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Iron, dopamine, genetics, and hormones in the pathophysiology of restless legs syndrome

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Abstract

Restless legs syndrome (RLS) is a common, chronic neurologic condition, which causes a persistent urge to move the legs in the evening that interferes with sleep. Human and animal studies have been used to study the pathophysiologic state of RLS and much has been learned about the iron and dopamine systems in relation to RLS. Human neuropathologic and imaging studies have consistently shown decreased iron in different brain regions including substantia nigra and thalamus. These same areas also demonstrate a state of relative dopamine excess. While it is not known how these changes in dopamine or iron produce the symptoms of RLS, genetic and hormone studies of RLS have identified other biologic systems or genes, such as the endogenous opioid and melanocortin systems and BTBD9 and MEIS1, that may explain some of the iron or dopamine changes in relation to RLS. This manuscript will review what is known about the pathophysiology of RLS, especially as it relates to changes in iron, dopamine, genetics, and hormonal systems.

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References

  1. Earley CJ, Silber MH (2010) Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med 11:807–815

    Article  PubMed  Google Scholar 

  2. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, Ferini-Strambi L (2005) Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 165:1286–1292

    Article  PubMed  Google Scholar 

  3. Ghorayeb I, Tison F (2009) Epidemiology of restless legs syndrome. Rev Neurol 165:641–649

    Article  CAS  PubMed  Google Scholar 

  4. Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, Zucconi M, Ferri R, Trenkwalder C, Lee HB (2014) Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med 15:860–873

    Article  PubMed  Google Scholar 

  5. Whittom S, Dauvilliers Y, Pennestri MH, Vercauteren F, Molinari N, Petit D, Montplaisir J (2007) Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep Med 9:54–59

    Article  CAS  PubMed  Google Scholar 

  6. Winkelmann J, Polo O, Provini F, Nevsimalova S, Kemlink D, Sonka K, Hogl B, Poewe W, Stiasny-Kolster K, Oertel W, de Weerd A, Strambi LF, Zucconi M, Pramstaller PP, Arnulf I, Trenkwalder C, Klein C, Hadjigeorgiou GM, Happe S, Rye D, Montagna P (2007) Genetics of restless legs syndrome (RLS): state-of-the-art and future directions. Mov Disord 22(Suppl 18):S449–S458

    Article  PubMed  Google Scholar 

  7. Moccia M, Erro R, Picillo M, Santangelo G, Spina E, Allocca R, Longo K, Amboni M, Palladino R, Assante R, Pappata S, Pellecchia MT, Barone P, Vitale C (2016) A four-year longitudinal study on restless legs syndrome in Parkinson disease. Sleep 39:405–412

    Article  PubMed  PubMed Central  Google Scholar 

  8. Trenkwalder C, Winkelmann J, Inoue Y, Paulus W (2015) Restless legs syndrome-current therapies and management of augmentation. Nat Rev Neurol 11:434–445

    Article  PubMed  Google Scholar 

  9. Nordlander NB (1953) Therapy in restless legs. Acta Med Scand 145:453–457

    CAS  PubMed  Google Scholar 

  10. Beard J (2003) Iron deficiency alters brain development and functioning. J Nutr 133:1468s–1472s

    CAS  PubMed  Google Scholar 

  11. Sadrzadeh SM, Saffari Y (2004) Iron and brain disorders. Am J Clin Pathol 121(Suppl):S64–S70

    PubMed  Google Scholar 

  12. Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, Mollica G, Ferini-Strambi L, Granieri E (2004) Restless legs syndrome and pregnancy. Neurology 63:1065–1069

    Article  CAS  PubMed  Google Scholar 

  13. Winkelman JW, Chertow GM, Lazarus JM (1996) Restless legs syndrome in end-stage renal disease. Am J Kidney Dis 28:372–378

    Article  CAS  PubMed  Google Scholar 

  14. Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ (2013) The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 88:261–264

    Article  PubMed  Google Scholar 

  15. Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rucker L, Poewe W, Hogl B (2009) The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 10:611–615

    Article  PubMed  Google Scholar 

  16. Allen RP, Barker PB, Wehrl FW, Song HK, Earley CJ (2001) MRI measurement of brain iron in patients with restless legs syndrome. Neurology 56:263–265

    Article  CAS  PubMed  Google Scholar 

  17. Earley CJ, Barker PB, Horská A, Allen RP (2006) MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med 7:458–461

    Article  PubMed  Google Scholar 

  18. Godau J, Klose U, Di Santo A, Schweitzer K, Berg D (2008) Multiregional brain iron deficiency in restless legs syndrome. Mov Disord 23:1184–1187

