnosis, found concordance in 10 of the twins (83.3%). Interestingly, all 10 pairs in which concordance was observed, in addition to 1 of the other 2 twin pairs, possessed a relative with an RLS diagnosis. In 4 cases, the relative was the twins’ mother, in 4 cases it was their father, and in 3 cases, the relative was unknown to the study authors. These data point to a highly penetrant autosomal dominant heredity in RLS. However, particular manifestations of RLS—including age at onset and severity of symptoms—varied in a high proportion of cases. In 1 twin pair, the age of onset differed between twins by 43 years, while a difference of 38 years was observed in age of onset with another twin pair. The gender of the parent with RLS was not associated with either severity of symptoms or age of onset.²⁴

A number of genomic studies in RLS have been undertaken, including a genomewide association study by Winkelmann et al, an expanded update of which was published in 2011, which included 922 RLS patients and 1526 controls.²⁵ Out of 301,406 single nucleotide polymorphisms (SNPs) tested for, the study authors successfully identified 6 significant loci associated with RLS risk.²⁵