Pathophysiology of restless legs syndrome: Evidence for iron involvement

Current Neurology and Neuroscience Reports

Volumn 8, Issue 2, 2008, Pages 162-166

  Connor, James R ^a  

^a PENN STATE MILTON S HERSHEY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 O METHYLDOPA; BIOLOGICAL MARKER; DOPAMINE; DOPAMINE 2 RECEPTOR; FERRITIN; FERROPORTIN; HEPCIDIN; IRON; IRON REGULATORY FACTOR; NEUROMELANIN; TETRAHYDROBIOPTERIN; TRANSFERRIN;

AUTOPSY; CEREBROSPINAL FLUID ANALYSIS; DEMYELINATION; DIAGNOSTIC VALUE; DISEASE ASSOCIATION; DISEASE SEVERITY; DOPAMINERGIC SYSTEM; DOPPLER ECHOGRAPHY; FERRITIN BLOOD LEVEL; HEMOCHROMATOSIS; HUMAN; IMAGE ANALYSIS; IMMUNOHISTOCHEMISTRY; IRON DEFICIENCY ANEMIA; NEUROIMAGING; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOPHYSIOLOGY; POSITRON EMISSION TOMOGRAPHY; PROGNOSIS; PROTEIN ANALYSIS; PROTEIN EXPRESSION; QUANTITATIVE ANALYSIS; RESTLESS LEGS SYNDROME; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; SUBSTANTIA NIGRA; TRANSFERRIN BLOOD LEVEL;

ANEMIA, IRON-DEFICIENCY; ANIMALS; HUMANS; IRON; RESTLESS LEGS SYNDROME;

EID: 41549095416     PISSN: 15284042     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11910-008-0026-x     Document Type: Review

References (48)

