RLS Research Review: Then & Now. David Rye, MD, PhD Professor of Neurology Emory University School of Medicine

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1 RLS Research Review: Then & Now David Rye, MD, PhD Professor of Neurology Emory University School of Medicine

2 Disclosures Fees for service from: Individual patients, UCB Pharmaceuticals, Jazz Pharma, Xenoport, Flamel Technologies, as well as patients and several branches of the US government US Patent (pending): US Use of GABA-A receptor antagonists for the treatment of excessive sleepiness and disorders associated with excessive sleepiness

3 RLS has a significant genetic component 30-65% of RLS patients have a first degree relative with the disorder High (54-83%) concordance in identical twins Most pedigrees described exhibit an autosomal dominant inheritance pattern Anticipation in some families Genetic Linkage Studies have been largely uninformative Winkelmann, J., et al., Mov Disord. (2007) 22 Suppl 18: S449. Trotti, L., et al., Curr Neurol Neurosci Rep. (2008) 8: 281.

4 10-15% 11.3% % % 11.3% 7.9% 5% 3.6% 3.5% 0%?? 2.0% 0.2% % % RLS prevalence is high and influenced by 2016 ethnicity RLS Foundation

5 The pattern of inheritance dictates the optimal genetic approach Rare sporadic childhood disorders -- Chromosomal rearrangements (or recessives) -- Responsible genes in breakpoints or duplications/deletions Sequencing Unusual high density families -- dominant -- point mutations (or microdeletions / duplications) in genes of major effect Linkage Common, adult disorders with/without pronounced familial grouping -- multiple genes of additive effect -- often major environmental interactions Association

6 Mullen et al., Neurology (2009) 72

7 Iceland N= N=498 Re-phenotyped PLM (by PAM-RL) IRLSSG severity scale Questionnaire Medical history PLM IRLSSG severity scale Revised Questionnaire Medical history Blood pressure(s) Orthostatics

8 US N= RLS(N=616; 65.5%) PLMs to RLS (N = 22) PLMs only (N=243; 25.8%) Non-Caucasian (N=82; 8.7%) N=188

9 Periodic leg movements in sleep (PLMs) exhibit heritability, at least as much as, if not more than, sensory symptoms.

10 An old South RLS/PLMs Family

11 PAM-RL (Respironics) for ambulatory PLMs assessment

12 Proband RLS with PLMs PLMi * 1 7 Baseline Medicated * = missed dinnertime dose Asymptomatic Sister Asymptomatic Night #

13 5 genetic variants account for ~80% of the population attributable risk for RLS

14 SNPs associating to RLS are intimately related to the disease biology: Multiple SNPs in the BTBD9 and Meis1 genes are related in a dose dependent fashion to PLMs bearing ZERO relationship to RLS rating scales Multiple SNPs in the BTBD9 gene are related in a dose dependent fashion to low iron stores At-risk SNP frequencies in disparate ethnic groups mirror the large range of ethnic differences in RLS prevalence

15 Gene/SNP RLS (N=616) p value PLMs Only p value (n= 243 / 265) Meis1 rs BTBD9 rs PTPRD rs PTPRD rs MAP2K5 rs TOX3 rs (OR) 2.3 e (OR) 1.8 e-4 (e-6) e (NS)

16 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 function(s) of these genes are in many cases still being investigated. The findings do not explain the high heritability for RLS/PLMs.

17 Loss of the fruit fly (Drosophila) homologue of human BTBD9 (e.g., CG1826) results in motor restlessness & sleep fragmentation

18 Sleep fragmentation: W S Control W S W S Excision W S

19 We have been unsuccessful in associating individual SNPs with other disease related features at Timepoint #1 such as: Pain vs. no pain Presence vs. absence of growing pains (retrospective) IRLSSG rating scale of severity PAM-RL metrics: Total sleep time Up time Sleep efficiency

20 We ve also probed for associations with genetic load calculated via polygenic risk scores (PGRS) derived from the 6 at-risk SNPs: Nothing for pain, growing pains, or severity. Weak association with lower sleep efficiency (p=0.046). Each 1 SD increase in PGRS yields nearly 3 more minutes of up time. Strong association with PLMs (p=6.6 e-7) Stronger in men: 1 SD increase in PGRS = 6.2 vs. 2.6 PLM/hour Association with worsening in pregnancy (p=0.0079; n= only 146)

21 Increased load of risk alleles at year follow-up predicts: MEN: * greater PLMs number WOMEN: * worse symptomatic RLS * more nocturnal up time * worse sleep efficiency

22 Nature (i.e., DNA) loads the gun Nuture (viz., the environment) pulls the trigger

23 Further Conclusions Only 3 4 genetic variants for RLS confer risk for PLMs in RLS and in those asymptomatic for RLS. How the different allelic variants confer risk for other symptoms or RLS comorbidities is unknown. There appear to be genetic and sex specific factors that modulate signs/symptoms and disease course.

24 Where we (may be) headed: Over time (i.e., longitudinally), what other disorders associate with RLS/PLMs (e.g., hypertension/cardiovascular disease)? Can novel therapeutics derive from greater knowledge of how specific genes or gene profiles fit into known biological pathways? Defining how RLS manifests in children (e.g., associated disorders such as ADD) informed by genetics in families.

25 Acknowledgements: RLS Foundation Art Williams Jr. Foundation UCB Pharma Woodruff Health Sciences Fund Individual patient contributions decode Genetics (Andrew Hicks, Hreinn Stefansson, Andres Ingason, Kari Stefansson).

26

27 Acknowledgements Emory Program in Sleep Emory Dept. of Cell Biology decode Genetics Dr. Donald Bliwise Dr. S. Sanyal Dr. Hreinn Stefansson Dr. Michael Decker Dr. Kristleifur Kristjansson Dr. Alex Iranzo Emory Dept. of Genetics Dr. Andrew Hicks Dr. Jeffrey Durmer Dr. Steve Warren Andres Ingason Dr. Lynn-Marie Trotti Dr. Mark Bouzyk Ingibjorg Eiriksdottir, RN Prabhyjot Saini MPH Dr. Jeffrey Gulcher Dr. Reddiah Mumanenni Dr. Kari Stefansson Dr. Glenda Keating Emory Dept. of Neurology Dr. Amanda Freeman Dr. Allan Levey Landspitali Dr. Tom Genetta Dr. Salina Waddy J Max Beck Ami Rosen Dr. Thordur Sigmundsson Gillian Hue CRIN Staff Dr. Albert Pal Sigdursson Daniel Miller Emory School of Public Health Dr. Harland Austin

28 Questions & Answers Join the RLS Foundation at

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