Restless Legs Syndrome (RLS) is a common sleep disorder especially for older adults. It is characterized by episodes of distressing sensations in the limbs, generally the legs, which are relieved by movement of the affected extremity. It is generally progressive starting at various ages but becoming both more common and more distressing for older adults. Symptoms become so severe, particularly for older adults, that in many cases activities in which movements are seriously limited and cognitive stimulation is minimal become difficult if not impossible. In addition, individuals usually have great difficulty initiating and maintaining sleep and experience severe, chronic, disabling sleep deprivation. Several reports have been published in which multiple family members are affected with RLS. Investigators have surmised that transmission of RLS follows a Mendelian autosomal dominant pattern. To date, however, no systematically ascertained family study of RLS has been published in the literature. Likewise, there are no studies of the mode of transmission for RLS. Despite this, there have been three unpublished attempts to use linkage analysis to find the gene(s) causing RLS. No vulnerability loci have been found. Our pilot data from 96 families of RLS patients show there is indeed a strong familial component to RLS, particularly in relatives of probands with onset earlier than 45 years of age. In these families, risk for RLS in first-degree relatives was 23.6 percent (by history as reported by the proband). This is significantly elevated over the 3.5 percent of first-degree relatives of unaffected controls found to be affected with RLS (also by history). Even within this early-onset group, there appear to be familial and non-familial groups.
The Aims of the current proposal are: (1) to use direct interview methods for assessing the presence of RLS in all first- and second-degree relatives of 130 probands with RLS and compare these rates to those found in a control sample assessed with the same methodology; (2) to test the hypothesis There exists a more familial, early-onset subgroup of RS and to determine the optimum age of onset for defining such a group: and (3) to deduce the most likely mode of genetic inheritance using segregation analysis on diagnostic data of the estimated 1700 family members in the RLS sample and to perform this analysis separately for the early and late onset RLS probands. The ultimate goal of this research would be to provide reliable data from a carefully characterized family study sample with attention to evaluating age-of-onset determination of two different phenotypes as the needed basic groundwork for research to determine the genetics of RLS, a relatively common and often severely distressing disorder.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (03))
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Monjan, Andrew A
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Johns Hopkins University
Schools of Medicine
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