Details of Disease

General Information of Disease (ID: DISNWY00)

• Disease Name: Restless legs syndrome
• Synonyms: RLS; WED; restless leg syndrome; Wittmaack-Ekbom syndrome; Willis-Ekbom disease
• Disease Class: 7A80: Restless legs syndrome
• Definition: A condition that occurs while resting or lying in bed; it is characterized by an irresistible urgency to move the legs to obtain relief from a strange and uncomfortable sensation in the legs.
• Disease Hierarchy:
  DISCFBRD: Neurological disorder
  DISNWY00: Restless legs syndrome
• ICD Code:
  ICD-11: ICD-11: 7A80
  ICD-10: ICD-10: G25.8
• Disease Identifiers:
  MONDO ID: MONDO_0005391
  MESH ID: D012148
  UMLS CUI: C0035258
  MedGen ID: 48427
  HPO ID: HP:0012452
  SNOMED CT ID: 32914008

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Neupro	DMHEAB1	Phase 4	Small molecular drug	[1]

This Disease is Treated as An Indication in 1 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
QLT-091001	DMZI4OV	Phase 2/3	NA	[2]

This Disease is Treated as An Indication in 1 Discontinued Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
IPX-159	DM9RMVX	Discontinued in Phase 2	NA	[3]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 13 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
LRRK2	TTK0FEA	Limited	Biomarker	[5]
MAP2K5	TTV3O87	Limited	Biomarker	[6]
CHM	TTOA18V	moderate	Genetic Variation	[7]
CPT1B	TTDL0NY	moderate	Genetic Variation	[8]
TF	TT8WXAV	moderate	Genetic Variation	[9]
ATXN3	TT6A17J	Strong	Biomarker	[10]
DRD3	TT4C8EA	Strong	Biomarker	[11]
GABRR2	TTQMXLS	Strong	Genetic Variation	[12]
HNMT	TT2B6EV	Strong	Genetic Variation	[13]
KNG1	TTDJ4MY	Strong	Altered Expression	[14]
RNMT	TTG45HY	Strong	Biomarker	[15]
SNCA	TT08OSU	Strong	Genetic Variation	[7]
TMPRSS6	TTL9KE7	Strong	Genetic Variation	[9]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC25A37	DTLBGTZ	Strong	Biomarker	[16]

This Disease Is Related to 2 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
CHKB	DEHWR6V	moderate	Genetic Variation	[8]
FXN	DEXVHDB	Strong	Biomarker	[17]

This Disease Is Related to 24 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
MFN2	OTPYN8A3	Limited	Biomarker	[18]
PRKN	OTJBN41W	Limited	Biomarker	[19]
CCDC148	OTAU2Y3S	moderate	Genetic Variation	[20]
FXYD1	OTNKT6GP	moderate	Biomarker	[21]
MYT1	OTC3660I	moderate	Genetic Variation	[20]
ATL1	OTR2788Y	Strong	Biomarker	[22]
ATRN	OTTCLOPV	Strong	Biomarker	[23]
ATXN1	OTQF0HNR	Strong	Biomarker	[24]
CNTN3	OTC1274J	Strong	Biomarker	[25]
EEF1A2	OT9Z23K5	Strong	Biomarker	[26]
FAT2	OTRGT3E8	Strong	Biomarker	[23]
GEMIN2	OT4L6TLL	Strong	Genetic Variation	[27]
KCTD18	OTU27AN5	Strong	Genetic Variation	[28]
LITAF	OTT5JX1F	Strong	Biomarker	[18]
MCF2L	OTEURA8N	Strong	Biomarker	[29]
MIXL1	OT584VOQ	Strong	Biomarker	[30]
MOCOS	OT0TL3Q5	Strong	Biomarker	[25]
NTS	OTPGDNQS	Strong	Genetic Variation	[31]
PCDHA3	OT7UREAI	Strong	Biomarker	[23]
REEP1	OTEMVFX7	Strong	Biomarker	[22]
SMCP	OTXKY794	Strong	Biomarker	[25]
SPATS2L	OTFO07H8	Strong	Genetic Variation	[28]
TOX3	OTC9NR4W	Strong	Genetic Variation	[32]
TRAPPC6B	OTDSWXHT	Strong	Genetic Variation	[33]

