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Restless legs syndrome, susceptibility to, 1(RLS1)

MedGen UID:
360293
•Concept ID:
C1876177
•
Finding
Synonyms: Acromelalgia hereditary; Ekbom syndrome; Restless legs syndrome 1; RLS1
 
Monarch Initiative: MONDO:0007053
OMIM®: 102300

Definition

Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (Bonati et al., 2003). Genetic Heterogeneity of Restless Legs Syndrome RLS1 has been mapped to chromosome 12q. Other susceptibility loci for RLS include RLS2 (608831) on chromosome 14q13-q31; RLS3 (610438) on chromosome 9p24-p22; RLS4 (610439) on chromosome 2q33; RLS5 (611242) on chromosome 20p13; RLS6 (611185) on chromosome 6p21; RLS7 (612853) on chromosome 2p14; and RLS8 (615197) on chromosome 5q31. [from OMIM]

Clinical features

From HPO
Myoclonus
MedGen UID:
10234
•Concept ID:
C0027066
•
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
See: Feature record | Search on this feature
Paresthesia
MedGen UID:
14619
•Concept ID:
C0030554
•
Disease or Syndrome
Abnormal sensations such as tingling, pricking, or numbness of the skin with no apparent physical cause.
See: Feature record | Search on this feature
Restless legs
MedGen UID:
48427
•Concept ID:
C0035258
•
Disease or Syndrome
Restless Leg Syndrome (RLS) is a condition characterized by an uncomfortable and restless sensation in the legs that occurs after going to bed, often leading to insomnia.
See: Feature record | Search on this feature
Sleep abnormality
MedGen UID:
52372
•Concept ID:
C0037317
•
Finding
An abnormal pattern in the quality, quantity, or characteristics of sleep.
See: Feature record | Search on this feature
Insomnia
MedGen UID:
214589
•Concept ID:
C0917801
•
Sign or Symptom
Persistent difficulty initiating or maintaining sleep.
See: Feature record | Search on this feature
Exercise-induced leg cramps
MedGen UID:
870174
•Concept ID:
C4024607
•
Sign or Symptom
Sudden and involuntary contractions of one or more muscles of the leg brought on by physical exertion.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

The solute carrier family 1 (glial high affinity glutamate transporter), member 2 gene, SLC1A2, rs3794087 variant and assessment risk for restless legs syndrome.
Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, Millán-Pascual J, Adeva-Bartolomé T, Cubo E, Navacerrada F, Rojo-Sebastián A, Rubio L, Calleja M, Plaza-Nieto JF, Pilo-de-la-Fuente B, Arroyo-Solera M, García-Martín E, Agúndez JA
Sleep Med 2014 Feb;15(2):266-8. Epub 2013 Dec 22 doi: 10.1016/j.sleep.2013.08.800. PMID: 24424098
Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment.
Picchietti MA, Picchietti DL
Sleep Med 2010 Aug;11(7):643-51. doi: 10.1016/j.sleep.2009.11.014. PMID: 20620105

