-
1.
Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia-Related Genes.
Chahal, CAA, Salloum, MN, Alahdab, F, Gottwald, JA, Tester, DJ, Anwer, LA, So, EL, Murad, MH, St Louis, EK, Ackerman, MJ, et al
Journal of the American Heart Association. 2020;(1):e012264
Abstract
Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.
-
2.
Bases of Bacterial Sodium Channel Selectivity Among Organic Cations.
Wang, Y, Finol-Urdaneta, RK, Ngo, VA, French, RJ, Noskov, SY
Scientific reports. 2019;(1):15260
Abstract
Hille's (1971) seminal study of organic cation selectivity of eukaryotic voltage-gated sodium channels showed a sharp size cut-off for ion permeation, such that no ion possessing a methyl group was permeant. Using the prokaryotic channel, NaChBac, we found some similarity and two peculiar differences in the selectivity profiles for small polyatomic cations. First, we identified a diverse group of minimally permeant cations for wildtype NaChBac, ranging in sizes from ammonium to guanidinium and tetramethylammonium; and second, for both ammonium and hydrazinium, the charge-conserving selectivity filter mutation (E191D) yielded substantial increases in relative permeability (PX/PNa). The relative permeabilities varied inversely with relative Kd calculated from 1D Potential of Mean Force profiles (PMFs) for the single cations traversing the channel. Several of the cations bound more strongly than Na+, and hence appear to act as blockers, as well as charge carriers. Consistent with experimental observations, the E191D mutation had little impact on Na+ binding to the selectivity filter, but disrupted the binding of ammonium and hydrazinium, consequently facilitating ion permeation across the NaChBac-like filter. We concluded that for prokaryotic sodium channels, a fine balance among filter size, binding affinity, occupancy, and flexibility seems to contribute to observed functional differences.
-
3.
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
-
-
Free full text
-
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.
-
4.
Heterozygous deletion of SCN2A and SCN3A in a patient with autism spectrum disorder and Tourette syndrome: a case report.
Nickel, K, Tebartz van Elst, L, Domschke, K, Gläser, B, Stock, F, Endres, D, Maier, S, Riedel, A
BMC psychiatry. 2018;(1):248
Abstract
BACKGROUND Mutations in voltage-gated sodium channel (SCN) genes are supposed to be of importance in the etiology of psychiatric and neurological diseases, in particular in the etiology of seizures. Previous studies report a potential susceptibility region at the chromosomal locus 2q including SCN1A, SCN2A and SCN3A genes for autism spectrum disorder (ASD). To date, there is no previous description of a patient with comorbid ASD and Tourette syndrome showing a deletion containing SCN2A and SCN3A. CASE PRESENTATION We present the unique complex case of a 28-year-old male patient suffering from developmental retardation and exhibiting a range of behavioral traits since birth. He received the diagnoses of ASD (in early childhood) and of Tourette syndrome (in adulthood) according to ICD-10 and DSM-5 criteria. Investigations of underlying genetic factors yielded a heterozygous microdeletion of approximately 719 kb at 2q24.3 leading to a deletion encompassing the five genes SCN2A (exon 1 to intron 14-15), SCN3A, GRB14 (exon 1 to intron 2-3), COBLL1 and SCL38A11. CONCLUSIONS We discuss the association of SCN2A, SCN3A, GRB14, COBLL1 and SCL38A11 deletions with ASD and Tourette syndrome and possible implications for treatment.
-
5.
Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density.
Lemoine, MD, Mannhardt, I, Breckwoldt, K, Prondzynski, M, Flenner, F, Ulmer, B, Hirt, MN, Neuber, C, Horváth, A, Kloth, B, et al
Scientific reports. 2017;(1):5464
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for drug testing and modelling genetic disorders. Abnormally low upstroke velocity is a current limitation. Here we investigated the use of 3D engineered heart tissue (EHT) as a culture method with greater resemblance to human heart tissue in comparison to standard technique of 2D monolayer (ML) format. INa was measured in ML or EHT using the standard patch-clamp technique. INa density was ~1.8 fold larger in EHT (-18.5 ± 1.9 pA/pF; n = 17) than in ML (-10.3 ± 1.2 pA/pF; n = 23; p < 0.001), approaching densities reported for human CM. Inactivation kinetics, voltage dependency of steady-state inactivation and activation of INa did not differ between EHT and ML and were similar to previously reported values for human CM. Action potential recordings with sharp microelectrodes showed similar upstroke velocities in EHT (219 ± 15 V/s, n = 13) and human left ventricle tissue (LV, 253 ± 7 V/s, n = 25). EHT showed a greater resemblance to LV in CM morphology and subcellular NaV1.5 distribution. INa in hiPSC-CM showed similar biophysical properties as in human CM. The EHT format promotes INa density and action potential upstroke velocity of hiPSC-CM towards adult values, indicating its usefulness as a model for excitability of human cardiac tissue.
-
6.
Pain thresholds, supra-threshold pain and lidocaine sensitivity in patients with erythromelalgia, including the I848Tmutation in NaV 1.7.
