The Molecular Genetics of Restless Legs Syndrome

Rye, David B.

doi:10.1016/j.jsmc.2015.05.015

Cited by 24 publications

(6 citation statements)

References 66 publications

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“…). Different subjects have different I h activity levels, presumably related to life‐style factors, to which I h is exquisitely sensitive (Pape, ; Robinson & Siegelbaum, ; Wahl‐Schott & Biel, ), and possibly genetic factors, which are prominent in idiopathic RLS (Rye, ; Winkelmann et al . ; Trenkwalder et al .…”

Section: Discussionmentioning

confidence: 99%

“…In earlier studies on healthy subjects, we have demonstrated that, although the between-subject variability of I h is high, within-subject variability is quite low, even in test-retest situations (Tomlinson et al 2010;Howells et al 2013), and also that the between-subject variability can be explained by differences in the voltage for half-activation of HCN channels (Howells et al 2012). Different subjects have different I h activity levels, presumably related to life-style factors, to which I h is exquisitely sensitive (Pape, 1996;Robinson & Siegelbaum, 2003;, and possibly genetic factors, which are prominent in idiopathic RLS (Rye, 2015;Winkelmann et al 2007;Trenkwalder et al 2016). In this respect, RLS patients may merely be at one end of a 'normal' spectrum of I h activity.…”

Section: Hcn Activity: the 'Chicken And Egg' Issuementioning

confidence: 99%

“…Restless legs syndrome (RLS) is a sensorimotor disorder with multiple aetiologies. The idiopathic end of the spectrum may be influenced by common allelic variants (Winkelmann et al 2007;Rye, 2015) and is associated with a number of co-morbidities including peripheral neuronal diseases such as polyneuropathy, central disturbances such as stroke and multiple sclerosis, or metabolic disorders such as iron deficiency, anaemia and diabetes (Allen et al 2014;Trenkwalder et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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I_h contributes to increased motoneuron excitability in restless legs syndrome

Czesnik

Howells

Bartl

et al. 2018

The Journal of Physiology

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Key points Restless legs patients complain about sensory and motor symptoms leading to sleep disturbances. Symptoms include painful sensations, an urge to move and involuntary leg movements. The responsible mechanisms of restless legs syndrome are still not known, although current studies indicate an increased neuronal network excitability. Reflex studies indicate the involvement of spinal structures. Peripheral mechanisms have not been investigated so far. In the present study, we provide evidence of increased hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channel‐mediated inward rectification in motor axons. The excitability of sensory axons was not changed. We conclude that, in restless legs syndrome, an increased HCN current in motoneurons may play a pathophysiological role, such that these channels could represent a valuable target for pharmaceutical intervention. Abstract Restless legs syndrome is a sensorimotor network disorder. So far, the responsible pathophysiological mechanisms are poorly understood. In the present study, we provide evidence that the excitability of peripheral motoneurons contributes to the pathophysiology of restless legs syndrome. In vivo excitability studies on motor and sensory axons of the median nerve were performed on patients with idiopathic restless legs syndrome (iRLS) who were not currently on treatment. The iRLS patients had greater accommodation in motor but not sensory axons to long‐lasting hyperpolarization compared to age‐matched healthy subjects, indicating greater inward rectification in iRLS. The most reasonable explanation is that hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels open at less hyperpolarized membrane potentials, a view supported by mathematical modelling. The half‐activation potential for HCN channels (Bq) was the single best parameter that accounted for the difference between normal controls and iRLS data. A 6 mV depolarization of Bq reduced the discrepancy between the normal control model and the iRLS data by 92.1%. Taken together, our results suggest an increase in the excitability of motor units in iRLS that could enhance the likelihood of leg movements. The abnormal axonal properties are consistent with other findings indicating that the peripheral system is part of the network involved in iRLS.

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Section: Discussionmentioning

confidence: 99%

Section: Hcn Activity: the 'Chicken And Egg' Issuementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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I_h contributes to increased motoneuron excitability in restless legs syndrome

Czesnik

Howells

Bartl

et al. 2018

The Journal of Physiology

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“…Despite these genetic advances, the pathophysiology of RLS has yet to be fully elaborated. What is known about the functions of the recently implicated genes does not yet explain RLS pathology, although both BTBD9 and MEIS1 are now known to interact with iron and dopamine homeostasis, both implicated in RLS (Rye 2015). From a clinical standpoint, a state of dopaminergic dysfunction is suspected to cause RLS because people with RLS frequently improve when given low doses of dopaminergic medications (Allen 2004).…”

Section: Description Of the Conditionmentioning

confidence: 99%

Iron for the treatment of restless legs syndrome

Trotti

Becker

2019

Cochrane Database of Systematic Reviews

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a We downgraded one level for publication bias for several reasons: 1) one study completed in 2012 (NCT00685815) for which published results could not be found in the search; 2) generally small sample sizes; and 3) the majority of participants were in trials funded by pharmaceutical companies. b We downgraded one level for the possibility of selective outcome reporting, as this outcome was infrequently reported across studies. c We downgraded one level because the Optimal Information Size (OIS) calculation suggests insu icient power for this outcome.

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“…34 Restless legs syndrome is a promising candidate for genetic linkage but clearly defined patients, and mice models are needed. 35…”

Section: Statement Of Significancementioning

confidence: 99%

New neuroscience tools that are identifying the sleep-wake circuit

Shiromani

Peever

2017

Sleep

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The complexity of the brain is yielding to technology. In the area of sleep neurobiology, conventional neuroscience tools such as lesions, cell recordings, c-Fos, and axon-tracing methodologies have been instrumental in identifying the complex and intermingled populations of sleep- and arousal-promoting neurons that orchestrate and generate wakefulness, NREM, and REM sleep. In the last decade, new technologies such as optogenetics, chemogenetics, and the CRISPR-Cas system have begun to transform how biologists understand the finer details associated with sleep-wake regulation. These additions to the neuroscience toolkit are helping to identify how discrete populations of brain cells function to trigger and shape the timing and transition into and out of different sleep-wake states, and how glia partner with neurons to regulate sleep. Here, we detail how some of the newest technologies are being applied to understand the neural circuits underlying sleep and wake.

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The Molecular Genetics of Restless Legs Syndrome

Cited by 24 publications

References 66 publications

I_h contributes to increased motoneuron excitability in restless legs syndrome

I_h contributes to increased motoneuron excitability in restless legs syndrome

Iron for the treatment of restless legs syndrome

New neuroscience tools that are identifying the sleep-wake circuit

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The Molecular Genetics of Restless Legs Syndrome

Cited by 24 publications

References 66 publications

Ih contributes to increased motoneuron excitability in restless legs syndrome

Ih contributes to increased motoneuron excitability in restless legs syndrome

Iron for the treatment of restless legs syndrome

New neuroscience tools that are identifying the sleep-wake circuit

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Product

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I_h contributes to increased motoneuron excitability in restless legs syndrome

I_h contributes to increased motoneuron excitability in restless legs syndrome