Presentation on theme: "Shedding light on Restless Legs Syndrome via the Human Genome"— Presentation transcript:
1 Shedding light on Restless Legs Syndrome via the Human Genome Pharmacogenomic ImplicationsShedding light on Restless Legs Syndrome via the Human GenomeDavid B. RyeProfessor of NeurologyDirector, Emory University Program in SleepAtlanta, GADavid Rye, MD, PhDProfessor of NeurologyDirector, Emory Healthcare Program in Sleep
2 RLS Affects Tens of Millions in the United States alone RLS is more prevalent than originally believed1RLS affects approximately 10% of the US adult population, yet often goes undiagnosed2Approximately 12 million Americans suffer from moderate to severe ‘primary’ RLS2,3RLS is more prevalent than originally believed1RLS affects approximately 10% of the US adult population, yet often goes undiagnosed2Approximately 12 million Americans suffer from moderate to severe primary RLS2,363% of patients with RLS report having at least one first-degree relative with the condition4Hening W. Clin Neurophysiol. 2004;115:Hening W, et al. Sleep Med. 2004;5:NINDS, NIH; NIH Publication NoReferences1Hening W. The clinical neurophysiology of the restless legs syndrome and periodic limb movements. Part I: diagnosis, assessment, and characterization. Clin Neurophysiol. 2004;115: ; 2Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5: ; 3Restless Legs Syndrome Fact Sheet. Bethesda, Md: National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH); NIH Publication No ; 4Montplaisir J, Boucher S, Poirier G, et al. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord. 1997;12:61-65.
3 Burden of RLS is Significant Depressed mood (OR = 2.6)Stroke & Cardiovascular disease (OR= )Hypertension (OR = 1.5; *PLMs > 30/hr OR = 2.3)Ulfberg J, Nystrom B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years:an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001;16:Winkelman J, Finn L, Young T. Prevalence and correlates of restless legs syndrome in the Wisconsinsleep cohort. Sleep 2005;28(Abst Suppl):A – Sleep Medicine 2006-May 30th (epub ahead of print)*Personal observations; Winkelman et al. (2008) Neurology 70:35-42
5 RLS remains a clinical diagnosis: IRLSSG/NIH Diagnostic Criteria for RLS Urge to move legs, usually accompanied by uncomfortable leg sensationsOnset or worsening of symptoms at rest or inactivity, such as when lying or sittingRelief with movement—partial or total relief from discomfort by walking or stretchingWorsening of symptoms in the evening and at nightA 2002 Workshop on RLS, held by the National Institutes of Health (NIH) in collaboration with the International RLS Study Group (IRLSSG), established four essential criteria—meaning that in this system all four are required to make the diagnosis. The four areAn urge to move the legs. Although some patients have only motor symptoms, most patients who seek treatment have also had sensory symptoms. The involuntary movements of RLS must be distinguished from unconscious repetitive movements such as foot tappingOnset or worsening during rest or inactivity. As resting begins, motor and sensory symptoms may both be absent, but the likelihood and the intensity of each side of RLS increases as resting goes on. Ordinary discomfort such as stiffness from prolonged immobility is not RLSRelief with movement. The relief is generally described as prompt, but it may not be complete, and in severe RLS it may have been possible only at earlier stagesWorsening (or occurrence) only in the evening or at night. In severe RLS with symptoms night and day, this too may be only the patient’s memory of earlier stagesAllen RP, et al, for the International Restless Legs Syndrome Study Group. Sleep Med. 2003;4:ReferenceAllen RP, Picchietti D, Hening WA, et al, for the International Restless Legs Syndrome Study Group. 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:
6 Periodic leg movements in sleep (PLMs) in RLS appear to exhibit heritability (at least as much as, if not more than, sensory symptoms)!