Recent clinical studies

Etiology

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
Schormair B, Zhao C, Bell S, Didriksen M, Nawaz MS, Schandra N, Stefani A, Högl B, Dauvilliers Y, Bachmann CG, Kemlink D, Sonka K, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek ZK, Ibrahim A, Bergmann M, Kittke V, Harrer P, Dowsett J, Chenini S, Ostrowski SR, Sørensen E, Erikstrup C, Pedersen OB, Topholm Bruun M, Nielsen KR, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Burchell B, Furlotte NA, Nandakumar P; 23andMe Research Team; D.E.S.I.R. study group, Earley CJ, Ondo WG, Xiong L, Desautels A, Perola M, Vodicka P, Dina C, Stoll M, Franke A, Lieb W, Stewart AFR, Shah SH, Gieger C, Peters A, Rye DB, Rouleau GA, Berger K, Stefansson H, Ullum H, Stefansson K, Hinds DA, Di Angelantonio E, Oexle K, Winkelmann J
Nat Genet 2024 Jun;56(6):1090-1099. Epub 2024 Jun 5 doi: 10.1038/s41588-024-01763-1. PMID: 38839884Free PMC Article
Why Are Women Prone to Restless Legs Syndrome?
Seeman MV
Int J Environ Res Public Health 2020 Jan 6;17(1) doi: 10.3390/ijerph17010368. PMID: 31935805Free PMC Article
Role of MEIS1 in restless legs syndrome: From GWAS to functional studies in mice.
Salminen AV, Lam DD, Winkelmann J
Adv Pharmacol 2019;84:175-184. Epub 2019 Apr 9 doi: 10.1016/bs.apha.2019.03.003. PMID: 31229170
Restless legs syndrome.
Ondo WG
Neurol Clin 2009 Aug;27(3):779-99, vii. doi: 10.1016/j.ncl.2009.04.007. PMID: 19555831
Genetics of restless legs syndrome.
Winkelmann J
Curr Neurol Neurosci Rep 2008 May;8(3):211-6. doi: 10.1007/s11910-008-0033-y. PMID: 18541116

Diagnosis

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
Schormair B, Zhao C, Bell S, Didriksen M, Nawaz MS, Schandra N, Stefani A, Högl B, Dauvilliers Y, Bachmann CG, Kemlink D, Sonka K, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek ZK, Ibrahim A, Bergmann M, Kittke V, Harrer P, Dowsett J, Chenini S, Ostrowski SR, Sørensen E, Erikstrup C, Pedersen OB, Topholm Bruun M, Nielsen KR, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Burchell B, Furlotte NA, Nandakumar P; 23andMe Research Team; D.E.S.I.R. study group, Earley CJ, Ondo WG, Xiong L, Desautels A, Perola M, Vodicka P, Dina C, Stoll M, Franke A, Lieb W, Stewart AFR, Shah SH, Gieger C, Peters A, Rye DB, Rouleau GA, Berger K, Stefansson H, Ullum H, Stefansson K, Hinds DA, Di Angelantonio E, Oexle K, Winkelmann J
Nat Genet 2024 Jun;56(6):1090-1099. Epub 2024 Jun 5 doi: 10.1038/s41588-024-01763-1. PMID: 38839884Free PMC Article
Biological and clinical insights from genetics of insomnia symptoms.
Lane JM, Jones SE, Dashti HS, Wood AR, Aragam KG, van Hees VT, Strand LB, Winsvold BS, Wang H, Bowden J, Song Y, Patel K, Anderson SG, Beaumont RN, Bechtold DA, Cade BE, Haas M, Kathiresan S, Little MA, Luik AI, Loudon AS, Purcell S, Richmond RC, Scheer FAJL, Schormair B, Tyrrell J, Winkelman JW, Winkelmann J; HUNT All In Sleep, Hveem K, Zhao C, Nielsen JB, Willer CJ, Redline S, Spiegelhalder K, Kyle SD, Ray DW, Zwart JA, Brumpton B, Frayling TM, Lawlor DA, Rutter MK, Weedon MN, Saxena R
Nat Genet 2019 Mar;51(3):387-393. Epub 2019 Feb 25 doi: 10.1038/s41588-019-0361-7. PMID: 30804566Free PMC Article
Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment.
Picchietti MA, Picchietti DL
Sleep Med 2010 Aug;11(7):643-51. doi: 10.1016/j.sleep.2009.11.014. PMID: 20620105
Restless legs syndrome.
Ondo WG
Neurol Clin 2009 Aug;27(3):779-99, vii. doi: 10.1016/j.ncl.2009.04.007. PMID: 19555831
Neurocognitive consequences of sleep deprivation.
Durmer JS, Dinges DF
Semin Neurol 2005 Mar;25(1):117-29. doi: 10.1055/s-2005-867080. PMID: 15798944

