Correspondence

A Genetic Risk Factor for Periodic Limb Movements in Sleep

N Engl J Med 2008; 358:425-428January 24, 2008

Article

To the Editor:

Stefansson et al. (Aug. 16 issue)1 report the results of a genomewide association study of the restless legs syndrome (RLS) in an Icelandic series. The analysis revealed that one single-nucleotide polymorphism (SNP) in the BTB (POZ) domain–containing 9 (BTBD9) gene was associated with RLS. Replication in smaller samples from Iceland and the United States showed that the discovery originated from a subgroup of patients with RLS who presented with periodic limb movements in sleep, a common feature of RLS. Winkelmann et al.2 performed a similar analysis for patients with RLS who were of European descent, with replication in samples of European or French-Canadian origin, and highlighted SNP associations in four genes in three chromosomal loci: MEIS1, BTBD9, and MAP2K5/LBXCOR1.

We have genotyped 11 SNPs spanning all three reported loci for disease susceptibility in a U.S. series of 244 patients with RLS (121 with sporadic cases and 123 familial probands) and 497 controls. Patients with sporadic cases have no known family history of RLS, whereas all probands have affected first-degree relatives (97%) or affected second-degree relatives, with an average of 3.7 affected persons per family (range, 2 to 7). RLS was clinically characterized by means of standardized methods with a series of questionnaires3; the initial presentation, RLS symptoms, and duration of and response to treatment were similar in the sporadic and familial groups. Genotyping was performed by means of the TaqMan or Sequenom assay or both assays; all markers were in Hardy–Weinberg equilibrium. All minor allele frequencies for patients with RLS and control subjects are similar to those reported previously.1,2 Statistical analysis confirmed the association with BTBD9 and MEIS1 genes but showed only a trend for variants in MAP2K5/LBXCOR1 and RLS. The odds ratio for the associated risk alleles ranged from 1.8 to 2.9 for BTBD9 and from 2.6 to 3.7 for MEIS1 (Table 1Table 1SNPs, Genotype Frequencies, and Odd Ratios for Each RLS Susceptibility Locus.). MEIS1 haplotype analysis confirmed a more significant association for the AG haplotype (odds ratio, 4.6; 95% confidence interval, 2.9 to 7.2; P<10⁻⁷), as previously reported.2

Given the magnitude of the effect, it is curious that MEIS1 was not detected in the Icelandic series1; whether this is because of the use of different genotyping platforms, detailed phenotyping of RLS versus a diagnosis based on a constellation of findings and symptoms, or population specificity should be addressed. Our study confirms that variants in BTBD9 and MEIS1 loci are involved in susceptibility to RLS susceptiband suggests that clinical differences between genetically defined groups may now be defined. The specific mutations and biological mechanism (or mechanisms) underlying familial RLS have yet to be elucidated, along with the environmental and stochastic factors that presumably play a greater role in sporadic RLS.

Carles Vilariño-Güell, Ph.D.
Matthew J. Farrer, Ph.D.
Siong-Chi Lin, M.D.
Mayo Clinic, Jacksonville, FL 32224
farrer.matthew@mayo.edu

3 References

1. 1

   Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357:639-647
   Full Text | Web of Science | Medline

2. 2

   Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39:1000-1006
   CrossRef | Web of Science | Medline

3. 3

   Allen RP, Kushida CA, Atkinson MJ. Factor analysis of the International Restless Legs Syndrome Study Group's scale for restless legs severity. Sleep Med 2003;4:133-135
   CrossRef | Web of Science | Medline

To the Editor:

In their article, Stefansson et al. say that we question the authenticity of RLS. This is a mischaracterization.

We described how GlaxoSmithKline generated — and the media, like Stefansson et al., uncritically repeated — exaggerated prevalence estimates.1 The typical high-end U.S. prevalence claim (“10% prevalence”) comes from a one-state survey using one unvalidated question.2 The editorialist's claim that 3% of adults have frequent, bothersome symptoms is also suspect.3 The telephone survey he cites used four validated questions but reported an implausible 98% response rate; selection bias undoubtedly has resulted in an exaggerated estimate of 3%.1

RLS — like many disorders — exists along a spectrum: from debilitating to ordinary experience. The question is where to draw the line identifying those who are “sick.” This matters: diagnosis leads to treatments with important side effects (nausea with ropinirole as compared with placebo, 40% vs. 8%4) and unknown long-term consequences.

We are concerned that the $100 million spent in 2007 on the marketing of RLS drugs5 is distorting what is known about restless legs.

Steven Woloshin, M.D.
Lisa M. Schwartz, M.D.
Veterans Affairs Outcomes Group, White River Junction, VT 05009
steven.woloshin@dartmouth.edu

5 References

1. 1

   Woloshin S, Schwartz L. Giving legs to restless legs: a case study of how the media helps make people sick. PLoS Med 2006;3:e170-e170
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2. 2

   Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med 2000;160:2137-2141
   CrossRef | Web of Science | Medline

3. 3

   Winkelman JW. Periodic limb movements in sleep -- endophenotype for restless legs syndrome? N Engl J Med 2007;357:703-705
   Full Text | Web of Science | Medline

4. 4

   Requip (ropinirole hydrochloride) prescribing information. GlaxoSmithKline, 2005. (Available at http://www.fda.gov/cder/foi/label/2005/020658s013lbl.pdf.)
   

