家族性不宁腿综合征候选基因的连锁分析

不宁腿综合征（restless legs syndrome,RLS)是以下肢部出现蚁行样及酸、麻、胀等不适感而使肢体不得休息为特征的一组病症。由于症状常在晚间发作并导致运动不安,患者长期入睡困难,经受严重的继发性失眠。作为一种常见的神经系统疾病,RLS发病率高达5％,其中原发性RLS多呈阳性家族史,表现为单基因决定的常染色体显性遗传。现在,人们普遍认为RLS的发生很可能与神经系统内多巴胺能功能异常和脑内铁缺乏有关,并初步建立了脑铁－多巴胺能系统的致病模型。为了探求脑铁－多巴胺能系统在RLS中的作用,选择了与脑铁－多巴胺能系统相关的16个疾病侯选基因,在每个候选基因附近染色体区域内选取若干个微卫星多态标记,应用微卫星引物荧光标记－基因扫描技术,对一个汉族家族性不宁腿综合征家系进行了基因分型和常染色体显性遗传模式下的连锁分析,试图从分子遗传学层面上确认或排除一些可能与RLS相关的重要侯选基因。结果显示,当重组系数θ=0.00时,LOD值均小于－2.00,所选位点与家族性不宁腿综合征不连锁。由此得出结论,在本家系中,所有候选基因均与家族性不宁腿综合征的发病无关,家族性不宁腿综合征可能是由其他多巴胺传导和脑铁代谢相关基因所致,或是存在全新的致病机制参与RLS的发生。     

Neurological disorders: towards a mechanistic understanding of restless legs syndrome

Restless legs syndrome is a curious neurological disorder of unknown aetiology. A new study has found that Drosophila mutants in the fly homologue of a human gene, BTBD9, that has been implicated as a risk factor for restless legs display important features of the syndrome.     

The Restless Leg Syndrome

The author reviews and provides examples of the restless leg syndrome (Ekbom''s syndrome), emphasizing the frequency of the disorder and its distressing symptoms. The syndrome is characterized by a creeping, crawling sensation in the lower legs, usually at night. It is accompanied by an irresistible urge to move the legs, and this movement eventually relieves the symptoms. It is found in 5% of the general population, with a higher incidence in pregnant women and people with anemia, but no vascular, neurological or other abnormalities are found on examination. Patients are treated empirically with vasodilators or intravenous iron. The etiology is unknown.     

Treatment of the restless legs syndrome with carbamazepine: a double blind study.

One hundred and seventy four patients suffering from the restless legs syndrome were examined in a double blind, between patient, placebo controlled study in general practice for five weeks to investigate the effects of carbamazepine and placebo on the syndrome. The syndrome was more common among middle aged women with relatively low systolic blood pressure. The median haemoglobin concentration was about average for the population, but the severity of the symptoms seemed to increase with decreasing concentrations of haemoglobin. Both placebo and carbamazepine showed a significant therapeutic effect (p less than 0.01). Carbamazepine was significantly more effective than placebo (p less than or equal to 0.03). The significant therapeutic effect of placebo in restless legs showed that only double blind controlled trials can confirm the efficacy of suggested treatments.     

Neurologic disorders responsive to folic acid therapy.

Six women aged 31 to 70 years had folate deficiency and neuropsychiatric disorders. The three with acquired folate deficiency were depressed and had permanent muscular and intellectual fatigue, mild symptoms of restless legs, depressed ankle jerks, diminution of vibration sensation in the legs, stocking-type hypoesthesia and long-lasting constipation; D-xylos absorption was abnormal. The bone marrow was megaloblastic in only one patient, and she and one other had atrophy of the jejunal mucosa. The third was a vegan. All three recovered after folic acid therapy. The other three were members of a family with the restless legs syndrome, fatigability and diffuse muscular pain. One also had subacute combined degeneration of the spinal cord and kidney disease but no megaloblastosis; she improved spectacularly after receiving large daily doses of folic acid. The other two also had minor neurologic signs, controlled with 5 to 10 mg of folic acid daily. Unrecognized and treatable folate deficiency (with low serum folic acid values but normal erythrocyte folate values) may be the basis of a well defined syndrome of neurologic, psychiatric and gastroenterologic disorders, and the restless legs syndrome may represent the main clinical expression of acquired and familial (or inborn) folate deficiency in adults.     

