Melody Ryan; John T. Slevin

Disclosures

Am J Health Syst Pharm. 2006;63(17):1599-1612. 

In This Article

Etiology

RLS can be either primary (idiopathic) or arise from secondary causes that lead to iron deficiency (sporadic or symptomatic forms). Ekbom[2] was the first to describe a familial component in primary RLS. Although the familial forms cannot be differentiated easily from the sporadic or symptomatic forms, it does appear that there is a significantly earlier age of onset and more frequent worsening during pregnancy in patients with hereditary RLS.[5] Clinical surveys have shown that at least 60% of individuals with idiopathic RLS reported a positive family history.[5,18,19] A study of 12 monozygotic twins in which at least one member expressed RLS suggested high concordance and high penetrance.[20] However, there is strong evidence for an autosomal dominant mode of inheritance transmitted by a single major gene only in families with a mean onset of symptoms at 30 years of age or less.[21]

Molecular genetic studies have identified at least three major susceptibility loci in large families from the United States, Canada, Germany, and Italy. A locus-conferring susceptibility to RLS was mapped in a large French-Canadian family to chromosome 12q13-23 (RLS-1) and connected with a series of adjacent microsatellite markers with an autosomal recessive mode of inheritance.[22] The locus has been confirmed in five more Canadian families[23] but not two northern Italian families.[24] Desautels et al.[25] reported that the gene for neurotensin, a modulator of dopamine neurotransmission, is contained within this region but is not likely responsible for RLS. Another locus was found in the chromosome 14q13-21 region (RLS-2) in a 30-member, three-generation northern Italian family affected by RLS and PLMS.[26] This locus, which has been confirmed in a single Canadian family,[27] fits an autosomal dominant inheritance pattern. A linkage analysis with the assumption of an autosomal-dominant mode of inheritance has indicated a chromosome 9p24-22 (RLS-3) linkage to RLS in two large American families.[28] As with other common diseases, RLS may ultimately prove to have a polygenic basis and complex interactions of genes with environmental factors.

Because the general physical and neurologic examinations are usually normal in patients with RLS, these examinations are performed to identify secondary causes and rule out other disorders. Potentially reversible causes of RLS that are associated with iron deficiency include pregnancy, renal failure, and anemia. RLS affects up to 19% of women during pregnancy; symptoms usually subside within a few weeks postpartum.[29] In patients with hereditary RLS, symptoms frequently worsen during pregnancy.[5] Fifty percent of patients with end-stage renal failure develop RLS that may improve after liver transplantation.[30]

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