And, another variant of that research.
This is from the New England Journal of Medicine:
Today, 350 years after its first description, the restless legs syndrome (RLS) is strangely controversial. Experts and patients alike describe RLS both as a miserably impairing disorder and as "the most common disorder you have never heard of." Critics do not regard RLS as a disorder at all but, rather, as the fabrication of an omnivorous pharmaceutical industry. RLS is a waking sensorimotor disturbance with features of both neurologic and sleep disorders. Those afflicted describe an intensely uncomfortable, overwhelming urge to move the legs (often accompanied by dysesthesias), predominantly in the evening or at night, that is present at rest and relieved only temporarily by movement. These leg sensations dramatically disturb sleep, and impairment in quality of life is common.1
Once asleep, the majority of (but not all) patients with RLS have periodic limb movements in sleep, which was originally called "nocturnal myoclonus." These movements consist of recurrent (every 20 to 30 seconds), involuntary dorsiflexion of the foot and lower leg, with each movement lasting about 2 to 5 seconds. Such movements can be recorded in the home with simple surface monitors on the leg. Roughly one quarter of such limb movements are associated with arousal from sleep, as seen on electroencephalography, and all are followed by large elevations in systolic (20 to 25 mm Hg) and diastolic (10 to 15 mm Hg) blood pressure.2 However, the vast majority of persons with periodic limb movements in sleep do not have waking symptoms of RLS. Such movements are common without RLS, with increased age, in patients who are taking antidepressant medications and in those with certain neurologic and sleep disorders (e.g., narcolepsy and rapid-eye-movement sleep behavior disorder). Outside of RLS, the clinical significance of periodic limb movements in sleep remains uncertain, though concern exists regarding the effects of the movements on sleep quality and cardiovascular functioning.3
Some of the earliest descriptions of RLS recognized its strongly familial nature. Recent linkage studies have shown a number of susceptibility loci for familial RLS.4 However, until now, no gene has been identified. For this reason, the report by Stefansson et al.5 in this issue of the Journal showing an association between a sequence variant in chromosome 6p and periodic limb movements in sleep in distinct Icelandic and American cohorts of subjects with RLS and their families, as well as controls, is exciting and important. The simultaneously published report by Winkelmann et al.6 showing an association between RLS and the same sequence variant, as well as two additional single-nucleotide polymorphisms (SNPs), in German and Canadian cohorts with RLS makes this finding even more secure.
Inspection of the data provided by Stefansson et al., however, shows that this sequence variant does not appear to be a gene for RLS but, rather, for periodic limb movements in sleep. The investigators observed the highest odds ratio in subjects with periodic limb movements in sleep without RLS. As this group became increasingly diluted with subjects with RLS, the association with the SNP became less and less apparent. Although a significant association with the SNP was still present in the entire group with RLS (with and without periodic limb movements), it disappeared completely in subjects with RLS without periodic limb movements in sleep. Since Winkelmann et al.6 did not report on periodic limb movements in sleep in their study, it is unclear whether the other sequence variants they found are truly for RLS, for periodic limb movements in sleep, or for some other RLS marker.
What is the advantage of knowing the genetic basis for periodic limb movements in sleep? These movements may serve as a heritable biologic marker, or endophenotype, for RLS. Disorders with a complex phenotype and heritability, such as RLS, are increasingly being dissected into their component parts with the use of endophenotypes. Endophenotypes are relatively simple, stable biologic phenomena that can be measured objectively and are genetically determined. To function as an endophenotype, a marker must be present both in affected patients with the disorder and in unaffected family members. In theory, although the disorder itself will usually result from a mixture of multiple genetic and nongenetic abnormalities, the endophenotype, as a simpler biologic phenomenon, will have a more straightforward genetic and pathophysiological basis. This method has been constructively applied to a number of disorders, such as hemochromatosis (with serum iron as the endophenotype), the long-QT syndrome (QT prolongation), and familial adenomatous polyposis coli (intestinal polyps).7
The use of periodic limb movements in sleep as an endophenotype for RLS may present a number of valuable opportunities and insights. From a genetic perspective, it might assist with linkage to other relevant susceptibility genes so that polygenic interactions can be discerned. From a diagnostic perspective, the use of periodic limb movements in sleep may improve diagnostic accuracy and provide a more homogeneous RLS phenotype for epidemiology, physiology, genotyping, and treatment studies. RLS has a number of clinical mimics (e.g., peripheral neuropathy and nocturnal leg cramps), and its diagnosis with the use of questionnaires is fraught with difficulty. The study by Stefansson et al. provides some insight into this problem since their questionnaire had a false positive rate of 25% and a similar false negative rate, as compared with an expert clinical interview.
