Abstract
Introduction: Restless legs syndrome (RLS) is a neurological sensorimotor disorder with both sporadic and familial forms, the latter frequently associated with a genetic basis. Materials and methods: Four members of a family from Yarumal, Antioquia, with symptoms suggestive of restless legs syndrome, underwent a neurological evaluation, including a workup for secondary causes. The diagnosis was established by applying the clinical criteria proposed by the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), thereby ensuring greater diagnostic certainty. Additionally, a narrative review was conducted using Medline to explore the genetic component of restless legs syndrome.
Results: Genetic studies, including genome-wide association studies (GWAS) and whole-exome sequencing (WES), have identified several risk variants associated with restless legs syndrome. In vivo mouse and zebrafish models have elucidated the role of some variants in the neurobiology of this syndrome.
Conclusion: This is the first case report of a Colombian family with four documented members and two deceased members affected by restless legs syndrome across three generations. The family exhibits an autosomal dominant inheritance pattern, although with significant clinical variability. Despite its complexity, restless legs syndrome demonstrates a significant genetic component contributing to its familial aggregation.
References
Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Genetics of restless legs syndrome: An update. Sleep Med Rev. 2018;39:108-121. https://doi.org/10.1016/j.smrv.2017.08.002
Ferré S, García-Borreguero D, Allen RP, Earley CJ. New insights into the neurobiology of restless legs syndrome. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry. 2018;25(2):113-125. https://doi.org/10.1177/1073858418791763
Chenini S, Barateau L, Dauvilliers Y. Restless legs syndrome: From clinic to personalized medicine. Rev Neurol (Paris). 2023;179(7):703-714. https://doi.org/10.1016/j.neurol.2023.08.009
Manconi M, Garcia-Borreguero D, Schormair B, Videnovic A, Berger K, Ferri R, et al. Restless legs syndrome. Nat Rev Dis Primer. 2021;7(1):80. https://doi.org/10.1038/s41572-021-00311-z
Khan M. Restless legs syndrome and other common sleep-related movement disorders. Contin Minneap Minn. 2023;29(4):1130-1148. https://doi.org/10.1212/CON.0000000000001269
Picchietti DL, Van Den Eeden SK, Inoue Y, Berger K. Achievements, challenges, and future perspectives of epidemiologic research in restless legs syndrome (RLS). Sleep Med. 2017;31:3-9. https://doi.org/10.1016/j.sleep.2016.06.007
Franco Velez A, Marín Agudelo A, Aguirre D, Cornejo W, Lopera F. Prevalence of sleep disorders in Colombia: P02.010. Neurology. 2006;66(5):A77-8.
Calle López Y, Montes Gaviria MI, Toro Pérez ME. Síndrome de piernas inquietas o enfermedad de Willis Ekbom. Acta Neurol Colomb. 2016;32(4):347-356. https://doi.org/10.22379/24224022119
Whittom S, Dauvilliers Y, Pennestri MH, Vercauteren F, Molinari N, Petit D, et al. Age-at-onset in restless legs syndrome: A clinical and polysomnographic study. Sleep Med. 2007;9(1):54-59. https://doi.org/10.1016/j.sleep.2007.01.017
Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: A systematic review and new concept. Neurology. 2016;86(14):1336-1343. https://doi.org/10.1212/WNL.0000000000002542
Cesnik E, Casetta I, Turri M, Govoni V, Granieri E, Strambi LF, et al. Transient RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology. 2010;75(23):2117-2120. https://doi.org/10.1212/WNL.0b013e318200d779
Manconi M, Ulfberg J, Berger K, Ghorayeb I, Wesström J, Fulda S, et al. When gender matters: Restless legs syndrome. Report of the «RLS and woman» workshop endorsed by the European RLS Study Group. Sleep Med Rev. 2012;16(4):297-307. https://doi.org/10.1016/j.smrv.2011.08.006
Ekbom K. Restless legs. A clinical study of a hitherto overlooked disease in the legs characterized by peculiar paresthesia (“anxietas tibiarum”), pain and weakness and occurring in two main forms, asthenia crurum paraesthetica and asthenia crurum dolorosa. A short review of paresthesias in general. Acta Med Scand. 1945;158:1-123.
Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol. 2013;88(4):261-264. https://doi.org/10.1002/ajh.23397
Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology. 2000;54(8):1698-1700. https://doi.org/10.1212/WNL.54.8.1698
Allen RP, Barker PB, Wehrl FW, Song HK, Earley CJ. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56(2):263-265. https://doi.org/10.1212/WNL.56.2.263
Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61(3):304-309. https://doi.org/10.1212/01.WNL.0000078887.16593.12
Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. Profile of altered brain iron acquisition in restless legs syndrome. Brain J Neurol. 2011;134(4):959-968. https://doi.org/10.1093/brain/awr012
Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain J Neurol. 2009;132(9):2403-2412. https://doi.org/10.1093/brain/awp125
Earley CJ, Hyland K, Allen RP. Circadian changes in CSF dopaminergic measures in restless legs syndrome. Sleep Med. 2006;7(3):263-268. https://doi.org/10.1016/j.sleep.2005.09.006
Earley CJ, Connor J, Garcia-Borreguero D, Jenner P, Winkelman J, Zee PC, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom Disease). Sleep Med. 2014;15(11):1288-1301. https://doi.org/10.1016/j.sleep.2014.05.009
Jordan I, Murray D. Thalamic glutamate/glutamine in restless legs syndrome: Increased and related to disturbed sleep. Neurology. 2014;82(4):372-373. https://doi.org/10.1212/01.wnl.0000443817.83968.a7
Ferré S, Quiroz C, Guitart X, Rea W, Seyedian A, Moreno E, et al. Pivotal role of adenosine neurotransmission in restless legs syndrome. Front Neurosci. 2017;11:722. https://doi.org/10.3389/fnins.2017.00722
Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. 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. 2014;15(8):860-873. https://doi.org/10.1016/j.sleep.2014.03.025
Winkelman JW, Berkowski JA, DelRosso LM, Koo BB, Scharf MT, Sharon D, et al. Treatment of restless legs syndrome and periodic limb movement disorder: An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025:21(1):137-152. https://doi.org/10.5664/jcsm.11390
Petramfar P, Jankovic J. Medication refractory restless legs syndrome: Real-world experience. J Neurol Sci. 2024;463:123121. https://doi.org/10.1016/j.jns.2024.123121
Xiong L, Montplaisir J, Desautels A, Barhdadi A, Turecki G, Levchenko A, et al. Family study of restless legs syndrome in Quebec, Canada: Clinical characterization of 671 familial cases. Arch Neurol. 2010;67(5):617-622. https://doi.org/10.1001/archneurol.2010.67
Winkelmann J, Muller-Myhsok B, Wittchen HU, Hock B, Prager M, Pfister H, et al. Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families. Ann Neurol. 2002;52(3):297-302. https://doi.org/10.1002/ana.10282
Babacan-Yildiz G, Gürsoy E, Kolukisa M, Karaköse F, Akkoyunlu EM, Celebi A, et al. Clinical and polysomnographic features of a large Turkish pedigree with restless leg syndrome and periodic limb movements. Sleep Breath Schlaf Atm. 2013;17(2):741-746. https://doi.org/10.1007/s11325-012-0756-5
Ondo WG, Vuong KD, Wang Q. Restless legs syndrome in monozygotic twins: Clinical correlates. Neurology. 2000;55(9):1404-1406. https://doi.org/10.1212/WNL.55.9.1404
Desai AV, Cherkas LF, Spector TD, Williams AJ. Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: A twin study. Twin Res Off J Int Soc Twin Stud. 2004;7(6):589-595. https://doi.org/10.1375/1369052042663841
Xiong L, Jang K, Montplaisir J, Levchenko A, Thibodeau P, Gaspar C, et al. Canadian restless legs syndrome twin study. Neurology. 2007;68(19):1631-1633. https://doi.org/10.1212/01.wnl.0000261016.90374.fd
Zimprich A. Phenocopies in families with essential tremor and restless legs syndrome challenge Mendelian laws. Epigenetics might provide answers. Parkinsonism Relat Disord. 2012;18(6):711-716. https://doi.org/10.1016/j.parkreldis.2012.03.019
Lazzarini A, Walters AS, Hickey K, Coccagna G, Lugaresi E, Ehrenberg BL, et al. Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord Off J Mov Disord Soc. 1999;14(1):111-116. https://doi.org/10.1002/1531-8257(199901)14:1<111::AID-MDS1018>3.3.CO;2-0
Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Pütz B, et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: A meta-analysis. Lancet Neurol. 2017;16(11):898-907.
Didriksen M, Nawaz MS, Dowsett J, Bell S, Erikstrup C, Pedersen OB, et al. Large genome-wide association study identifies three novel risk variants for restless legs syndrome. Commun Biol. 2020;3(1):703. https://doi.org/10.1038/s42003-020-01430-1
Winkelmann J, Schormair B, Xiong L, Dion PA, Rye DB, Rouleau GA. Genetics of restless legs syndrome. Sleep Med. 2017;31:18-22. https://doi.org/10.1016/j.sleep.2016.10.012
Aridon P, De Fusco M, Winkelmann JW, Zucconi M, Arnao V, Ferini-Strambi L, et al. A TRAPPC6B splicing variant associates to restless legs syndrome. Parkinsonism Relat Disord. 2016;31:135-138. https://doi.org/10.1016/j.parkreldis.2016.08.016
Gan-Or Z, Zhou S, Ambalavanan A, Leblond CS, Xie P, Johnson A, et al. Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome. Sleep Med. 2015;16(9):1151-1155. https://doi.org/10.1016/j.sleep.2015.06.002
Ergun U, Say B, Ergun SG, Percin FE, Inan L, Kaygisiz S, et al. Genome-wide association and whole exome sequencing studies reveal a novel candidate locus for restless legs syndrome. Eur J Med Genet. 2021;64(4):104186. https://doi.org/10.1016/j.ejmg.2021.104186
Weissbach A, Siegesmund K, Brüggemann N, Schmidt A, Kasten M, Pichler I, et al. Exome sequencing in a family with restless legs syndrome. Mov Disord Off J Mov Disord Soc. 2012;27(13):1686-1689. https://doi.org/10.1002/mds.25191
Akçimen F, Sarayloo F, Liao C, Ross JP, Oliveira RDB, Dion PA, et al. Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes. Commun Biol. 2020;3(1):373. https://doi.org/10.1038/s42003-020-1105-z
Schormair B, Zhao C, Bell S, Didriksen M, Nawaz MS, Schandra N, et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction. Nat Genet. 2024;56(6):1090-1099. https://doi.org/10.1038/s41588-024-01763-1
Catoire H, Dion PA, Xiong L, Amari M, Gaudet R, Girard SL, et al. Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Ann Neurol. 2011;70(1):170-175. https://doi.org/10.1002/ana.22435
Spieler D, Kaffe M, Knauf F, Bessa J, Tena JJ, Giesert F, et al. Restless legs syndrome-associated intronic common variant in MEIS1 alters enhancer function in the developing telencephalon. Genome Res. 2014;24(4):592-603. https://doi.org/10.1101/gr.166751.113
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