Restless Legs Syndrome: Epidemiological and Clinicogenetic Study in a South Tyrolean Population Isolate Florian D. Vogl, MSc, MD, 1 Irene Pichler, MSc, 1 Susanna Adel, MD, 2 Gerd K. Pinggera, PhD, 1 Stefano Bracco, BSc, 1 Alessandro De Grandi, MSc, 1 Claudia Beu Volpato, PhD, 1 Paolo Aridon, MD, 2 Thomas Mayer, MD, 3 Thomas Meitinger, MD, 3 Christine Klein, MD, 4,5 Giorgio Casari, PhD, 2 and Peter P. Pramstaller, MD 1,4,6 * 1 Institute of Genetic Medicine, European Academy, Bolzano, Italy 2 Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy 3 Institute of Human Genetics, Technical University of Munich, Munich, Germany 4 Department of Neurology, University of Lu ¨beck, Lu ¨beck, Germany 5 Department of Human Genetics, University of Lu ¨beck, Lu ¨beck, Germany 6 Department of Neurology, General Regional Hospital, Bolzano, Italy Abstract: Genetic contributions to restless legs syndrome (RLS) have been consistently recognized from population and family studies. To determine the clinical and genetic features of RLS in a population isolate and explore linkage to three pre- viously described susceptibility loci on chromosomes 12q, 14q, and 9p, respectively, an isolated population in the South Ty- rolean Alps was identified and 530 adults participated in the study. Using a two-step strategy, 47 patients with idiopathic RLS were ascertained. The prevalence in the population was 8.9%. Twenty-eight patients (59.6%) had at least one affected first-degree relative and were classified as hereditary cases. In a single extended pedigree, linkage to known RLS loci was investigated specifying autosomal dominant and recessive models; parametric and nonparametric multipoint linkage scores were computed. None of the calculated linkage scores was suggestive of linkage between RLS and any of the three investigated loci. This study was conducted in a population isolate providing for a homogeneous genetic and environmental background. The absence of a suggestive linkage signal at the three known RLS susceptibility loci is indicative of further locus heterogeneity of this frequent disorder and encourages further studies to unveil the genetic causes of RLS. © 2006 Movement Disorder Society Key words: restless legs syndrome; population isolate; prev- alence; genetics Restless legs syndrome (RLS) is a common movement disorder affecting between 2% and 15% of the general population. 1–5 In 1995, the International RLS Study Group defined four minimal criteria required to diagnose RLS, 6 which were revised in a National Institutes of Health consensus statement issued in 2003. 7 RLS is generally classified into idiopathic and symptomatic forms. In idiopathic RLS, which includes both sporadic and familial cases, physical and neurological examina- tions are normal. The etiology of RLS currently remains elusive. Several studies suggested a substantial genetic contribution to idio- pathic RLS. A family history of RLS was described in up to 60% to 65% of patients, 2,8 –11 and a high concordance rate of 83.3% between identical twins was reported. 12 Heritabil- ity of RLS was estimated to be 0.60. 13 Inheritance was consistent with autosomal dominant transmission. 10,14 To date, linkage studies identified three susceptibility loci, i.e., on chromosomes 12q, 14q, and 9p, in RLS families from different populations. 13,15–17 These molecular findings, together with the previously reported variable expressivity of the phenotype, 8,18,19 Drs. Vogl and Pichler contributed equally to this study. *Correspondence to: Dr. Peter P. Pramstaller, Institute of Genetic Medicine, European Academy, Viale Druso 1, 39100 Bolzano, Italy. E-mail: peter.pramstaller@eurac.edu Received 2 September 2005; Revised 13 December 2005; Accepted 23 December 2005 Published online 9 May 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.20922 Movement Disorders Vol. 21, No. 8, 2006, pp. 1189 –1195 © 2006 Movement Disorder Society 1189