Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity.

BACKGROUND: Genes are involved in the etiology of restless legs syndrome, a common sensorimotor disorder. OBJECTIVES: To replicate and to further characterize our previously reported chromosome 12q linkage results. DESIGN: Family linkage study. SETTING AND PARTICIPANTS: A total of 276 individuals from 19 families have been examined using a selection of markers spanning the identified candidate interval on chromosome 12q. RESULTS: Two-point analyses of individual pedigrees indicated that 5 kindreds were consistent with linkage to chromosome 12q. When considering these 5 pedigrees along with the family in which linkage was originally reported, we observed a maximum 2-point logarithm-of-odds score of 5.67 (at theta = 0.10; for marker D12S1636; autosomal recessive) and a maximum multipoint logarithm-of-odds score of 8.84 between the interval defined by markers D12S326 and D12S304. Furthermore, our results also suggest the presence of heterogeneity in restless legs syndrome as linkage was formally excluded across the region in 6 pedigrees. Interestingly, significantly higher periodic leg movements during sleep indices were observed for all probands with restless legs syndrome from linked families. CONCLUSIONS: These results support the presence of a major restless legs syndrome-susceptibility locus on chromosome 12q, which has been designated as RLS1, and also suggest that at least one additional locus may be involved in the origin of this prevalent condition.

Analysis of CAG repeat expansions in restless legs syndrome.

STUDY OBJECTIVES: A relatively high prevalence of restless legs syndrome symptoms has been recently reported in a substantial proportion of patients affected with spinocerebellar ataxia type 3. Our aim was to investigate whether there is a common genetic etiology between restless legs syndrome and spinocerebellar ataxia type 3. DESIGN: Systematic differences in the number of spinocerebellar ataxia type 3 trinucleotide repeat were investigated by means of an association study. The relationship between the size of the expanded alleles and several clinical features was also considered. PARTICIPANTS AND SETTING: 125 extensively characterized restless legs syndrome patients compared with 188 healthy controls matched for ethnic background. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: No CAG repeat expansions in the pathologic or intermediate range were detected in any of the examined subjects, including patients and controls. A similar allelic distribution was observed in both groups (Mann-Whitney U test = 78406; P = 0.99). Moreover, stratification analyses of the patients' samples according to different clinical and polysomnographic variables disclosed no significant differences. CONCLUSIONS: These results do not provide evidence toward an involvement of large CAG trinucleotide expansions at the spinocerebellar ataxia type 3 locus in idiopathic restless legs syndrome.