    Article  PubMed  Google Scholar 

  19. Nie G, Sheftel AD, Kim SF, Ponka P (2005) Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105:2161–2167

    Article  CAS  PubMed  Google Scholar 

  20. Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ (2003) Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61:304–309

    Article  CAS  PubMed  Google Scholar 

  21. Connor JR, Wang XS, Patton SM, Menzies SL, Troncoso JC, Earley CJ, Allen RP (2004) Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 62:1563–1567

    Article  CAS  PubMed  Google Scholar 

  22. Clardy SL, Earley CJ, Allen RP, Beard JL, Connor JR (2006) Ferritin subunits in CSF are decreased in restless legs syndrome. J Lab Clin Med 147:67–73

    Article  CAS  PubMed  Google Scholar 

  23. Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP (2000) Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 54:1698–1700

    Article  CAS  PubMed  Google Scholar 

  24. Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J (2005) CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 14:43–47

    Article  PubMed  Google Scholar 

  25. Dean T Jr, Allen RP, O’Donnell CP, Earley CJ (2006) The effects of dietary iron deprivation on murine circadian sleep architecture. Sleep Med 7:634–640

    Article  PubMed  Google Scholar 

  26. Unger EL, Earley CJ, Beard JL (2009) Diurnal cycle influences peripheral and brain iron levels in mice. J Appl Physiol (Bethesda, Md: 1985) 106:187–193

    Article  Google Scholar 

  27. Patton SM, Ponnuru P, Snyder AM, Podskalny GD, Connor JR (2011) Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol 18:1329–1335

    Article  CAS  PubMed  Google Scholar 

  28. Bunn HF, Poyton RO (1996) Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76:839–885

    CAS  PubMed  Google Scholar 

  29. Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274:24147–24152

    Article  CAS  PubMed  Google Scholar 

  30. Connor JR, Ponnuru P, Lee BY, Podskalny GD, Alam S, Allen RP, Earley CJ, Yang QX (2011) Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome. Sleep Med 12:614–619

    Article  PubMed  PubMed Central  Google Scholar 

  31. Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ (2011) Profile of altered brain iron acquisition in restless legs syndrome. Brain 134:959–968

    Article  PubMed  PubMed Central  Google Scholar 

  32. Earley CJ, Ponnuru P, Wang X, Patton SM, Conner JR, Beard JL, Taub DD, Allen RP (2008) Altered iron metabolism in lymphocytes from subjects with restless legs syndrome. Sleep 31:847–852

    Article  PubMed  PubMed Central  Google Scholar 

  33. Erikson KM, Jones BC, Beard JL (2000) Iron deficiency alters dopamine transporter functioning in rat striatum. J Nutr 130:2831–2837

    CAS  PubMed  Google Scholar 

  34. Bruenger FW, Stover BJ, Atherton DR (1967) The incorporation of various metal ions into in vivo- and in vitro-produced melanin. Radiat Res 32:1–12

    Article  CAS  PubMed  Google Scholar 

  35. Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74:199–205

    Article  CAS  PubMed  Google Scholar 

  36. Dowling P, Klinker F, Stadelmann C, Hasan K, Paulus W, Liebetanz D (2011) Dopamine D3 receptor specifically modulates motor and sensory symptoms in iron-deficient mice. J Neurosci 31:70–77

    Article  CAS  PubMed  Google Scholar 

  37. Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, Earley CJ (2009) Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 132:2403–2412

    Article  PubMed  PubMed Central  Google Scholar 

  38. Beard JL, Chen Q, Connor J, Jones BC (1994) Altered monamine metabolism in caudate-putamen of iron-deficient rats. Pharmacol Biochem Behav 48:621–624

    Article  CAS  PubMed  Google Scholar 

  39. Bianco LE, Wiesinger J, Earley CJ, Jones BC, Beard JL (2008) Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats. J Neurochem 106:205–215

    Article  CAS  PubMed  Google Scholar 

  40. Ashkenazi R, Ben-Shachar D, Youdim MB (1982) Nutritional iron and dopamine binding sites in the rat brain. Pharmacol Biochem Behav 17(Suppl 1):43–47

    Article  CAS  PubMed  Google Scholar 

  41. Erikson KM, Jones BC, Hess EJ, Zhang Q, Beard JL (2001) Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav 69:409–418

