1. [even prior to taking drugs] Where in the brain, how and at what level of resolution should we look for variants that alter vulnerability to RLS? Brain regional resolution? Ultrastructural resolution? Can CAM molecules help us to integrate the two levels of resolution?

2. Cell adhesion genes harbor variants that contribute to human individual differences in vulnerability to RLS

3. Consequences of likely heterogeneity of etiology and pathophyciology for RLS: Potential for missing large effects in subgroups based on heterogeneity Working hypothesis: Dopamine system differences are likely to be more evident in RLS subgroups Clinical definition (including Fe) provides one major subdivision Classical genetics (eg familiality) provides one major subdivision Molecular genetics with oligogenic influences now provides one major subdivision that may be (based on coexpression) especially likely to interact with DA systems

4. Do recent genetic observations support roles for dopaminergic neurons? Allen brain atlas data displays significant expression in SNc and VTA neurons, as well as many dbEST brain ESTs for genes with RLS allelic variants PTPRD (SNc; coronal) BTBD9 (saggital VTA) MAP2K5 (coronal, SNc)

5. Environment e 2 Genetic a 2 Working idea: Substantial overall genetic influences Genetic architecture with large effects at (at least) several loci Current working model for genetic architecture for RLS in the population includes oligogenic effects

6. 4000 2400 6400 Generations from present 800 Need to consider genetic background in these studies

7. Consequences of likely heterogeneity of etiology and pathophysiology for RLS: Potential for missing large effects in subgroups based on heterogeneity Potential advantage of following the working hypothesis that dopamine system differences are likely to be more evident in RLS subgroups Potential for understanding individual differences in responses to DA mimetics (eg good response, poorer responses, “augmentation” of sx) Potential for aiding understanding individual differences in responses to DA agents in a variety of clinical circumstances where there are similar problems that limit their long term utility

8. Questions: In RLS patients there is a slight reduction in dopamine concentration, artificially reversed in augmentation by overtreatment. Augmentation is due to a chronically intermittently elevated level of dopamine The spinal cord is particularly vulnerable due to lack of D2 receptor autoinhibition of dopamine concentration High dopamine leads to a relative overstimuation of dopamine D1 receptors Iron deficiency is a main (probably not the only) predisposing factor of augmentation, possibly caused by a reduced function of the dopamine transporter