What Causes Primary Restless Legs Syndrome?

The Genetic Basis of RLS:

To map a gene or genes that may play a role in the vulnerability to restless legs syndrome, Desautels et al. conducted a genome-wide scan in a large French-Canadian family. This group reported a significant linkage chromosome 12q for RLS with a significant LOD score of 3.59. These findings represent the first mapping of a genetic locus (RLS 1) conferring susceptibility to RLS although the inheritance pattern in this family appeared to be autosomal recessive but the authors suggest a "pseudo-dominant pattern" of inheritance.

More recently, Desautels et al. (2005) carried out another study which supported the previously reported chromosome 12q linkage results. A total of 276 individuals from 19 families were examined using a selection of markers spanning the identified candidate interval on chromosome 12q. Two-point analyses of individual pedigrees indicated that 5 kindreds were consistent with linkage to chromosome 12q and a maximum 2-point logarithm-of-odds score of 5.67 was observed. The results supported the presence of a major restless legs syndrome-susceptibility locus on chromosome 12q, which has been designated as RLS.1

Thereafter, Bonati et al. reported a significant evidence of linkage to a new locus for RLS on chromosome 14q13-21 region in a 30-member, three-generation Italian family affected by RLS and PLMS. This was the second RLS locus identified (RLS 2) and the first consistent with an autosomal dominant inheritance pattern. The accurate clinical evaluation of RLS-affected, as well as unaffected, family members allowed for the configuring of RLS as a phenotypic spectrum ranging from PLMS to RLS.

Levchenko et al. (2004) aimed to replicate this finding and determine the importance of this locus in the French Canadian population. The results supported the existence of the 14q locus and indicated that this locus may also be responsible for a small fraction of French Canadian restless legs syndrome patients. However absence of linkage in most of the relations suggests that the genetic cause of RLS in the French Canadian population is largely distinct from that in Italy.

Most recently, Chen et al. characterized 15 large and extended multiplex pedigrees consisting of 453 subjects, of whom 134 were affected with restless legs syndrome. A weighted average correlation of 0.17 between first-degree relatives was obtained, and heritability was estimated to be 0.60 for all types of relative pairs, indicating that the disorder was highly heritable in this cohort. Model-free linkage analysis identified 1 novel significant RLS susceptibility locus on 9p24-p22 with a multipoint nonparametric linkage (NPL) score of 3.22 (RLS 3). Chen et al. also suggested an indirect confirmation of an RLS gene on chromosome 12q22-q23.23

Thus, identification of three genetic loci for RLS on three different chromosomes, 12q22-23 (Desautels et al. 2001), 14q13-21 (Bonati et al. 2003), and 9p24-22 (Chen et al. 2004), suggests that RLS is a genetically highly heterogeneous disorder.

The Neurochemical Basis of RLS:

RLS: A brain neurochemcal dysfunction?

RLS may result from a combination dysfunction of signalling of the brain chmical dopamine along with iron and opiates.

Iron: A metabolic basis of RLS has been postulated and a common association of RLS is iron deficiency anaemia. Serum iron levels exhibits circadian variation with up to a 50% drop in iron concentration at night when the symptoms of RLS are most obvious. In RLS, MRI brain studies demonstrate reduced iron in the substantia nigra. In a post mortem study of RLS brains compared to controls, H-ferritin staining in the substantia nigra was significantly reduced as was ferritin and transferrin receptor staining in neurons containing neuromelanin. Furthermore the total iron regulatory protein activity, specifically the IRP1 activity were significantly decreased in the neuromelanin cells suggesting defects in the "post-transcription regulatory mechanism" for transferrin receptor expression. This could form the basis of the mechanism of cellular iron deficiency.

More recently, a novel hypothesis has been suggested on the basis of the reduced expression of Thy-1 in the substantia nigra of RLS patients. Thy-1 is a cell adhesion molecule that is involved in the regulation of vesicular release of neurotransmitters. Thy1 concentrations are decreased in cell and animal models by iron chelation. Thus the novel concept of the compromise of dapominergic neurotransmitter release by iron deficiency is proposed.

Dopamine and RLS: In RLS, dysfunction of the central dopaminergic system due to cellular loss in the mesocorticolimbic dopamine systems have been implicated, and this hypothesis has been supported by the beneficial effects of various dopaminergic agents in RLS. However, striatal deafferentation due to nigral dopaminergic cell loss that characterises PD, has not been noted in RLS. Functional imaging studies have been used to investigate the central dopamine and other receptor status in an effort to understand the link between RLS and the dopamine system but have reported conflicting data. Eisensehr et al (2001) have shown no differences in pre-synaptic (dopamine transporter) or post-synaptic (123I-IBZM) D2 receptor binding. In another study, Linke and colleagues (2004) studied the striatal dopamine transporter with (123)I IPT (a tropane ligand) using SPECT in 28 RLS, 29 early PD patients and 23 age matched controls and reported no difference in IPT binding between RLS and controls. This study, therefore disputes further the link between RLS and PD based on nigrostriatal presynaptic dopaminergic dysfunction. A recent study by Mrowka and colleagues (2005) investigated RLS patients and controls using a three dimensional ultrasound based movement analysis before and after a levodopa test dose and beta CIT-SPECT scans. No significant change in movement analysis in response to levodopa or beta-CIT signals in caudate or putamen were observed.