412 Sleep-Wake Disorders
duration of sitting or lying down in the day to sitting or lying down in the evening or night.
Nocturnal worsening tends to persist even in the context of pediatric RLS. As with RLS in
adults, there is a significant negative impact on sleep, mood, cognition, and function. Im-
pairment in children and adolescents is mani fested more often in behavioral and educa-
tional domains. 
Risk and Prognostic Factors 
Genetic and physiological. Predisposing factors includ e female gender, advancing
age, genetic risk variants, an d family history of RLS. Precipitating factors are often time-
limited, such as iron defici ency, with most individuals resuming normal sleep patterns
after the initial triggering even t has disappeared. Genetic risk variants also play a role in
RLS secondary to such disorder s as uremia, suggesting that individuals with a genetic sus-
ceptibility develop RLS in the presence of further risk factors. RLS has a strong familial
component. 
There are defined pathophysi ological pathways subserving RLS. Genome-wide asso-
ciation studies have found that RLS is significantly associated with common genetic vari-
ants in intronic or intergenic regions in MEIS1 , BTBD9 , and MAP2K5  on chromosomes 2p,
6p, and 15q, respectively. The ass ociation of these three varian ts with RLS has been inde-
pendently replicated. BTBD9  confers a very large (80%) exce ssive risk when even a single
allele is present. Because of the high frequenc y of this variant in individuals of European
descent, the population attributable risk (P AR) approximates 50%. At-risk alleles associ-