    Article  CAS  PubMed  Google Scholar 

  42. Unger EL, Wiesinger JA, Hao L, Beard JL (2008) Dopamine D2 receptor expression is altered by changes in cellular iron levels in PC12 cells and rat brain tissue. J Nutr 138:2487–2494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Unger EL, Bianco LE, Jones BC, Allen RP, Earley CJ (2014) Low brain iron effects and reversibility on striatal dopamine dynamics. Exp Neurol 261:462–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Montplaisir J, Godbout R, Boghen D, DeChamplain J, Young SN, Lapierre G (1985) Familial restless legs with periodic movements in sleep: electrophysiologic, biochemical, and pharmacologic study. Neurology 35:130–134

    Article  CAS  PubMed  Google Scholar 

  45. Allen RP, Connor JR, Hyland K, Earley CJ (2009) Abnormally increased CSF 3-ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis. Sleep Med 10:123–128

    Article  PubMed  Google Scholar 

  46. Earley CJ, Hyland K, Allen RP (2006) Circadian changes in CSF dopaminergic measures in restless legs syndrome. Sleep Med 7:263–268

    Article  PubMed  Google Scholar 

  47. Allen RP (2015) Restless leg syndrome/Willis-Ekbom disease pathophysiology. Sleep Med Clin 10:207–214

    Article  PubMed  PubMed Central  Google Scholar 

  48. Earley CJ, Connor J, Garcia-Borreguero D, Jenner P, Winkelman J, Zee PC, Allen R (2014) Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). Sleep Med 15:1288–1301

    Article  PubMed  Google Scholar 

  49. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J (2003) Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 4:101–119

    Article  PubMed  Google Scholar 

  50. Rye DB, Trotti LM (2012) Restless legs syndrome and periodic leg movements of sleep. Neurol Clin 30:1137–1166

    Article  PubMed  Google Scholar 

  51. Winkelman JW (2007) Periodic limb movements in sleep–endophenotype for restless legs syndrome? N Engl J Med 357:703–705

    Article  CAS  PubMed  Google Scholar 

  52. Lazzarini A, Walters AS, Hickey K, Coccagna G, Lugaresi E, Ehrenberg BL, Picchietti DL, Brin MF, Stenroos ES, Verrico T, Johnson WG (1999) Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord 14:111–116

    Article  CAS  PubMed  Google Scholar 

  53. Trenkwalder C, Seidel VC, Gasser T, Oertel WH (1996) Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 11:389–394

    Article  CAS  PubMed  Google Scholar 

  54. Pichler I, Hicks AA, Pramstaller PP (2008) Restless legs syndrome: an update on genetics and future perspectives. Clin Genet 73:297–305

    Article  CAS  PubMed  Google Scholar 

  55. Winkelmann J (2008) Genetics of restless legs syndrome. Curr Neurol Neurosci Rep 8:211–216

    Article  CAS  PubMed  Google Scholar 

  56. Ht Moore, Winkelmann J, Lin L, Finn L, Peppard P, Mignot E (2014) Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Sleep 37:1535–1542

    Article  Google Scholar 

  57. Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P, Ripke S, Trenkwalder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Hogl B, Frauscher B, Gschliesser V, Poewe W, Peglau I, Vodicka P, Vavrova J, Sonka K, Nevsimalova S, Montplaisir J, Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE, Holsboer F, Muller-Myhsok B, Meitinger T, Winkelmann J (2008) PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 40:946–948

    Article  CAS  PubMed  Google Scholar 

  58. Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, Palsson S, Sigmundsson T, Sigurdsson AP, Eiriksdottir I, Soebech E, Bliwise D, Beck JM, Rosen A, Waddy S, Trotti LM, Iranzo A, Thambisetty M, Hardarson GA, Kristjansson K, Gudmundsson LJ, Thorsteinsdottir U, Kong A, Gulcher JR, Gudbjartsson D, Stefansson K (2007) A genetic risk factor for periodic limb movements in sleep. N Engl J Med 357:639–647

    Article  CAS  PubMed  Google Scholar 

  59. Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, Fulda S, Putz B, Eckstein G, Hauk S, Trenkwalder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Peglau I, Eisensehr I, Montplaisir J, Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE, Holsboer F, Muller-Myhsok B, Meitinger T (2007) Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 39:1000–1006

    Article  CAS  PubMed  Google Scholar 

  60. Yang Q, Li L, Chen Q, Foldvary-Schaefer N, Ondo WG, Wang QK (2011) Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. Sleep Med 12:800–804

