| Restless legs syndrome (RLS) is a neurological condition characterized by an irresistible urge to move the limb associated with paresthesia. These symptoms, occurring predominantly at night, often interfere with nocturnal sleep, resulting in daytime somnolence and chronic sleep deprivation. Despite recurrent epidemiological reports suggesting a genetic contribution to the etiology of RLS, thus far no predisposing gene has been reported. Aiming to identify a susceptibility locus for RLS, several studies using two complementary approaches have been undertaken.; In order to map genes that may play a major role in the vulnerability to RLS, linkage analyses have been performed and a genomewide scan was conducted in a large French-Canadian family. Significant linkage was established on chromosome 12q, for a series of adjacent microsatellite markers with a maximum two-point LOD score of 3.42 (&thgr; = 0.05; P = 6 × 10−4; autosomal recessive mode of inheritance). This result has been corroborated in five additional kindreds confirming the presence of a major susceptibility locus on chromosome 12 (multipoint LOD score = 8.84). However, our linkage results also indicate that at least one additional RLS locus may exist as linkage was formally excluded in six pedigrees. In addition, mutational analyses ruled out the involvement of neurotensin as a functional and positional candidate gene. These findings represent the first mapping of a locus conferring susceptibility to RLS.; Furthermore, association studies have been carried out to evaluate the causal involvement of different candidate genes. In order to examine the genetic substrate of the dopamine hypothesis in RLS, several genes coding for receptors and enzymes related to dopaminergic transmission have been investigated. Analyses indicated that genes coding for dopaminergic receptors D1 through D5, presynaptic transporter, as well as dopamine β-hydroxylase, tyrosine hydroxylase and monoamines oxidase B have no major effect on the vulnerability to RLS. However, a positive association has been identified with the monoamine oxidase A gene. Indeed, while no positive association was observed among the men subjects, women with the high activity allele had a greater risk (OR: 2.0; 95% CI: 1.06 to 3.77) of being affected with RLS than those carrying the low activity alleles. Interestingly, women carrying the high transcription alleles showed a longer sleep onset latency (U = 163.5; p = 0.015) and exhibited a higher movement index during the Suggested Immobilization Test (Student's t-test = −2.02; p = 0.048). (Abstract shortened by UMI.)... |
