Causes of Restless Legs Syndrome
Restless legs syndrome is classified as either primary (idiopathic) with a genetic basis, or secondary due to iron deficiency states including iron-deficiency anemia, end-stage renal disease, and pregnancy. 1
Primary (Idiopathic) RLS
Primary RLS develops at an earlier age, has no identifiable associated conditions, and has a strong genetic component. First and second-degree relatives of patients with idiopathic RLS have a significantly increased risk of developing RLS compared with matched controls. 1 Genetic variants on chromosomes 6p21.2, 9p, 12q, and 14q have been identified that increase RLS risk 1, 2.
The underlying pathophysiology involves impaired dopamine transport in the substantia nigra due to reduced intracellular iron, which appears to play a critical role in most patients 1. The spinal cord, peripheral nerves, and central dopamine and narcotic receptors are also involved 1.
Secondary RLS
Secondary RLS results from medical conditions that share iron deficiency as a common pathway 1:
Medical Conditions with High RLS Prevalence:
- End-stage renal disease: 24% 3
- Iron deficiency anemia: 23.9% 3
- Pregnancy (especially third trimester): 22% 3
- Peripheral neuropathy (diabetic, idiopathic): 21.5% 3
- Parkinson disease: 20% 3
- Multiple sclerosis: 27.5% 3
Iron deficiency becomes progressively more common with later age of symptom onset: present in 22% of patients with onset before age 50,39% with onset at 50-64 years, and 58% in those with onset after age 64 4. Conversely, family history becomes less common with increasing age of onset 4.
Medication-Induced RLS
Several medications exacerbate or trigger RLS 1:
- Tricyclic antidepressants
- SSRIs (serotonergic antidepressants)
- Lithium
- Dopamine antagonists (antipsychotics)
- Centrally acting H1 antihistamines (e.g., diphenhydramine) 3
Lifestyle and Risk Factors
Additional contributing factors include 1:
- Increased body mass index (BMI)
- Caffeine intake
- Sedentary lifestyle
- Tobacco use
- Lower socioeconomic status
- Female sex (2:1 ratio vs. males) 3
- Northern European descent 3
- Older age (prevalence of 10% in adults ≥65 years) 3
Clinical Pitfall
Check serum ferritin in all RLS patients—values less than 50 ng/mL are consistent with RLS diagnosis and indicate need for iron supplementation 1. However, most RLS patients have normal serum ferritin levels despite reduced cerebrospinal fluid ferritin and transferrin, suggesting central nervous system iron deficiency despite normal peripheral iron stores 5, 6. This explains why iron supplementation is recommended for ferritin ≤100 ng/mL or transferrin saturation <20% in RLS patients 3.
The relationship between dopaminergic dysfunction and iron deficiency likely involves iron's necessity for tyrosine hydroxylase activity, the rate-limiting step in dopamine synthesis, though the exact mechanism remains unclear 5.