Therapy

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
Schormair B, Zhao C, Bell S, Didriksen M, Nawaz MS, Schandra N, Stefani A, Högl B, Dauvilliers Y, Bachmann CG, Kemlink D, Sonka K, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek ZK, Ibrahim A, Bergmann M, Kittke V, Harrer P, Dowsett J, Chenini S, Ostrowski SR, Sørensen E, Erikstrup C, Pedersen OB, Topholm Bruun M, Nielsen KR, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Burchell B, Furlotte NA, Nandakumar P; 23andMe Research Team; D.E.S.I.R. study group, Earley CJ, Ondo WG, Xiong L, Desautels A, Perola M, Vodicka P, Dina C, Stoll M, Franke A, Lieb W, Stewart AFR, Shah SH, Gieger C, Peters A, Rye DB, Rouleau GA, Berger K, Stefansson H, Ullum H, Stefansson K, Hinds DA, Di Angelantonio E, Oexle K, Winkelmann J
Nat Genet 2024 Jun;56(6):1090-1099. Epub 2024 Jun 5 doi: 10.1038/s41588-024-01763-1. PMID: 38839884Free PMC Article
Restless Legs Syndrome among patients receiving antipsychotic and antidepressant drugs.
Elrassas HH, Elsayed YAR, Abdeen MS, Shady MM, Shalash A, Morsy M
Hum Psychopharmacol 2022 Mar;37(2):e2817. Epub 2021 Sep 17 doi: 10.1002/hup.2817. PMID: 34533852
Restless legs syndrome in dialysis patients: a meta-analysis.
Mao S, Shen H, Huang S, Zhang A
Sleep Med 2014 Dec;15(12):1532-8. Epub 2014 Oct 2 doi: 10.1016/j.sleep.2014.07.017. PMID: 25450056
Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment.
Picchietti MA, Picchietti DL
Sleep Med 2010 Aug;11(7):643-51. doi: 10.1016/j.sleep.2009.11.014. PMID: 20620105
Restless legs syndrome.
Ondo WG
Neurol Clin 2009 Aug;27(3):779-99, vii. doi: 10.1016/j.ncl.2009.04.007. PMID: 19555831

Prognosis

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
Schormair B, Zhao C, Bell S, Didriksen M, Nawaz MS, Schandra N, Stefani A, Högl B, Dauvilliers Y, Bachmann CG, Kemlink D, Sonka K, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek ZK, Ibrahim A, Bergmann M, Kittke V, Harrer P, Dowsett J, Chenini S, Ostrowski SR, Sørensen E, Erikstrup C, Pedersen OB, Topholm Bruun M, Nielsen KR, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Burchell B, Furlotte NA, Nandakumar P; 23andMe Research Team; D.E.S.I.R. study group, Earley CJ, Ondo WG, Xiong L, Desautels A, Perola M, Vodicka P, Dina C, Stoll M, Franke A, Lieb W, Stewart AFR, Shah SH, Gieger C, Peters A, Rye DB, Rouleau GA, Berger K, Stefansson H, Ullum H, Stefansson K, Hinds DA, Di Angelantonio E, Oexle K, Winkelmann J
Nat Genet 2024 Jun;56(6):1090-1099. Epub 2024 Jun 5 doi: 10.1038/s41588-024-01763-1. PMID: 38839884Free PMC Article
Genome-wide estimates of heritability and genetic correlations in essential tremor.
Diez-Fairen M, Bandres-Ciga S, Houle G, Nalls MA, Girard SL, Dion PA, Blauwendraat C, Singleton AB, Rouleau GA, Pastor P
Parkinsonism Relat Disord 2019 Jul;64:262-267. Epub 2019 May 4 doi: 10.1016/j.parkreldis.2019.05.002. PMID: 31085086Free PMC Article
Susceptible genes of restless legs syndrome in migraine.
Fuh JL, Chung MY, Yao SC, Chen PK, Liao YC, Hsu CL, Wang PJ, Wang YF, Chen SP, Fann CS, Kao LS, Wang SJ
Cephalalgia 2016 Oct;36(11):1028-1037. Epub 2016 Jul 19 doi: 10.1177/0333102415620907. PMID: 26643377
Restless legs syndrome and pregnancy.
Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, Mollica G, Ferini-Strambi L, Granieri E
Neurology 2004 Sep 28;63(6):1065-9. doi: 10.1212/01.wnl.0000138427.83574.a6. PMID: 15452299
Transient restless legs syndrome after spinal anesthesia: a prospective study.
Högl B, Frauscher B, Seppi K, Ulmer H, Poewe W
Neurology 2002 Dec 10;59(11):1705-7. doi: 10.1212/01.wnl.0000036606.56405.3d. PMID: 12473756

