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The RLS (PLM) story unfolds David Rye, MD, PhD Professor of Neurology Director, Emory Healthcare Program in Sleep [Pathology] is the only basis of positive knowledge in medicine and one should never lose sight of it in etiological research for fear of chasing chimeras or creating phantoms to combat…. But, I also believe that it is dangerous to study local conditions exclusively and to the extent that their difference from the causes on which they depend is lost from view…. The necessary shortcomings of a limited outlook is often to take the effect for the cause, or to fall into the even greater error of considering them as identical. • Laennec, René-Théophile-Hyacinthe. Traité de l'Auscultation Médiate, vols. 1,2. Paris: J.A. Brosson and J.S. Chaude; 1819, pp. 413-4 (vol. 1), pp. 233-4 (vol. 2). RLS PLM An “old South” RLS/PLMs family Proband – RLS with PLMs + lifelong unrefreshing sleep 25 20 PLMi 15 Baseline 10 * 5 Medicated 1 7 * = missed dinnertime dose 0 1 2 3 4 5 6 7 8 Asymptomatic Sister – lifelong unrefreshing sleep 25 20 15 10 Asymptomatic 5 0 1 2 3 4 5 Night # 6 7 8 Mean Percentage of Nights with PLMI Exceeding Threshold Variability in PLMs within RLS is substantial and an individual’s PLMi represents a robust quantitative trait 100 90 80 70 60 50 40 30 20 10 0 PLMI >= 5 PLMI >= 10 PLMI >= 15 1 2 3 4 5 6 7 Number of Nights Examined Trotti, Bliwise et al., Sleep Medicine (in press) 8 9 10 PLMs are a common ‘forme fruste’ of RLS • 10.6% of the family members of our 514 Icelandic ‘ probands’ exhibited a maximum PLMi > 10/hour in the absence of sensory complaints • Recognized by others: • • • • • • Walters et al., Arch Neurol 1990;47:1219-20. Walters et al., Sleep 1996;19:825-26. Allen and Earley, Sleep 1996;19:205-13. Lazzarini et al., Mov Disord 1999;14:111-6. Santamaria et al., Sleep Med 2003;4:153-55. Bonati et al., Brain 2003;126:1485-92. Four gene variants account for > 80% of the population attritubable risk for RLS SNPs associating to RLS are intimately related to disease biology: • Multiple SNPs in the BTBD9 and Meis1 genes are related in a dose dependent fashion to PLMs • 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 RLS gene variants are related to PLMs in a dose-dependent manner H Stefansson, H Petursson and DB Rye et. al., submitted BTBD9 genotypes predict lower ferritin SNPs in BTBD9, Meis1, MAP2K5 bear NO relationship to age of onset or RLS rating scales Age of Onset RLS severity – IRRLSSG Rating Scale Periodic limb movements during sleep: population prevalence, clinical correlates, and racial differences. Scofield H, Roth T, Drake C (Sleep. 2008 Sep 1;31(9):1221-7) This ethnic difference in PLMi has a parsimonious explanation • African-American RLS Genotype frequencies: • Caucasian RLS Genotype frequencies: Meis1 rs12469063 = 0.058 0.286 (vs. controls 0.21) BTBD9 rs3923809 = 0.777 0.762 (vs. controls 0.68) Putting this into perspective: • A PAR of 0.5 for BTBD9 implies that it is causative in 50% of RLS cases – this is a level unprecedented for a common disease. • The genetic contribution of BTBD9 to RLS approximates that of the ApoE4 allele association to Alzheimer’s disease. • The results are extremely credible – the gene variants and their effect sizes are similar in 5 different populations in which RLS was diagnosed by 3 different groups. As all mammals are not the same: All RLS is not created equal • Disease nosologies are human constructs informed by physician experience, clinical expediency, and regulatory agencies, but are most often lack a complete understanding of the biology of the disease. • The RLS story provides the best example to date of how discovery of sequence variants can influence the way in which we detect a common disease trait and subsequently monitor it. • To disregard PLMs in favor of a clinical diagnosis of RLS incorrectly presumes that changes in brain function reflective of genetic variants must always have a relevant verbal complaint. • RLS is a complex, polygenic disease (heterogeneity should be expected – time to forgo lumping for splitting?) • Multiple genes = Multiple phenotypes? (i.e., all RLS is not created equal) • What to split by? – Genotypes (of course) PLMs is an endophenotype of RLS that bypasses imprecision of clinical diagnoses PLMs are critical to traditional epidemiological investigations (commonly seen to predate RLS or remain ‘asymptomatic’) PLMi vs. periodicity vs. COV vs. diurnal preference vs. intensity (e.g., amplitude) Advancing RLS Science – one potential way forward: • Genotype-phenotype correlations including individuals who harbor copy number variants (CNVs). • Identify putative molecular networks through which RLS genes act by gene expression profiling of blood harboring systematic variations of RLS risk genotypes. • Test and refine these networks employing standard cell biological approaches. • Establish etiologically valid RLS models in animals (mice, flies, zebrafish, and worms) to derive mechanistic understanding of additional pathway components. • PTPRD (protein tyrosine phosphatase receptor type delta) functions in the guidance and termination of mammalian motor neuron axons (Uetani, Chagnon et al. 2006), and its expression is dampened in a dose-dependent fashion by estradiol (Naciff, Overmann et al. 2003). • Copy Number Variant – small deletion exon 3 – IRLSSG rating scale = 37 of 40 PLM index (single leg, 5 nights) = 25/hr Acknowledgements Emory Program in Sleep Dr. Donald Bliwise Dr. Michael Decker Dr. Alex Iranzo Dr. Jeffrey Durmer Dr. Lynn-Marie Trotti Dr. Lisa Billars Dr. Reddiah Mumanenni Dr. Glenda Keating Dr. Amanda Freeman Dr. Tom Genetta J Max Beck Dr. Gillian Hue Daniel Miller Kaniyika Freeman Emory Dept. of Physiology deCODE Genetics Dr. Shawn Hochman Dr. Hreinn Stefansson Dr. KristleifurKristjansson Emory Dept. of Genetics Dr. Andrew Hicks Dr. Steve Warren Dr. Larus Gudmundsson Dr. Mark Bouzyk Ingibjorg Eiriksdottir, RN Dr. Jeffrey Gulcher Dr. Kari Stefansson Emory Dept. of Neurology Dr. Allan Levey Landspitali Dr. Salina Waddy Ami Rosen Dr. Thordur Sigmundsson CRIN Staff Dr. Albert Pal Sigdursson Emory School of Public Health Dr. Harland Austin Funding RLS Foundation Arthur L. Williams Jr. Foundation Woodruff Health Sciences