Genetics of restless legs syndrome: An update

Jiménez‐Jiménez, Félix Javier; Alonso‐Navarro, Hortensia; García‐Martín, Elena; Agúndez, José A. G.

doi:10.1016/j.smrv.2017.08.002

Cited by 89 publications

(57 citation statements)

References 98 publications

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“…Compared with participants without RLS, those with RLS have a higher rate of a family history of PD. However, nighttime problems, EDS, and pRBD have no correlation with a family history of PD, which was consistent with other studies 20 . RLS results in fewer sleep interruptions, while nighttime problems, EDS, and pRBD are typically accompanied by frequent sleep interruptions.…”

Section: Discussionsupporting

confidence: 92%

Multiple comorbid sleep disorders adversely affect quality of life in Parkinson’s disease patients

Zhang

Zhao

Huang

et al. 2020

npj Parkinsons Dis.

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Sleep disorders are common non-motor symptoms in patients with Parkinson’s disease (PD). The characteristics and impact of multiple comorbid sleep disorders remain to be elucidated. Our goal was to investigate the characteristics of various sleep disorder comorbidities, and their association with motor complications and the impact on the quality of life in PD patients. In this multicenter, observational, cross-sectional study, data concerning the clinical characteristics of complicated sleep disorders were collected from PD patients treated at 40 different hospitals in Shanghai. Sleep disorders were evaluated using the PD Sleep Scale-2, Epworth Sleepiness Scale, Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong, and the International Restless Legs Scale. Among the 1006 subjects evaluated, 77.53% exhibited signs of sleep disorders, and most had multiple sleep disorders (n = 502, 49.9%). A smaller percentage of patients with sleep disorders had a single disorder (n = 278, 27.6%). Furthermore, an increased number of sleep disorders, including nighttime problems, excessive daytime sleepiness, rapid eye movement sleep behavior disorder, and restless legs syndrome was a significant contributor to a poor quality of life (β = 4.33, CI: 3.33–5.33, P for trend <0.001), even when controlling for multiple factors. Moreover, motor complications partially mediated this relationship (indirect effect: β = 0.355, 95% boot CI: 0.134, 0.652).Our study showed that a large proportion of PD patients suffer from multiple comorbid sleep disorders, which greatly decreases the quality of life in PD patients and is partially mediated by motor complications.

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Section: Discussionsupporting

confidence: 92%

Multiple comorbid sleep disorders adversely affect quality of life in Parkinson’s disease patients

Zhang

Zhao

Huang

et al. 2020

npj Parkinsons Dis.

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“…The non-coding region of MEIS1 represents one of the strongest genetic associations reported for any common disease and is part of a regulatory network implicated in iron metabolism [17]. The exact function of the protein in the biological pathway of RLS remains to be discovered [18]. This gene is known to be highly expressed in dopaminergic neurons of the substantia nigra, which suggests that it plays a role in movement, but what it precisely does in the substantia nigra dopamine cells remains unknown.…”

Section: Geneticsmentioning

confidence: 99%

Why Are Women Prone to Restless Legs Syndrome?

Seeman

2020

IJERPH

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Restless legs syndrome is a relatively common neurologic disorder considerably more prevalent in women than in men. It is characterized by an inactivity-induced, mostly nocturnal, uncomfortable sensation in the legs and an urge to move them to make the disagreeable sensation disappear. Some known genes contribute to this disorder and the same genes contribute to an overlapping condition—periodic leg movements that occur during sleep and result in insomnia. Dopamine and glutamate transmission in the central nervous system are involved in the pathophysiology, and an iron deficiency has been shown in region-specific areas of the brain. A review of the literature shows that pregnant women are at particular risk and that increased parity is a predisposing factor. Paradoxically, menopause increases the prevalence and severity of symptoms. This implies a complex role for reproductive hormones. It suggests that changes rather than absolute levels of estrogen may be responsible for the initiation of symptoms. Both iron (at relatively low levels in women) and estrogen (at relatively high oscillating levels in women) influence dopamine and glutamate transmission, which may help to explain women’s vulnerability to this condition. The syndrome is comorbid with several disorders (such as migraine, depression, and anxiety) to which women are particularly prone. This implies that the comorbid condition or its treatment, or both, contribute to the much higher prevalence in women than in men of restless legs syndrome.

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“…Genome-wide association studies (GWAS) have implicated up to 19 risk loci, including BTBD9 , as genetic risk factors of RLS (Schormair et al, 2017; Jiménez-Jiménez et al, 2018). BTBD9 codes for a protein belonging to the BTB (POZ) protein family, which modulates transcription, cytoskeletal arrangement, ion conductance and protein ubiquitination (Stogios and Privé, 2004; Stogios et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The Role of BTBD9 in Striatum and Restless Legs Syndrome

Lyu

Xiao

DeAndrade

et al. 2019

eNeuro

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Restless legs syndrome (RLS) is a sensory-motor neurological disorder characterized by uncomfortable sensations in the extremities, generally at night, which is often relieved by movements. Genome-wide association studies (GWAS) have identified mutations in BTBD9 conferring a higher risk of RLS. Knockout of the BTBD9 homolog in mice (Btbd9) and fly results in motor restlessness and sleep disruption. Clinical studies have found RLS patients have structural and functional abnormalities in the striatum; however, whether and how striatal pathology contributes to the pathogenesis of RLS is not known. Here, we used fMRI to map regions of altered synaptic activity in basal ganglia of systematic Btbd9 knock-out (KO) mice. We further dissected striatal circuits using patch-clamp electrophysiological recordings in brain slices. Two different mouse models were generated to test the effect of specific knockout of Btbd9 in either striatal medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) using the electrophysiological recording, motor and sensory behavioral tests. We found that Btbd9 KO mice showed enhanced neural activity in the striatum, increased postsynaptic currents in the MSNs, and decreased excitability of the striatal ChIs. Knocking out Btbd9 specifically in the striatal MSNs, but not the ChIs, led to rest-phase specific motor restlessness, sleep disturbance, and increased thermal sensation in mice, which are consistent with results obtained from the Btbd9 KO mice. Our data establish the role of Btbd9 in regulating the activity of striatal neurons. Increased activity of the striatal MSNs, possibly through modulation by the striatal ChIs, contributes to the pathogenesis of RLS.

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Genetics of restless legs syndrome: An update

Cited by 89 publications

References 98 publications

Multiple comorbid sleep disorders adversely affect quality of life in Parkinson’s disease patients

Multiple comorbid sleep disorders adversely affect quality of life in Parkinson’s disease patients

Why Are Women Prone to Restless Legs Syndrome?

The Role of BTBD9 in Striatum and Restless Legs Syndrome

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