In addition, RLS may have a number of subtypes, some with and some without periodic limb movements in sleep. For instance, many, but not all, patients with RLS have an excellent response to dopaminergic therapy, which also nearly eliminates periodic limb movements in sleep.8 The subtyping of patients with RLS may predict treatment responses to these agents. Finally, patients with end-stage renal failure who have periodic limb movements in sleep are at increased risk of death,9 and such movements may also contribute to the observed elevated risk of cardiovascular disease in patients with RLS.10 Use of the endophenotype for periodic limb movements, or even of the sequence variant itself, may allow stratification of these risks in patients with RLS or other conditions marked by such movements.
The association between the SNP and reduced serum ferritin indexes is an important feature of the study by Stefansson et al. Multiple studies that used magnetic resonance imaging scans, analysis of cerebrospinal fluid, transcranial ultrasonography, and analysis of autopsy specimens11 showed that patients with RLS had a reduction in iron in the central nervous system. Iron levels in the brain may thus reflect an independent endophenotype for RLS or may be a causative factor for RLS or periodic limb movements in sleep.
The demonstration of a strong association between a sequence variant and periodic limb movements in sleep and, to a lesser extent, RLS does not validate RLS as a "genuine" disorder. Many physiological features that vary in the otherwise normal population (e.g., baldness, height, and eye color) have genetic bases. The legitimacy of RLS as a bona fide disorder is provided by the clinically apparent and well-documented sleep disturbance and distress of the roughly 3% of the adult population with frequent and bothersome RLS symptoms. The genetic finding reported by Stefansson et al. offers hope to patients with periodic limb movements in sleep and RLS that the syndrome's pathophysiology will be understood and that such knowledge will lead to additional effective and durable treatments.
Dr. Winkelman reports receiving research support and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, and Schwarz Pharma and lecture fees from Boehringer Ingelheim and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.
From the Division of Sleep Medicine, Brigham and Women's Hospital, and Harvard Medical School — both in Boston.
This article (10.1056/NEJMe078129) was published at www.nejm.org
on July 18, 2007. It will appear in the August 16 issue of the Journal.
Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286-1292. [Free Full Text]
Pennestri MH, Montplaisir J, Colombo R, Lavigne G, Lanfranchi PA. Nocturnal blood pressure changes in patients with restless legs syndrome. Neurology 2007;68:1213-1218. [Free Full Text]
Hornyak M, Feige B, Riemann D, Voderholzer U. Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006;10:169-177. [CrossRef][ISI][Medline]
Winkelmann J, Polo O, Provini F, et al. Genetics of restless legs syndrome (RLS): state-of-the-art and future directions. Mov Disord (in press).
Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357. DOI: 10.1056/NEJMoa072743.
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 (in press).
Braff DL, Freedman R, Schork NJ, Gottesman II. Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr Bull 2007;33:21-32. [Free Full Text]
Hening WA. Current guidelines and standards of practice for restless legs syndrome. Am J Med 2007;120:Suppl 1:S22-S27. [CrossRef][ISI][Medline]
Benz RL, Pressman MR, Hovick ET, Peterson DD. Potential novel predictors of mortality in end-stage renal disease patients with sleep disorders. Am J Kidney Dis 2000;35:1052-1060. [ISI][Medline]
Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology (in press).
Allen RP, Earley CJ. The role of iron in restless legs syndrome. Mov Disord (in press).