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Associated conditions in small fiber neuropathy - a large cohort study and review of the literature.
de Greef, BTA, Hoeijmakers, JGJ, Gorissen-Brouwers, CML, Geerts, M, Faber, CG, Merkies, ISJ
European journal of neurology. 2018;(2):348-355
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Abstract
BACKGROUND AND PURPOSE Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. METHODS A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. RESULTS No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. CONCLUSIONS Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.
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Epithelial Sodium and Chloride Channels and Asthma.
Wang, W, Ji, HL
Chinese medical journal. 2015;(16):2242-9
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OBJECTIVE To focus on the asthmatic pathogenesis and clinical manifestations related to epithelial sodium channel (ENaC)/chlorine ion channel. DATA SOURCES The data analyzed in this review were the English articles from 1980 to 2015 from journal databases, primarily PubMed and Google Scholar. The terms used in the literature search were: (1) ENaCs; cystic fibrosis (CF) transmembrane conductance regulator (CFTR); asthma/asthmatic, (2) ENaC/sodium salt; CF; asthma/asthmatic, (3) CFTR/chlorine ion channels; asthma/asthmatic, (4) ENaC/sodium channel/scnn1a/scnn1b/scnn1g/scnn1d/amiloride-sensitive/amiloride-inhibtable sodium channels/sodium salt; asthma/asthmatic, lung/pulmonary/respiratory/tracheal/alveolar, and (5) CFTR; CF; asthma/asthmatic (ti). STUDY SELECTION These studies included randomized controlled trials or studies covering asthma pathogenesis and clinical manifestations related to ENaC/chlorine ion channels within the last 25 years (from 1990 to 2015). The data involving chronic obstructive pulmonary disease and CF obtained from individual studies were also reviewed by the authors. RESULTS Airway surface liquid dehydration can cause airway inflammation and obstruction. ENaC and CFTR are closely related to the airway mucociliary clearance. Ion transporters may play a critical role in pathogenesis of asthmatic exacerbations. CONCLUSIONS Ion channels have been the center of many studies aiming to understand asthmatic pathophysiological mechanisms or to identify therapeutic targets for better control of the disease.
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Painful neuropathies: the emerging role of sodium channelopathies.
Brouwer, BA, Merkies, IS, Gerrits, MM, Waxman, SG, Hoeijmakers, JG, Faber, CG
Journal of the peripheral nervous system : JPNS. 2014;(2):53-65
Abstract
Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations. Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch-clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell-type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length-dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain-of-function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.
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Pathophysiology and treatment of resistant hypertension: the role of aldosterone and amiloride-sensitive sodium channels.
Judd, EK, Calhoun, DA, Warnock, DG
Seminars in nephrology. 2014;(5):532-9
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Abstract
Resistant hypertension is a clinically distinct subgroup of hypertension defined by the failure to achieve blood pressure control on optimal dosing of at least 3 antihypertensive medications of different classes, including a diuretic. The pathophysiology of hypertension can be attributed to aldosterone excess in more than 20% of patients with resistant hypertension. Existing dogma attributes the increase in blood pressure seen with increases in aldosterone to its antinatriuretic effects in the distal nephron. However, emerging research, which has identified and has begun to define the function of amiloride-sensitive sodium channels and mineralocorticoid receptors in the systemic vasculature, challenges impaired natriuresis as the sole cause of aldosterone-mediated resistant hypertension. This review integrates these findings to better define the role of the vasculature and aldosterone in the pathophysiology of resistant hypertension. In addition, a brief guide to the treatment of resistant hypertension is presented.
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Mechanisms of axonal dysfunction in diabetic and uraemic neuropathies.
Arnold, R, Kwai, NC, Krishnan, AV
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2013;(11):2079-90
Abstract
The global burden imposed by metabolic diseases and associated complications continue to escalate. Neurological complications, most commonly peripheral neuropathy, represent a significant cause of morbidity and disability in patients with diabetes and chronic kidney disease. Furthermore, health care costs are substantially increased by the presence of complications making investigation into treatment a matter of high priority. Over the last decade nerve excitability techniques have entered the clinical realm and enabled in vivo assessment of biophysical properties and function of peripheral nerves in health and disease. Studies of excitability in diabetic neuropathy have demonstrated alteration in biophysical properties, including changes in Na(+) conductances and Na(+)/K(+) pump function, which may contribute to the development of neuropathic symptoms. Interventional studies have demonstrated that these changes are responsive to pharmacological agents. Excitability studies in patients with chronic kidney disease have demonstrated prominent changes that may contribute to the development of uraemic neuropathy. In particular, these studies have demonstrated strong correlation between hyperkalaemia and the development of nerve dysfunction. These studies have provided a basis for future work assessing the benefits of potassium restriction as a therapeutic strategy in this condition.
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Anti-anginal and anti-ischemic effects of late sodium current inhibition.
