Etiology and risk factors for Restless Leg Syndrome (RLS)
There is increasing evidence of a genetic predisposition with Restless Legs Syndrome (RLS),31 especially in early-onset RLS (i.e., before age 40 - 45).32 33 In about 50% of cases, RLS is thought to be genetic.34
A central dopaminergic dysfunction is also thought to be a contributing factor in primary RLS.35 36 Brain iron deficiency — even with normal peripheral iron — is a well-documented biological abnormality of RLS and is considered to be a major cause of the disorder.37 38 39
RLS can also be induced or worsened by certain conditions, such as iron-deficiency anemia, end-stage renal disease, pregnancy, low-density lipoprotein apheresis, and gastric surgery.40 People who smoke, are obese, or not physically active are also more likely to experience RLS.41 Some medications can make RLS worse, such as antidepressants, non-selective antihistamines, anti-psychotics, and anti-nausea medications.42
31 Desautels A, Turecki G, Montplaisir J, et al. Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity. Arch Neurol. 2005;62:591-596.
32 Allen R, Earley C. Defining the phenotype of the restless legs syndrome (RLS) using age-of-onset. Sleep Med. 2000;1:11-19.
33 Hening WA, Washburn T, Somel D, LeSage S, Allen RP, Earley CJ. RLS patients with a younger age of onset have a higher frequency of affected relatives [abstract]. Neurology. 2003;60(suppl1):S05.004.
34 Cleveland Clinic, Restless Leg Syndrome, Cleveland: Cleveland Clinic, 2015. Available online at: http://my.clevelandclinic.org/services/neurological_institute/sleep-disorders-center/disorders-conditions/hic-restless-legs-syndrome.
35 Stiasny-Kolster K, Trenkwalder C, Fogel W, et al. Restless legs syndrome—new insights into clinical characteristics, pathophysiology, and treatment options. J Neurol. 2004;251(suppl6):39-43.
36 Montplasir J, Allen RP, Walters A, Ferini-Strambi L, “Restless Legs Syndrome and Period Limb Movements During Sleep,” in Kryger M, Roth T, Dement W (ed.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, 2011, pages 1026 - 1037.
37 Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. Profile of altered brain iron acquisition in restless legs syndrome. Brain 2011;134:959-68.
38 Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med 2014.
39 Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord 2007;22:S440-S8
40 Montplasir J, Allen RP, Walters A, Ferini-Strambi L, “Restless Legs Syndrome and Period Limb Movements During Sleep,” in Kryger M, Roth T, Dement W (ed.), Principles and Practice of Sleep Medicine (5th Edition), St. Louis: Elsevier Saunders, 2011, pages 1026 - 1037.
41 Allen RP, Walters AS, Montplaisir J, et al. Restless Legs Syndrome Prevalence and Impact. REST General Population Study. Arch Intern Med. 2005;165:1286-1292.
42 Hoque, R., and Chesson, A., Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis, J. Clin Sleep Med;6(1):79-83, 2010.