    Article  PubMed  PubMed Central  Google Scholar 

  61. Birinyi PV, Allen RP, Hening W, Washburn T, Lesage S, Earley CJ (2006) Undiagnosed individuals with first-degree relatives with restless legs syndrome have increased periodic limb movements. Sleep Med 7:480–485

    Article  PubMed  Google Scholar 

  62. Kemlink D, Polo O, Frauscher B, Gschliesser V, Hogl B, Poewe W, Vodicka P, Vavrova J, Sonka K, Nevsimalova S, Schormair B, Lichtner P, Silander K, Peltonen L, Gieger C, Wichmann HE, Zimprich A, Roeske D, Muller-Myhsok B, Meitinger T, Winkelmann J (2009) Replication of restless legs syndrome loci in three European populations. J Med Genet 46:315–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Stogios PJ, Downs GS, Jauhal JJ, Nandra SK, Prive GG (2005) Sequence and structural analysis of BTB domain proteins. Genome Biol 6:R82

    Article  PubMed  PubMed Central  Google Scholar 

  64. DeAndrade MP, Johnson RL Jr, Unger EL, Zhang L, van Groen T, Gamble KL, Li Y (2012) Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Hum Mol Genet 21:3984–3992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Freeman A, Pranski E, Miller RD, Radmard S, Bernhard D, Jinnah HA, Betarbet R, Rye DB, Sanyal S (2012) Sleep fragmentation and motor restlessness in a Drosophila model of restless legs syndrome. Curr Biol 22:1142–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hashimoto Y, Muramatsu K, Kunii M, Yoshimura S, Yamada M, Sato T, Ishida Y, Harada R, Harada A (2012) Uncovering genes required for neuronal morphology by morphology-based gene trap screening with a revertible retrovirus vector. FASEB J 26:4662–4674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rye DB (2015) The molecular genetics of restless legs syndrome. Sleep Med Clin 10:227–233

    Article  PubMed  Google Scholar 

  68. Argiropoulos B, Yung E, Humphries RK (2007) Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis. Genes Dev 21:2845–2849

    Article  CAS  PubMed  Google Scholar 

  69. Azcoitia V, Aracil M, Martinez AC, Torres M (2005) The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol 280:307–320

    Article  CAS  PubMed  Google Scholar 

  70. Minehata K, Kawahara A, Suzuki T (2008) meis1 regulates the development of endothelial cells in zebrafish. Biochem Biophys Res Commun 374:647–652

    Article  CAS  PubMed  Google Scholar 

  71. Davidson S, Miller KA, Dowell A, Gildea A, Mackenzie A (2006) A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P. Mol Psychiatry 11(323):410

    Article  CAS  Google Scholar 

  72. Catoire H, Dion PA, Xiong L, Amari M, Gaudet R, Girard SL, Noreau A, Gaspar C, Turecki G, Montplaisir JY, Parker JA, Rouleau GA (2011) Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Ann Neurol 70:170–175

    Article  PubMed  Google Scholar 

  73. Dinev D, Jordan BW, Neufeld B, Lee JD, Lindemann D, Rapp UR, Ludwig S (2001) Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. EMBO Rep 2:829–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cavanaugh JE, Jaumotte JD, Lakoski JM, Zigmond MJ (2006) Neuroprotective role of ERK1/2 and ERK5 in a dopaminergic cell line under basal conditions and in response to oxidative stress. J Neurosci Res 84:1367–1375

    Article  CAS  PubMed  Google Scholar 

  75. Arndt S, Poser I, Moser M, Bosserhoff AK (2007) Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling. Mol Cell Neurosci 34:603–611

    Article  CAS  PubMed  Google Scholar 

  76. Pulido R, Krueger NX, Serra-Pages C, Saito H, Streuli M (1995) Molecular characterization of the human transmembrane protein-tyrosine phosphatase delta. Evidence for tissue-specific expression of alternative human transmembrane protein-tyrosine phosphatase delta isoforms. J Biol Chem 270:6722–6728

    Article  CAS  PubMed  Google Scholar 

  77. O’Flaherty E, Kaye J (2003) TOX defines a conserved subfamily of HMG-box proteins. BMC Genom 4:13

    Article  Google Scholar 

  78. Dauvilliers Y, Winkelmann J (2013) Restless legs syndrome: update on pathogenesis. Curr Opin Pulm Med 19:594–600

    Article  CAS  PubMed  Google Scholar 

  79. Wetter TC, Collado-Seidel V, Oertel H, Uhr M, Yassouridis A, Trenkwalder C (2002) Endocrine rhythms in patients with restless legs syndrome. J Neurol 249:146–151