1. Allen RP, Picchietti D, Hening WA, et al.: 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 2003, 4:101-119.
2. Ekbom KA: Restless legs syndrome. Neurology 1960, 10:868-873.
3. Nordlander NB: Therapy in restless legs. Acta Med Scand 1953, 145:453-457.
4. Sun ER, Chen CA, Ho G, et al.: Iron and the restless legs syndrome. Sleep 1998, 21:371-377.
5. O'Keeffe ST, Gavin K, Lavan JN: Iron status and restless legs syndrome in the elderly. Age Ageing 1994, 23:200-203.
6. Trenkwalder C, Högl B, Benes H, Kohnen R: Augmentation in restless legs syndrome is associated with low ferritin. Sleep Med 2007 [Epub ahead of print].
7. Earley CJ, Heckler D, Horská A, et al.: The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 2004, 5:231-235.
8. Beard JL, Connor JR: Iron status and neural functioning. Annu Rev Nutr 2003, 23:41-58.
9. Hening WA, Allen RP, Earley CJ, et al.: An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004, 27:560-583.
10. Ortiz E, Pasquini JM, Thompson K, et al.: Effect of manipulation of iron storage, transport or availability on myelin composition and brain iron content in three different animal models. J Neurosci Res 2004, 77:681-689.
11. Allen RP, Barker PB, Wehrl F, et al.: MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001, 56:263-265.
12. Schmidauer C, Sojer M, Septti K, et al.: Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol 2005, 58:630-634.
13. Lee BY, Farace E, Wang J, et al.: In vivo measurement of iron deficiency in RLS with voxel-based MRI relaxometry. Neurology 2007, 68(Suppl 1):A356.
14. Turjanski N, Lees AJ, Brooks DJ: Striatal dopaminergic function in restless legs syndrome: 18F-dopa and 11C-raclopride PET studies. Neurology 1999, 52:932-937.
15. Trenkwalder C, Walters AS, Hening WA, et al.: Positron emission tomographic studies in restless legs syndrome. Mov Disord 1999, 14:141-145.
16. Michaud M, Soucy JP, Chabli A, et al.: SPECT imaging of striatal pre- and postsynaptic dopaminergic status in restless legs syndrome with periodic leg movements in sleep. J Neurol 2002, 249:164-170.
17. Nelson C, Erikson K, Pinero DJ, Beard JL: In vivo dopamine metabolism is altered in iron-deficient anemic rats. J Nutr 1997, 127:2282-2288.
18. Erikson KM, Jones BC, Beard JL: Iron deficiency alters dopamine transporter functioning in rat striatum. J Nutr 2000, 130:2831-2837.
19. Earley CJ, Connor JR, Beard JL, et al.: Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000, 54:1698-1700.
20. Mizuno S, Mihara T, Miyaoka T, et al.: CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 2005, 14:43-47.
21. Earley CJ, Connor JR, Beard JL, et al.: Ferritin levels in the cerebrospinal fluid and restless legs syndrome: effects of different clinical phenotypes. Sleep 2005, 28:1069-1075.
22. Clardy SL, Wang X, Boyer PJ, et al.: Is ferroportin-hepcidin signaling altered in restless legs syndrome? J Neurol Sci 2006, 247:173-179.
23. Long WI, Lönnerdal B: Hepcidin, the recently identified peptide that appears to regulate iron absorption. J Nutr 2004, 134:1-4.
24. Tsutsumi M, Skinner MK, Sanders-Bush E: Transferrin gene expression and synthesis by cultured choroid plexus epithelial cells. Regulation by serotonin and cyclic adenosine 3′,5′-monophosphate. J Biol Chem 1989, 5:9626-9631.
25. Geguchadze RN, Coe CL, Lubach GR, et al.: CSF proteomic analysis reveals persistent iron deficiency-induced alterations in nonhuman primate infants. J Neurochem 2007, In press.
26. Allen RP, Connor JR, Earley CJ: Abnormally increased CSF 3-ortho-methyldopa (3OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease. Sleep Med 2007, In press.
27. Minami M, Takahashi T, Maruyama W, et al.: Allosteric effect of tetrahydrobiopterin cofactors on tyrosine hydroxylase activity. Life Sci 1992, 50:15-20.
28. Connor JR, Boyer PJ, Menzies SL, et al.: Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003, 61:304-309.
29. Pittock SJ, Parrett T, Adler CH, et al.: Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. Mov Disord 2004, 19:695-699.
30. Connor JR, Wang XS, Patton SM, et al.: Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 2004, 62:1563-1567.
31. Aisen P, Enns C, Wessling-Resnick M: Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 2001, 33:940-959.
32. Ondo WG, He Y, Rajasekaran S, Le WD: Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 2000, 15:154-158.
33. Qu S, Le W, Zhang X, et al.: Locomotion is increased in A11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome. J Neuropathol Exp Neurol 2007, 66:383-388.
34. Frauscher B, Löscher W, Högl B, et al.: Auditory startle reaction is disinhibited in idiopathic restless legs syndrome. Sleep 2007, 30:489-493.
35. Quatrale R, Manconi M, Gastaldo E, et al.: Neurophysiological study of corticomotor pathways in restless legs syndrome. Clin Neurophysiol 2003, 114:1638-1645.
36. Morris R: Thy-1 in developing nervous tissue. Dev Neurosci 1985, 7:133-160.
37. Ye Z, Connor JR: Identification of iron responsive genes by screening cDNA libraries from suppression subtractive hybridization with antisense probes from three iron conditions. Nucleic Acids Res 2000, 28:1802-1807.
38. Jeng CJ, McCarroll SA, Martin TF, et al.: Thy-1 is a component common to multiple populations of synaptic vesicles. J Cell Biol 1998, 140:685-698.
39. Wang X, Wiesinger J, Beard J, et al.: Thy1 expression in the brain is affected by iron and is decreased in restless legs syndrome. J Neurol Sci 2004, 220:59-66.
40. Winkelmann J, Schormair B, Lichtner P, et al.: Genomewide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007, 39:1000-1006.
41. Stefansson H, Rye DB, Hicks A, et al.: A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007, 357:639-647.
42. Jones LC, McCarthy KA, Beard JL, et al.: Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice. Nutr Neurosci 2006, 9:81-92.
43. Clardy SL, Wang X, Zhao W, et al.: Acute and chronic effects of developmental iron deficiency on nRNA expression patterns in the brain. J Neural Transm Suppl 2006, 71:173-196.
44. McEchron MD, Smith ME, Goletiani J, et al.: Impaired dopaminergic modulation of corticostriatal synaptic transmission in the Thy-1 knockout mouse: a model for restless legs syndrome? Soc Neurosci 2007, Abstract #622.10.
45. Beard JL, Erikson KM, Jones BC: Neurobehavioral analysis of developmental iron deficiency in rats. Behav Brain Res 2002, 134:517-524.
46. Burdo JR, Connor JR: Brain iron uptake and homeostatic mechanisms: an overview. BioMetals 2003, 16:63-75.
47. Dale JC, Burritt MF, Zinsmeister AR: Diurnal variation of serum iron, iron-binding capacity, transferrin saturation, and ferritin levels. Am J Clin Pathol 2002, 117:802-808.
48. Carmena AO, Portuondo H, Callejas J, Alvarez ME: Ferrokinetic circadian rhythm in normal subjects. Haematologia (Budapest) 1976, 10:179-184.