The Restless Legs Syndrome (RLS) is a heterogeneous disease. Symptomatic or secondary forms encompass iron deficiency, uremia, pregnancy, polyneuropathy, and other causes. The so-called idiopathic RLS Show more
The Restless Legs Syndrome (RLS) is a heterogeneous disease. Symptomatic or secondary forms encompass iron deficiency, uremia, pregnancy, polyneuropathy, and other causes. The so-called idiopathic RLS syndrome preferentially affects patients with a younger onset before the age of 30. Here we summarize pathophysiological results along the anatomical route, beginning at the cortex and followed by the basal ganglia, thalamus, A11 neurones, substantia nigra, brainstem nuclei, and spinal cord. Genetic risk variants for RLS have recently been identified in two genes, one of them the homeobox gene MEIS1, known to be involved in embryonic development and variants in a second locus containing the genes encoding mitogen-activated protein kinase MAP2K5, and the transcription factor LBXCOR1. A third one, the BTBD9 gene with unknown function encodes a BTB(POZ) domain. Accordingly, new concepts on pathophysiology have to bridge conventional knowledge with possible consequences deriving from these findings. Furthermore, this may create a framework to help understand why dopamine, opioid, and some anticonvulsant therapies are effective in RLS patients. Show less
Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increas Show more
Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. Show less