8 Iron is central to RLS symptomatology RLS symptoms occur in > 40% of subjects with iron deficiencyAkyol et al., Clin Neurol Neurosurg Dec;106:In vivo and in vitro iron depletion in dopamine rich brain regions of RLS patientsAllen et al., Neurology Jan 56:Connor et al., Neurology Aug 61:Iron deficiency adversely affects dopamine signalingAllen et al, Sleep Med Jul 5:385-91Oral and intravenous iron can ameliorate RLS symptoms.Earley, Heckler and Allen Sleep Med May 5:
9 Iron trafficking appears to be awry in RLS/PLMs – A “leaky” bucket RLS PatientEarley, Heckler and Allen, Sleep Medicine (2005) 6: 301
10 Treatment OptionsOral or intravenous iron repletion when iron deficiency confirmed (9-50% of cases)Dopaminergics – 1st line treatment as per American Sleep Disorders Assoc. Standards of Practice Committee and the Medical Advisory Board of the RLS FoundationPramipexole ( mg) – Ropinirole ( mg) minutes before typical symptom onset–FDA approved for idiopathic, moderate-severe RLSOff-label:Opioids –Anticonvulsants – gabapentinBenzodiazepines –
12 A genetic-linkage analysis of RLS in Iceland Funded in part by the Restless Legs Syndrome Foundation in collaboration with deCODE Genetics, Reykjavik, IcelandHomogeneityExcellent genealogic recordsExcellent record keeping in health careHighest literacy rate in the worldParticipation in clinical studies is high (80-85%)
13 4 recently identified gene variants account for at least 80% of the population attritubable risk for RLS
14 To everyone’s surprise/dismay: None of the implicated genes directly or indirectly affect iron or dopamine.The implicated regions are intronic or intergenic and suggest regulatory roles.The functions are in many cases not well known.
15 SNPs associating to RLS are intimately related to the disease biology: Multiple SNPs in at least the BTBD9 and Meis1 genes are related in a dose dependent fashion to PLMs – bearing ZERO relationship to RLS rating scalesMultiple SNPs in the BTBD9 gene are inversely related in a dose dependent fashion to low iron storesAt-risk SNP frequencies in disparate ethnic groups mirrors the large range of ethnic differences in RLS prevalence
16 RLS at-risk variants are COMMON and considerably impact population risk for RLS AlleleGene OR Frequency PAR p valueBTBD (0.656) x10-7 – x10-18MEIS (0.114) ~ x10-3 – x10-16MAP2K (0.692) ~ x10-2 – x10-5PTPRD (0.13) <0.10(X.XX) = allele frequency in Icelandic population controls
18 Pondering the Genetics Landscape: Will genotypes correlate with specific phenotypes?Can genetic testing inform diagnosis and treatment decisions?What are the downstream molecular networks that effect disease expression?
19 Pharmacogenics for RLS – targets? Treatment stratificationDopaminergics vs. opioids vs. iron vs. ?Complication stratificationDopaminergic augmentationAggravators (e.g., antihistamines; metaclopramide)Predictive HealthEnd-Stage Renal DiseasePregnancy
20 RLS pharmacogenomics - challenges RLS genesDespite high ORs, commonality of at-risk SNPs necessitates large ( ) sample sizesChoice of (endo) phenotypeLatent or incipient diseaseNon-RLS genes
22 AcknowledgementsEmory Program in Sleep Emory Dept. of Cell Biology deCODE GeneticsDr. Donald Bliwise Dr. S. Sanyal Dr. Hreinn StefanssonDr. Michael Decker Dr. KristleifurKristjanssonDr. Alex Iranzo Emory Dept. of Genetics Dr. Andrew HicksDr. Jeffrey Durmer Dr. Steve Warren Dr. Larus GudmundssonDr. Lynn-Marie Trotti Dr. Mark Bouzyk Ingibjorg Eiriksdottir, RNDr. Lisa Billars Dr. Jeffrey GulcherDr. Reddiah Mumanenni Dr. Kari StefanssonDr. Glenda Keating Emory Dept. of NeurologyDr. Amanda Freeman Dr. Allan Levey LandspitaliDr. Tom Genetta Dr. Salina WaddyJ Max Beck Ami Rosen Dr. Thordur SigmundssonGillian Hue CRIN Staff Dr. Albert Pal SigdurssonDaniel MillerKaniyika Freeman Emory School of Public HealthDr. Harland Austin FundingRLS FoundationArthur L. Williams Jr.FoundationWoodruff Health Sciences