RLS is a genetically complex
RLS is a genetically complex disorder in which genetic and environmental factors contribute to the phenotype (Trenkwalder, Allen, Högl, Paulus, & Winkelmann, 2016). This disease is highly familial and six genetic variants with single nucleotide polymorphisms have been identified by genome-wide association studies (Scholz, 2017; Winkelman et al., 2011, Winkelman et al., 2007). It is interesting to notice that the products of three of these genes (BTBD9, MAP2K5 and MEIS1) are highly expressed in the basal ganglia, red nucleus, cerebral cortex and spinal cord (Guo et al., 2017; Winkelman, 2008). Recently, Schormair et al. (2017) described a meta-analysis of genome-wide association studies of RLS in which they demonstrated strong and reproducible evidence for 13 new genetic loci that contribute to risk of RLS and have provided further insights into the molecular mechanisms underlying the disorder, evidencing possible novel therapeutic targets or avenues for the repurposing of existing drugs.
Although the pathophysiology of RLS is not fully understood, evidence indicates that both iron deficiency and dopaminergic abnormalities are involved in its etiology. As iron is a major cofactor in dopaminergic neurotransmission, iron deficits may produce dopaminergic changes that exacerbate RLS symptoms (Allen & Earley, 2007; Becker & Novak, 2014). However, the fact that there is an overall increase in severity of symptoms after long-term dopaminergic therapy is leading to a shift towards non-dopaminergic alternatives such as calcium channel α2δ ligands (i.e., gabapentin, gabapentin enacarbil and pregabalin), opioids (i.e., oxycodone and methadone), and substances that act on glutamate and adenosine systems (Anguelova, Vlak, Kurvers, & Rijsman, 2018; Faulkner, 2018; Garcia-Borreguero & Cano-Pumarega, 2017; Garcia-Borreguero et al., 2018; Quiroz et al., 2016; Silber et al., 2018; Trenkwalder, Zieglgänsberger, Ahmedzai, & Högl, 2017) (see Table 1).
Dopaminergic abnormalities in RLS and treatments Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of dopamine, which catalyzes the non-heme ferrous-mediate incorporation of one atom of molecular oxygen into both the amino EGTA substrate and the reducing cofactor 6R-tetrahydrobiopterin. The reaction produces the catechol amino acid l-3,4-dihydroxyphenylalanine (l-DOPA) and the pterin product via an electrophilic aromatic substitution (Roberts & Fitzpatrick, 2013). As iron is a cofactor of this enzyme, iron deficiency may affect dopamine production indirectly and can alter the dopaminergic system in the brain (Dauvilliers & Winkelmann, 2013). Moreover, iron deficiency has been shown to alter the expression of dopamine-related genes, including a ferritin regulatory gene SDF-1 (Hare, Ayton, Bush, & Lei, 2013; Jellen et al., 2013). In addition, a preclinical study found that loss of the transferrin receptor causes neuronal iron deficiency and dopaminergic neurodegeneration (Matak et al., 2016). Altered dopamine function plays an important role in PLMS symptomatology of RLS. The most compelling argument that supports this idea is that RLS symptoms are strikingly improved after the treatment with dopaminergic drugs that target D2R/D3R, and it is also in agree with the repeated demonstration of biochemical changes related to the dopaminergic system (Earley et al., 2014; Garcia-Borreguero et al., 2013; Yepes et al., 2017). The dopaminergic profile in RLS includes abnormally high levels of the dopamine metabolites 3-ortho-methyldopa and homovanillic acid in the cerebrospinal fluid, a decrease in the density of striatal D2R and in the mesolimbic D2R/D3R and dopamine transporters (mostly membrane-bound transporters) and a pronounced increase in tyrosine hydroxylase activity in the striatum and substantia nigra (Earley et al., 2011; Ferré, Quiroz, et al., 2018; Garcia-Borreguero & Cano-Pumarega, 2017; Oboshi et al., 2012; Wijemanne & Ondo, 2017). These data, when taken together, would be mostly compatible with a hyperdopaminergic-presynaptic state: increased synthesis and release and a decreased uptake of dopamine, leading to an increase in synaptic dopamine (Earley et al., 2014). In addition, the findings also predict the existence of a hypodopaminergic-postsynaptic state with decreased D2R/D3R. Overall, these data suggest that a hyperdopaminergic-presynaptic state in RLS is in balance or in opposition to a hypodopaminergic-postsynaptic state (Earley et al., 2014; Earley, Uhl, Clemens, & Ferré, 2017). Recently, Rizzo, Li, Galantucci, Filippi, and Cho (2017) indicated the existence of an even more complex dopaminergic change in RLS, with different dopamine levels depending on the disease duration and clinical severity, and with some brain regions presenting hyperdopaminergic and other hypodopaminergic activity.