Wimmer, NJ, Stone, PH
Cardiovascular drugs and therapy. 2013;(1):69-77
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The effective treatment of coronary artery disease targets two distinct goals, controlling symptomatic angina and decreasing the adverse events associated with ischemia. Traditional anti-anginal and anti-ischemic drugs function by altering the determinants of myocardial oxygen supply or demand, usually by altering loading conditions, changing the heart rate, or impacting contractility. Blockade of the late inward sodium current, late I(Na), offers another target for the treatment of ischemia. Blockade of late I(Na) reduces the sodium and calcium overload that follows ischemia. This improves myocardial relaxation and reduces left ventricular diastolic stiffness, in turn enhancing myocardial contractility and perfusion. Ranolazine, a late I(Na) inhibitor, has been shown to provide both anti-anginal and anti-ischemic benefits without significant alterations in the heart rate and blood pressure in patients with stable coronary artery disease. When evaluated in patients with acute coronary syndrome, ranolazine has been shown to decrease recurrent ischemia, but not significantly reduce the risk of death or myocardial infarction. This review will address the rationale that inhibition of the late sodium current is beneficial in reducing cardiac dysfunction during ischemia, and discuss the clinical studies supporting the use of ranolazine for its anti-anginal and anti-ischemic effects.
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A hot topic: temperature sensitive sodium channelopathies.
Egri, C, Ruben, PC
Channels (Austin, Tex.). 2012;(2):75-85
Abstract
Perturbations to body temperature affect almost all cellular processes and, within certain limits, results in minimal effects on overall physiology. Genetic mutations to ion channels, or channelopathies, can shift the fine homeostatic balance resulting in a decreased threshold to temperature induced disturbances. This review summarizes the functional consequences of currently identified voltage-gated sodium (NaV) channelopathies that lead to disorders with a temperature sensitive phenotype. A comprehensive knowledge of the relationships between genotype and environment is not only important for understanding the etiology of disease, but also for developing safe and effective treatment paradigms.
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Two barriers for sodium in vascular endothelium?
Oberleithner, H
Annals of medicine. 2012;(Suppl 1):S143-8
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Abstract
Vascular endothelium plays a key role in blood pressure regulation. Recently, it has been shown that a 5% increase of plasma sodium concentration (sodium excess) stiffens endothelial cells by about 25%, leading to cellular dysfunction. Surface measurements demonstrated that the endothelial glycocalyx (eGC), an anionic biopolymer, deteriorates when sodium is elevated. In view of these results, a two-barrier model for sodium exiting the circulation across the endothelium is suggested. The first sodium barrier is the eGC which selectively buffers sodium ions with its negatively charged proteoglycans. The second sodium barrier is the endothelial plasma membrane which contains sodium channels. Sodium excess, in the presence of aldosterone, leads to eGC break-down and, in parallel, to an up-regulation of plasma membrane sodium channels. The following hypothesis is postulated: Sodium excess increases vascular sodium permeability. Under such conditions (e.g. high-sodium diet), day-by-day ingested sodium, instead of being readily buffered by the eGC and then rapidly excreted by the kidneys, is distributed in the whole body before being finally excreted. Gradually, the sodium overload damages the organism.
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Genetic and clinical aspects of Brugada syndrome: an update.
Lippi, G, Montagnana, M, Meschi, T, Comelli, I, Cervellin, G
Advances in clinical chemistry. 2012;:197-208
Abstract
The Brugada Syndrome (BS) is a "channellopathy," characterized by ion (e.g., sodium, calcium, and potassium) channel dysfunction and typical ECG alterations, originally described by Osher and Wolff in 1953 and further elucidated by Josep and Pedro Brugada in 1991. BS is typically associated with a high risk for sudden cardiac death (SCD) in young and otherwise healthy adults. Although in several patients the heart is structurally normal, subtle structural abnormalities in the right ventricular outflow tract are increasingly been reported. The worldwide prevalence of this disorder is still uncertain, and there are some significant regional differences. The syndrome is characterized by a strong genetic basis, and several mutations have been identified in genes encoding subunits of cardiac sodium, potassium, and calcium channels, as well as in genes involved in the trafficking or regulation of these channels. Accordingly, eight types of BS (from BS1 to BS8) have already been described, involving mutations in SCN5A, GPD1-L, CACNA1c, CACNB2b, SCN1B, KCNE3, SCN3B, and HCN4 genes. The vast majority (i.e., up to two-third) of BS patients is asymptomatic, whereas the leading clinical manifestation is polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation (VF) and SCD. The diagnosis is still challenging, and ECG abnormalities represent one component of the diagnostic criteria which also include clinical and demographic data. Although molecular genetic testing is effective in detecting mutations in 20-38% of BS patients, it represents an appealing option for stratifying the risk of adverse events as well as for prenatal testing.
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Desmosome-ion channel interactions and their possible role in arrhythmogenic cardiomyopathy.
Delmar, M
Pediatric cardiology. 2012;(6):975-9
Abstract
Most commonly, arrhythmogenic cardiomyopathy (also known as arrhythmogenic right ventricular cardiomyopathy, or ARVC) is caused by mutations in desmosomal proteins. The question arises as to the mechanisms by which mutations in mechanical junctions, affect the rhythm of the heart. We have proposed that a component of the arrhythmogenic substrate may include changes in the function of both, gap junctions and sodium channels. Here, we review the relevant literature on this subject.