Clinical prediction guides

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
Schormair B, Zhao C, Bell S, Didriksen M, Nawaz MS, Schandra N, Stefani A, Högl B, Dauvilliers Y, Bachmann CG, Kemlink D, Sonka K, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek ZK, Ibrahim A, Bergmann M, Kittke V, Harrer P, Dowsett J, Chenini S, Ostrowski SR, Sørensen E, Erikstrup C, Pedersen OB, Topholm Bruun M, Nielsen KR, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Burchell B, Furlotte NA, Nandakumar P; 23andMe Research Team; D.E.S.I.R. study group, Earley CJ, Ondo WG, Xiong L, Desautels A, Perola M, Vodicka P, Dina C, Stoll M, Franke A, Lieb W, Stewart AFR, Shah SH, Gieger C, Peters A, Rye DB, Rouleau GA, Berger K, Stefansson H, Ullum H, Stefansson K, Hinds DA, Di Angelantonio E, Oexle K, Winkelmann J
Nat Genet 2024 Jun;56(6):1090-1099. Epub 2024 Jun 5 doi: 10.1038/s41588-024-01763-1. PMID: 38839884Free PMC Article
Large genome-wide association study identifies three novel risk variants for restless legs syndrome.
Didriksen M, Nawaz MS, Dowsett J, Bell S, Erikstrup C, Pedersen OB, Sørensen E, Jennum PJ, Burgdorf KS, Burchell B, Butterworth AS, Soranzo N, Rye DB, Trotti LM, Saini P, Stefansdottir L, Magnusson SH, Thorleifsson G, Sigmundsson T, Sigurdsson AP, Van Den Hurk K, Quee F, Tanck MWT, Ouwehand WH, Roberts DJ, Earley EJ, Busch MP, Mast AE, Page GP, Danesh J, Di Angelantonio E, Stefansson H, Ullum H, Stefansson K
Commun Biol 2020 Nov 25;3(1):703. doi: 10.1038/s42003-020-01430-1. PMID: 33239738Free PMC Article
Susceptible genes of restless legs syndrome in migraine.
Fuh JL, Chung MY, Yao SC, Chen PK, Liao YC, Hsu CL, Wang PJ, Wang YF, Chen SP, Fann CS, Kao LS, Wang SJ
Cephalalgia 2016 Oct;36(11):1028-1037. Epub 2016 Jul 19 doi: 10.1177/0333102415620907. PMID: 26643377
Restless legs syndrome in dialysis patients: a meta-analysis.
Mao S, Shen H, Huang S, Zhang A
Sleep Med 2014 Dec;15(12):1532-8. Epub 2014 Oct 2 doi: 10.1016/j.sleep.2014.07.017. PMID: 25450056
Autosomal dominant restless legs syndrome maps to chromosome 20p13 (RLS-5) in a Dutch kindred.
Sas AM, Di Fonzo A, Bakker SL, Simons EJ, Oostra BA, Maat-Kievit AJ, Boon AJ, Bonifati V
Mov Disord 2010 Aug 15;25(11):1715-22. doi: 10.1002/mds.23248. PMID: 20645405

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