5. 5

   Nielsen Monitor-Plus. New York: The Nielsen Company, 2007. (Available at http://www.NielsenMedia.com.)
   

Citing Articles (15)

Citing Articles

1. 1

   David B. Rye, Lynn Marie. Trotti. 2012. Restless Legs Syndrome and Periodic Limb Movement Disorders. , 307-323.
   CrossRef

2. 2

   Lan Xiong. (2011) What’s next after the exciting discovery and reassuring replications of genome-wide association studies of restless legs syndrome?. Sleep Medicine 12:8, 733-734
   CrossRef

3. 3

   Qinbo Yang, Lin Li, Qiuyun Chen, Nancy Foldvary-Schaefer, William G. Ondo, Qing Kenneth Wang. (2011) Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. Sleep Medicine 12:8, 800-804
   CrossRef

4. 4

   Hélène Catoire, Patrick A. Dion, Lan Xiong, Mourabit Amari, Rebecca Gaudet, Simon L. Girard, Anne Noreau, Claudia Gaspar, Gustavo Turecki, Jacques Y. Montplaisir, J. Alex Parker, Guy A. Rouleau. (2011) Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Annals of Neurology 70:1, 170-175
   CrossRef

5. 5

   Barbara Schormair, Juliane Winkelmann. (2011) Genetics of Restless Legs Syndrome: Mendelian, Complex, and Everything in Between. Sleep Medicine Clinics 6:2, 203-215
   CrossRef

6. 6

   Allan I. Pack, Grace W. Pien. (2011) Update on Sleep and Its Disorders. Annual Review of Medicine 62:1, 447-460
   CrossRef

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   Juliette Faraco, Emmanuel Mignot. 2011. Genetics of Sleep and Sleep Disorders in Humans. , 184-198.
   CrossRef

8. 8

   Lynn marie Trotti, David B. Rye. 2011. Restless legs syndrome. , 661-673.
   CrossRef

9. 9

   Robert Arbuckle, Linda Abetz, Jeffrey S. Durmer, Anna Ivanenko, Judith A. Owens, Jens Croenlein, Kate Bolton, Adam Moore, Richard P. Allen, Arthur S. Walters, Daniel L. Picchietti. (2010) Development of the Pediatric Restless Legs Syndrome Severity Scale (P-RLS-SS)©: A patient-reported outcome measure of pediatric RLS symptoms and impact. Sleep Medicine 11:9, 897-906
   CrossRef

10. 10

    Matthew A. Picchietti, Daniel L. Picchietti. (2010) Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment. Sleep Medicine 11:7, 643-651
    CrossRef

11. 11

    Mathieu Raux, Elias G. Karroum, Isabelle Arnulf. (2010) Case Scenario: Anesthetic Implications of Restless Legs Syndrome. Anesthesiology 112:6, 1511-1517
    CrossRef

12. 12

    J. E. Young, C. Vilarino-Guell, S.-C. Lin, Z. K. Wszolek, M. J. Farrer. (2009) Clinical and Genetic Description of a Family With a High Prevalence of Autosomal Dominant Restless Legs Syndrome. Mayo Clinic Proceedings 84:2, 134-138
    CrossRef

13. 13

    L. Xiong, H. Catoire, P. Dion, C. Gaspar, R. G. Lafreniere, S. L. Girard, A. Levchenko, J.-B. Riviere, L. Fiori, J. St-Onge, I. Bachand, P. Thibodeau, R. Allen, C. Earley, G. Turecki, J. Montplaisir, G. A. Rouleau. (2009) MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels. Human Molecular Genetics 18:6, 1065-1074
    CrossRef

14. 14

    Javier Simón-Sánchez, Andrew Singleton. (2008) Genome-wide association studies in neurological disorders. The Lancet Neurology 7:11, 1067-1072
    CrossRef

15. 15

    Barbara Schormair, David Kemlink, Darina Roeske, Gertrud Eckstein, Lan Xiong, Peter Lichtner, Stephan Ripke, Claudia Trenkwalder, Alexander Zimprich, Karin Stiasny-Kolster, Wolfgang Oertel, Cornelius G Bachmann, Walter Paulus, Birgit Högl, Birgit Frauscher, Viola Gschliesser, Werner Poewe, Ines Peglau, Pavel Vodicka, Jana Vávrová, Karel Sonka, Sona Nevsimalova, Jacques Montplaisir, Gustavo Turecki, Guy Rouleau, Christian Gieger, Thomas Illig, H-Erich Wichmann, Florian Holsboer, Bertram Müller-Myhsok, Thomas Meitinger, Juliane Winkelmann. (2008) PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nature Genetics 40:8, 946-948
    CrossRef