References

• [1] ClinicalTrials.gov (NCT01976871) Switching From Oral Dopamine Agonists to Rotigotine (SWITCH). U.S. National Institutes of Health.
• [2] QLT Begins Dosing In Phase 2 Trial Of QLT091001 For Impaired Dark Adaptation. RTT NEWS. 12/9/2013.
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034142)
• [4] Optimizing levodopa therapy for Parkinson's disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective. Neuropsychiatr Dis Treat. 2008 February; 4(1): 39-47.
• [5] A case of restless leg syndrome in a family with LRRK2 gene mutation.Int J Neurosci. 2013 Apr;123(4):283-5. doi: 10.3109/00207454.2012.756485. Epub 2013 Feb 4.
• [6] Haplotype Association of the MAP2K5 Gene with Antipsychotics-Induced Symptoms of Restless Legs Syndrome among Patients with Schizophrenia.Psychiatry Investig. 2018 Jan;15(1):84-89. doi: 10.4306/pi.2018.15.1.84. Epub 2018 Jan 16.
• [7] Association between restless legs syndrome and other movement disorders.Neurology. 2019 May 14;92(20):948-964. doi: 10.1212/WNL.0000000000007500. Epub 2019 Apr 19.
• [8] Genome-wide association studies of sleep disorders.Chest. 2011 Feb;139(2):446-452. doi: 10.1378/chest.10-1313.
• [9] Genetic factors influencing ferritin levels in 14,126 blood donors: results from the Danish Blood Donor Study.Transfusion. 2016 Mar;56(3):622-7. doi: 10.1111/trf.13397. Epub 2015 Nov 23.
• [10] Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3.J Neurol. 2001 Apr;248(4):311-4. doi: 10.1007/s004150170206.
• [11] Association study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia.Neuropsychobiology. 2008;57(1-2):49-54. doi: 10.1159/000129667. Epub 2008 May 2.
• [12] Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome.Pharmacogenomics J. 2018 Jul;18(4):565-577. doi: 10.1038/s41397-018-0023-7. Epub 2018 May 3.
• [13] Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome.J Neural Transm (Vienna). 2017 Mar;124(3):285-291. doi: 10.1007/s00702-016-1645-z. Epub 2016 Nov 11.
• [14] Evaluation of potential cardiovascular risk protein biomarkers in high severity restless legs syndrome.J Neural Transm (Vienna). 2019 Oct;126(10):1313-1320. doi: 10.1007/s00702-019-02051-7. Epub 2019 Jul 23.
• [15] Sleep disorders in Charcot-Marie-Tooth disease type 1.J Neurol Neurosurg Psychiatry. 2014 Mar;85(3):319-25. doi: 10.1136/jnnp-2013-305296. Epub 2013 May 23.
• [16] Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome. Mov Disord. 2019 Jan;34(1):114-123.
• [17] Expression and localization of mitochondrial ferritin mRNA in Alzheimer's disease cerebral cortex.PLoS One. 2011;6(7):e22325. doi: 10.1371/journal.pone.0022325. Epub 2011 Jul 20.
• [18] Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?.Brain Behav. 2016 Mar 4;6(4):e00451. doi: 10.1002/brb3.451. eCollection 2016 Apr.
• [19] Parkin gene modifies the effect of RLS4 on the age at onset of restless legs syndrome (RLS).Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):350-5. doi: 10.1002/ajmg.b.30988.
• [20] 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 Nov;16(11):898-907. doi: 10.1016/S1474-4422(17)30327-7.
• [21] Asymmetry of Periodic Leg Movements in Sleep (PLMS) in Parkinson's Disease.J Parkinsons Dis. 2020;10(1):255-266. doi: 10.3233/JPD-191667.
• [22] ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes.J Neurol. 2013 Mar;260(3):869-75. doi: 10.1007/s00415-012-6723-z. Epub 2012 Oct 30.
• [23] Exome sequencing in a family with restless legs syndrome.Mov Disord. 2012 Nov;27(13):1686-9. doi: 10.1002/mds.25191.
• [24] Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomography.Mov Disord. 2006 Oct;21(10):1667-73. doi: 10.1002/mds.20978.
• [25] Restless legs syndrome is associated with major comorbidities in a population of Danish blood donors.Sleep Med. 2018 May;45:124-131. doi: 10.1016/j.sleep.2018.02.007. Epub 2018 Mar 8.
• [26] Improvement of Subthalamic Nucleus Deep Brain Stimulation in Sleeping Symptoms in Parkinson's Disease: A Meta-Analysis.Parkinsons Dis. 2019 Oct 8;2019:6280896. doi: 10.1155/2019/6280896. eCollection 2019.
• [27] Possible joint origin of restless leg syndrome (RLS) and migraine.Med Hypotheses. 2007;69(1):64-6. doi: 10.1016/j.mehy.2006.10.060. Epub 2007 Jan 26.
• [28] Fine-mapping of restless legs locus 4 (RLS4) identifies a haplotype over the SPATS2L and KCTD18 genes.J Mol Neurosci. 2013 Mar;49(3):600-5. doi: 10.1007/s12031-012-9891-5. Epub 2012 Oct 2.
• [29] The impact of subthalamic deep brain stimulation on polysomnographic sleep pattern in patients with Parkinson's disease - Preliminary report.Neurol Neurochir Pol. 2018 Aug;52(4):514-518. doi: 10.1016/j.pjnns.2018.05.006. Epub 2018 Jun 1.
• [30] Liver disease severity is poorly related to the presence of restless leg syndrome in patients with cirrhosis.Neurol India. 2019 May-Jun;67(3):732-737. doi: 10.4103/0028-3886.263171.
• [31] Genetic association studies of neurotensin gene and restless legs syndrome in French Canadians.Sleep Med. 2008 Mar;9(3):273-82. doi: 10.1016/j.sleep.2007.03.020. Epub 2007 Jul 17.
• [32] TOX3 gene variant could be associated with painful restless legs.Sleep Med. 2020 Jan;65:4-7. doi: 10.1016/j.sleep.2019.07.003. Epub 2019 Jul 11.
• [33] A TRAPPC6B splicing variant associates to restless legs syndrome.Parkinsonism Relat Disord. 2016 Oct;31:135-138. doi: 10.1016/j.parkreldis.2016.08.016. Epub 2016 Aug 18.