    Article  CAS  PubMed  Google Scholar 

  80. Garcia-Borreguero D, Larrosa O, Granizo JJ, de la Llave Y, Hening WA (2004) Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome. Sleep 27:669–673

    PubMed  Google Scholar 

  81. Lee KA, Zaffke ME, Baratte-Beebe K (2001) Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J Womens Health Gend-Based Med 10:335–341

    Article  CAS  PubMed  Google Scholar 

  82. Dzaja A, Wehrle R, Lancel M, Pollmacher T (2009) Elevated estradiol plasma levels in women with restless legs during pregnancy. Sleep 32:169–174

    Article  PubMed  PubMed Central  Google Scholar 

  83. Budhiraja P, Budhiraja R, Goodwin JL, Allen RP, Newman AB, Koo BB, Quan SF (2012) Incidence of restless legs syndrome and its correlates. J Clin Sleep Med 8:119–124

    PubMed  PubMed Central  Google Scholar 

  84. Lattova Z, Keckeis M, Maurovich-Horvat E, Wetter TC, Wilde-Frenz J, Schuld A, Pollmacher T (2011) The stress hormone system in various sleep disorders. J Psychiatr Res 45:1223–1228

    PubMed  Google Scholar 

  85. Hornyak M, Rupp A, Riemann D, Feige B, Berger M, Voderholzer U (2008) Low-dose hydrocortisone in the evening modulates symptom severity in restless legs syndrome. Neurology 70:1620–1622

    Article  CAS  PubMed  Google Scholar 

  86. Koo BB, Feng P, Dostal J, Strohl KP (2008) Alpha-melanocyte stimulating hormone and adrenocorticotropic hormone: an alternative approach when thinking about restless legs syndrome? Mov Disord 23:1234–1242

    Article  PubMed  Google Scholar 

  87. Walters AS, Ondo WG, Zhu W, Le W (2009) Does the endogenous opiate system play a role in the restless legs syndrome? A pilot post-mortem study. J Neurol Sci 279:62–65

    Article  CAS  PubMed  Google Scholar 

  88. von Spiczak S, Whone AL, Hammers A, Asselin MC, Turkheimer F, Tings T, Happe S, Paulus W, Trenkwalder C, Brooks DJ (2005) The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study. Brain 128:906–917

    Article  Google Scholar 

  89. Dutia R, Meece K, Dighe S, Kim AJ, Wardlaw SL (2012) Beta-endorphin antagonizes the effects of alpha-MSH on food intake and body weight. Endocrinology 153:4246–4255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ukai M, Kameyama T (1984) Nonopiate effects of alpha-neo-endorphin on mouse behavior using multi-dimensional behavioral analyses. Peptides 5:129–131

    Article  CAS  PubMed  Google Scholar 

  91. Williams DW Jr, Lipton JM, Giesecke AH Jr (1986) Influence of centrally administered peptides on ear withdrawal from heat in the rabbit. Peptides 7:1095–1100

    Article  CAS  PubMed  Google Scholar 

  92. Kastin AJ, Schally AV, Kostrzewa RM (1980) Possible aminergic mediation of MSH release and of the CNS effects of MSH and MIF-I. Fed Proc 39:2931–2936

    CAS  PubMed  Google Scholar 

  93. Sharp B, Ross R, Levin E, Sowers J (1982) Dopamine regulates canine plasma beta-endorphin-immunoreactivity levels. Endocrinology 110:1828–1830

    Article  CAS  PubMed  Google Scholar 

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  1. Lippard Laboratory of Clinical Investigation, Division of Movement Disorders, Department of Neurology, Yale University School of Medicine, Room 710, West Haven VAMC, 950 Campbell Avenue, West Haven, CT, 06516, USA

    Farhan H. Khan, Christopher A. Chow, Divya R. Shah & Brian B. Koo

  2. Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    Caitlyn D. Ahlberg

  3. Connecticut Veterans Affairs Medical Center, 950 Campbell Avenue, West Haven, CT, 06516, USA

    Brian B. Koo

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  1. Farhan H. Khan
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Khan, F.H., Ahlberg, C.D., Chow, C.A. et al. Iron, dopamine, genetics, and hormones in the pathophysiology of restless legs syndrome. J Neurol 264, 1634–1641 (2017). https://doi.org/10.1007/s00415-017-8431-1

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