Restless Legs Syndrome: Causes

Pathogenesis (disease development)

One can distinguish a primary (genetic disposition) from a secondary (symptomatic) form of restless legs syndrome (RLS).The pathogenesis probably lies in a disorder in the area of neurotransmitters, especially in the area of dopamine (biogenic amine from the group of catecholamines; neurotransmitter). Furthermore, a disturbance of the iron metabolism is the cause. Functional impairments in the endogenous opioid system are also discussed.

Apparently, there is also a peripheral component in the pathogenesis: a lack of oxygen in the microvessels of the legs has been found in RLS patients; nicely, the more severe the RLS, the more severe the hypoxia (lack of oxygen supply to the tissue). Increased excitability of peripheral motor neurons in RLS also appears to play a role. The symptomatic form of RLS is often associated with the comorbidity (concomitant disease) of iron deficiency; the presence of gravidity (pregnancy) is also typical.

Etiology (causes)

Biographic causes

• Genetic burden – genetic disposition is now considered proven/approximately half of the diseases occur in families; the first degree of relationship is affected
  • In the case that three of the known genomic regions are detectable, the risk of RLS increases by 50%.
  • In a genome-wide association study (GWAS), an additional 19 gene variants were found to increase the risk of restless legs syndrome – these explained 60% of the heritability (inheritability), which was only about 20% in the cohorts studied
  • Genetic risk dependent on gene polymorphisms:
    • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
      • Genes: BTBD9, MEIS1, PTPRD.
      • SNP: rs2300478 in the MEIS1 gene.
        • Allele constellation: GT (1.7-fold).
        • Allele constellation: GG (> 1.7-fold)
      • SNP: rs1975197 in the PTPRD gene.
        • Allele constellation: CT (1.3-fold).
        • Allele constellation: TT (> 1.3-fold)
      • SNP: rs3923809 in the BTBD9 gene.
        • Allele constellation: AG (0.57-fold).
        • Allele constellation: GG (0.32-fold)

Behavioral causes

• Nutrition
  • Micronutrient deficiency (vital substances) – iron deficiency; see Prevention with micronutrients.
• Pleasure food consumption
  • Alcohol
  • Coffee
  • Tobacco (smoking)
• Drug use
  • Opiates – powerful painkillers such as morphine.
• Sleep deprivation – this can have an acute exacerbating effect on restless legs syndrome

Disease-related causes

• Endocrine diseases
• Neurological diseases such as polyneuropathies (diseases of peripheral nerves), motoneuron diseases (group of diseases affecting motoneurons. Motoneurons are nerve cells of the central nervous system that use their axon to exert direct or indirect control over a muscle), myelopathies (diseases of the spinal cord), Parkinson’s disease
• Renal insufficiency (kidney weakness).
• Rheumatoid arthritis
• Disorders of the iron store ferritin
• Uremia (occurrence of urinary substances in the blood above normal values).

Medication

• Antidepressants (drugs for depression) – esp. selective serotonin reuptake inhibitors (SSRIs); tri- and tetracyclic antidepressants.
• Antipsychotics (neuroleptics/nerve depressants) that act antagonistically at the dopamine D2 receptor.
• Β-Sympathomimetics (asthma therapy).
• Lithium
• Metoclopramide (antiemetic/anti-nausea medication).
• Mirtazapine (may cause exacerbation/aggravation of RLS).
• Steroids?

Other causes

• Spinal anesthesia
• Pregnancy