Systems genetics analysis of iron regulation in the brain

Iron imbalances in the brain, including excess accumulation and deficiency, are associated with neurological disease and dysfunction; yet, their origins are poorly understood. Using systems genetics analysis, we have learned that large individual differences exist in brain iron concentrations, even in the absence of neurological disease. Much of the individual differences can be tied to the genetic makeup of the individual. This genetic-based differential regulation can be modeled in genetic reference populations of rodents. The work in our laboratory centers on iron regulation in the brain and our animal model consists of 25 BXD/Ty recombinant inbred mouse strains. By studying naturally occurring variation in iron phenotypes, such as tissue iron concentration, we can tie that variability to one or more genes by way of quantitative trait loci (QTL) analysis. Moreover, we can conduct genetic correlation analyses between our phenotypes and others previously measured in the BXD/Ty strains. We have observed several suggestive QTL related to ventral midbrain iron content, including one on chromosome 17 that contains btbd9, a gene that in humans has been associated with restless legs syndrome and serum ferritin. We have also observed gene expression correlations with ventral midbrain iron, including btbd9 expression and dopamine receptor expression. In addition, we have observed significant correlations between ventral midbrain iron content and dopamine-related phenotypes. The following is a discussion of iron regulation in the brain and the contributions a systems genetics approach can make toward understanding the genetic underpinnings and relation to neurological disease.     

Therapeutic experience of deep vein thrombosis prevention system for restless legs syndrome

Sleep and Biological Rhythms - The present paper reports a case of restless legs syndrome (RLS) in which the Flowtron DVT (Huntleigh Technologies, Luton, UK) was used as a deep vein thrombosis...     

Restless Legs Syndrome in Chronic Pulmonary Disease

Eight consecutive patients referred for neurological opinion because of very severe “restless legs” all suffered from chronic pulmonary disease. It was considered that the restless legs syndrome was not a metabolic consequence of respiratory failure but a nervous manifestation of their invalidism.     

Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome

Background  

Low doses of dopamine agonists (DA) and levodopa are effective in the treatment of restless legs syndrome (RLS). A range of impulse control and compulsive behaviours (ICBs) have been reported following the use of DAs and levodopa in patients with Parkinson's disease. With this study we sought to assess the cross-sectional prevalence of impulse control behaviours (ICBs) in restless legs syndrome (RLS) and to determine factors associated with ICBs in a population cohort in Germany.     

Restless legs syndrome and arterial stiffness in pre-dialysis chronic kidney disease

Sleep and Biological Rhythms - Despite plenty of restless legs syndrome (RLS) studies conducted with hemodialysis patients, it has been scarcely studied in patients with predialysis chronic kidney...     

Restless Legs Syndrome,with Particular Reference to its Occurrence After Gastric Surgery

There is a higher incidence of restless legs syndrome (Ekbom''s syndrome) in patients after gastric surgery (11·3%) and with diabetes mellitus (17·0%) and uraemia (17·3%) than in patients who have been diagnosed as having a psychonoeurosis (4·0%) and in controls (2·0%). Three patients with malabsorption syndrome complained of restless legs, but these patients had abnormal neurological signs. The incidence after gastric surgery and in diabetes mellitus and uraemia remained high even when patients with any abnormal neurological signs were excluded.     

Rifaximin antibiotic treatment for restless legs syndrome: a double-blind,placebo-controlled study

Sleep and Biological Rhythms - The purpose was to evaluate rifaximin antibiotic therapy for restless legs syndrome (RLS) patients who have small intestinal bacterial overgrowth (SIBO). Patients...     

Prevalence and clinical features of restless legs syndrome among Japanese pregnant women without gestational complications

Sleep and Biological Rhythms - To determine the prevalence of restless legs syndrome (RLS) among Japanese pregnant women without complications and to clarify the correlation between RLS and...     

Restless legs syndrome and pregnancy in Kayseri,Turkey: A hospital based survey

Sleep and Biological Rhythms - The prevalence of restless legs syndrome (RLS) is low in the general population in Turkey. To assess the prevalence of RLS in pregnancy, a hospital-based survey...     

Microstructural changes of basal ganglia in migraine with restless legs syndrome: findings from a neuroimaging study

Sleep and Biological Rhythms - In this study, it is planned to investigate the integrity of the basal ganglia structures in migraineurs with restless legs syndrome (RLS) to explore this...     

