Aetiology
The aetiology is not fully understood, but dopamine and iron have been associated with RLS.
Primary RLS often occurs in a familial pattern with strong penetrance and is thought to follow an autosomal-dominant inheritance in many families.[4] However, linkage and genome-wide studies suggest a more complex pattern. Several different gene loci have been associated with RLS, but no specific gene mutations have been identified.[5] Patients with familial RLS show an earlier onset of the disease compared with those with sporadic RLS.[6]
Factors associated with secondary RLS are iron deficiency, pregnancy, uraemia, and renal dialysis.[6][13][14][15][16]
An estimated 26% of pregnant women develop RLS symptoms, primarily during the third trimester.[17] In most cases it disappears in the month after delivery.[6] Transient RLS during pregnancy confers an approximately fourfold increased risk of developing chronic RLS.[6] Other possible conditions associated with RLS are obesity, diabetes, multiple sclerosis, Parkinson's disease, and neuropathy.[3][18][19][20]
Pathophysiology
It is suggested, although not yet demonstrated, that dopamine follows the circadian rhythm; hence, symptoms of RLS often occur in the evening. Conditions that decrease iron stores, such as iron deficiency, end-stage renal disease, and pregnancy, often initiate symptoms or worsen existing symptoms. Iron and dopamine are related because the rate-limiting step of dopamine synthesis, tyrosine hydroxylase, requires iron.[21]
Anti-parkinsonian drugs have been known to alleviate the symptoms of RLS. Patients with conditions known to decrease circulating iron have been successfully treated with iron supplementation.
Classification
Primary and secondary RLS
Primary RLS and secondary RLS typically have different ages of onset, rates of disease progression, and initial treatments.[3]
Primary RLS often occurs in a familial pattern with strong penetrance and is thought to follow an autosomal-dominant inheritance in many families.[4] However, linkage and genome-wide studies suggest a more complex pattern. Several different gene loci have been associated with RLS, but no specific gene mutations have been identified.[5] Patients with familial RLS show an earlier onset of the disease compared with those with sporadic RLS.[6]
Secondary RLS can occur due to iron deficiency, pregnancy, and renal insufficiency (usually in patients receiving haemodialysis). It can remit after the resolution of these states.[7]
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