Helås, T, Sagafos, D, Kleggetveit, IP, Quiding, H, Jönsson, B, Segerdahl, M, Zhang, Z, Salter, H, Schmelz, M, Jørum, E
European journal of pain (London, England). 2017;(8):1316-1325
Abstract
OBJECTIVES Nociceptive thresholds and supra-threshold pain ratings as well as their reduction upon local injection with lidocaine were compared between healthy subjects and patients with erythromelalgia (EM). METHODS Lidocaine (0.25, 0.50, 1.0 or 10 mg/mL) or placebo (saline) was injected intradermally in non-painful areas of the lower arm, in a randomized, double-blind manner, to test the effect on dynamic and static mechanical sensitivity, mechanical pain sensitivity, thermal thresholds and supra-threshold heat pain sensitivity. RESULTS Heat pain thresholds and pain ratings to supra-threshold heat stimulation did not differ between EM-patients (n = 27) and controls (n = 25), neither did the dose-response curves for lidocaine. Only the subgroup of EM-patients with mutations in sodium channel subunits NaV 1.7, 1.8 or 1.9 (n = 8) had increased lidocaine sensitivity for supra-threshold heat stimuli, contrasting lower sensitivity to strong mechanical stimuli. This pattern was particularly clear in the two patients carrying the NaV 1.7 I848T mutations in whom lidocaine's hyperalgesic effect on mechanical pain sensitivity contrasted more effective heat analgesia. CONCLUSION Heat pain thresholds are not sensitized in EM patients, even in those with gain-of-function mutations in NaV 1.7. Differential lidocaine sensitivity was overt only for noxious stimuli in the supra-threshold range suggesting that sensitized supra-threshold encoding is important for the clinical pain phenotype in EM in addition to lower activation threshold. Intracutaneous lidocaine dose-dependently blocked nociceptive sensations, but we did not identify EM patients with particular high lidocaine sensitivity that could have provided valuable therapeutic guidance. SIGNIFICANCE Acute pain thresholds and supra-threshold heat pain in controls and patients with erythromelalgia do not differ and have the same lidocaine sensitivity. Acute heat pain thresholds even in EM patients with the NaV 1.7 I848T mutation are normal and only nociceptor sensitivity to intradermal lidocaine is changed. Only in EM patients with mutations in NaV 1.7, 1.8 or 1.9 supra-threshold heat and mechanical pain shows differential lidocaine sensitivity as compared to controls.
-
7.
Effect of late sodium current inhibition on MRI measured diastolic dysfunction in aortic stenosis: a pilot study.
Singh, A, Steadman, CD, Khan, JN, Reggiardo, G, McCann, GP
BMC research notes. 2016;:64
Abstract
BACKGROUND Ranolazine is a new anti-anginal drug that acts via late sodium current inhibition, and has been shown to improve diastolic dysfunction in isolated myocytes. Diastolic dysfuntion is common in patients with aortic stenosis (AS), and precedes symptom development and systolic dysfunction. The purpose of this study was to assess the effects of ranolazine on peak early diastolic strain rate (PEDSR) and exercise capacity in patients with AS. METHODS Patients with asymptomatic moderate to severe AS and diastolic dysfunction underwent trans-thoracic echocardiography, exercise testing and cardiac magnetic resonance (CMR) imaging at baseline, 6 weeks after commencing ranolazine and at 10 weeks (4 weeks after discontinuation). Diastolic function was assessed using PEDSR measured on tagged CMR images. RESULTS Fifteen patients (peak pressure gradient 48.8 ± 12.4 mmHg, mean pressure gradient 27.1 ± 7.5 mmHg, aortic valve area 1.26 ± 0.31 cm(2)) completed the week-6 visit and 13 completed the final visit. Global PEDSR did not significantly increase from baseline (0.79 ± 0.15) to week-6 (0.86 ± 0.18, p = 0.198). There was a borderline significant increase in total exercise duration from 10.47 ± 3.68 min to 11.60 ± 3.25 min (p = 0.06). CONCLUSION This small pilot study did not show a significant improvement in diastolic function with the use of ranolazine in asymptomatic patients with moderate-severe AS. Further studies with a larger population may be indicated. EduraCT number 2011-000111-26.
-
8.
Refractoriness in human atria: Time and voltage dependence of sodium channel availability.
Skibsbye, L, Jespersen, T, Christ, T, Maleckar, MM, van den Brink, J, Tavi, P, Koivumäki, JT
Journal of molecular and cellular cardiology. 2016;:26-34
Abstract
BACKGROUND Refractoriness of cardiac cells limits maximum frequency of electrical activity and protects the heart from tonic contractions. Short refractory periods support major arrhythmogenic substrates and augmentation of refractoriness is therefore seen as a main mechanism of antiarrhythmic drugs. Cardiomyocyte excitability depends on availability of sodium channels, which involves both time- and voltage-dependent recovery from inactivation. This study therefore aims to characterise how sodium channel inactivation affects refractoriness in human atria. METHODS AND RESULTS Steady-state activation and inactivation parameters of sodium channels measured in vitro in isolated human atrial cardiomyocytes were used to parameterise a mathematical human atrial cell model. Action potential data were acquired from human atrial trabeculae of patients in either sinus rhythm or chronic atrial fibrillation. The ex vivo measurements of action potential duration, effective refractory period and resting membrane potential were well-replicated in simulations using this new in silico model. Notably, the voltage threshold potential at which refractoriness was observed was not different between sinus rhythm and chronic atrial fibrillation tissues and was neither affected by changes in frequency (1 vs. 3Hz). CONCLUSIONS Our results suggest a preferentially voltage-dependent, rather than time-dependent, effect with respect to refractoriness at physiologically relevant rates in human atria. However, as the resting membrane potential is hyperpolarized in chronic atrial fibrillation, the voltage-dependence of excitability dominates, profoundly increasing the risk for arrhythmia re-initiation and maintenance in fibrillating atria. Our results thereby highlight resting membrane potential as a potential target in pharmacological management of chronic atrial fibrillation.
-
9.
Epithelial Sodium and Chloride Channels and Asthma.
Wang, W, Ji, HL
Chinese medical journal. 2015;(16):2242-9
-
-
Free full text
-
Abstract
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.