Pathogenetic heterogeneity of restless legs syndrome in Parkinson’s disease

Sleep and Biological Rhythms - In order to clarify the pathogenetic heterogeneity of restless legs syndrome (RLS), we compared the clinical characteristics of RLS between six patients with...     

Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study.

Sleep disorders, such as obstructive sleep apnoea (OSA) and restless legs syndrome (RLS), are very common. The relative importance of genetic and nongenetic (environmental) influences on the symptomatology of these conditions has not been well studied. This study uses the twin design to examine this by evaluating OSA and RLS symptoms in monozygotic (MZ) and dizygotic (DZ) twins. Six thousand six hundred unselected female twin pairs, identified from a national volunteer twin register, were asked to complete a medical questionnaire. This questionnaire included questions on OSA and RLS symptoms, as well as questions on subject demographics, past medical history, smoking history and menopausal status. Responses were obtained from 4503 individuals (68% response rate). A total of 1937 twin pairs were evaluable: 933 MZ pairs (mean [range] age 51 [20-76] years) and 1004 DZ pairs (age 51 [20-80] years). Concordance rates were higher for MZ than DZ twins for OSA and RLS symptoms. Multifactorial liability threshold modeling suggests that additive genetic effects combined with unique environmental factors provide the best model for OSA and RLS symptoms. Heritability was estimated to be 52% (95% confidence interval 36% to 68%) for disruptive snoring, 48% (37% to 58%) for daytime sleepiness, 54% (44% to 63%) for restless legs, and 60% (51% to 69%) for legs jerking. These estimates dropped only slightly after adjustment for potential confounding influences on the symptoms of snoring and daytime sleepiness. These results suggest a substantial genetic contribution to the symptomatology of OSA and RLS. More research is needed to identify the genes responsible, and may ultimately lead to new therapies.     

Frequent Periodic Leg Movement During Sleep Is an Unrecognized Risk Factor for Progression of Atrial Fibrillation

Sleep apnea has been recognized as a factor predisposing to atrial fibrillation recurrence and progression. The effect of other sleep-disturbing conditions on atrial fibrillation progression is not known. We sought to determine whether frequent periodic leg movement during sleep is a risk factor for progression of atrial fibrillation. In this retrospective study, patients with atrial fibrillation and a clinical suspicion of restless legs syndrome who were referred for polysomnography were divided into two groups based on severity of periodic leg movement during sleep: frequent (periodic movement index >35/h) and infrequent (≤35/h). Progression of atrial fibrillation to persistent or permanent forms between the two groups was compared using Wilcoxon rank-sum test, chi-square tests and logistic regression analysis. Of 373 patients with atrial fibrillation (77% paroxysmal, 23% persistent), 108 (29%) progressed to persistent or permanent atrial fibrillation during follow-up (median, 33 months; interquartile range, 16-50). Compared to patients with infrequent periodic leg movement during sleep (n=168), patients with frequent periodic leg movement during sleep (n=205) had a higher rate of atrial fibrillation progression (23% vs. 34%; p=0.01). Patients with frequent periodic leg movement during sleep were older and predominantly male; however, there were no significant differences at baseline in clinical factors that promote atrial fibrillation progression between both groups. On multivariate analysis, independent predictors of atrial fibrillation progression were persistent atrial fibrillation at baseline, female gender, hypertension and frequent periodic leg movement during sleep. In patients with frequent periodic leg movement during sleep, dopaminergic therapy for control of leg movements in patients with restless legs syndrome reduced risk of atrial fibrillation progression. Frequent leg movement during sleep in patients with restless legs syndrome is associated with progression of atrial fibrillation to persistent and permanent forms.     

Restless legs syndrome in a 5-year-old boy with low body stores of iron

Restless legs syndrome (RLS) is a common sleep disorder characterized by disagreeable sensations in the legs that occur at rest and are relieved by movement. Little has been reported about pediatric RLS in Asian people. We report the case of a 5-year-old preschooler with RLS, who presented with an uncomfortable sensation in his toes before bedtime and insomnia. Blood tests showed reduced iron stores (serum ferritin, 15.9 ng/mL). The subjective symptoms and a maternal history of RLS were consistent with pediatric RLS. Iron supplement therapy resulted in improvement in the leg sensation and subjective daytime alertness. We recommend detailed evaluation of iron status in preschoolers with suspected RLS.

     

Enhanced hippocampal long-term potentiation and fear memory in Btbd9 mutant mice

Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.