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Sodium channelopathies

Maroua Boukhabza, Jaouad El Hilaly, Nourdine Attiya, Ahmed El-Haidani, Younes Filali-Zegzouti, Driss Mazouzi, Mohamed-Yassine Amarouch
Ion channels are transmembrane proteins that allow the passage of ions according to the direction of their electrochemical gradients. Mutations in more than 30 genes encoding ion channels have been associated with an increasingly wide range of inherited cardiac arrhythmias. In this line, ion channels become one of the most important molecular targets for several classes of drugs, including antiarrhythmics. Nevertheless, antiarrhythmic drugs are usually accompanied by some serious side effects. Thus, developing new approaches could offer added values to prevent and treat the episodes of arrhythmia...
2016: Computational and Mathematical Methods in Medicine
Laura A Foster, Maria R Johnson, John T MacDonald, Peter I Karachunski, Thomas R Henry, David R Nascene, Brian P Moran, Gerald V Raymond
BACKGROUND: Genetic alterations are significant causes of epilepsy syndromes; especially early-onset epileptic encephalopathies and voltage-gated sodium channelopathies are among the best described. Mutations in the SCN2A subunit of voltage-gated sodium channels have been associated with benign familial neonatal-infantile seizures, generalized epilepsy febrile seizures plus, and an early-onset infantile epileptic encephalopathy. METHOD: We describe two infants with medically refractory seizures due to a de novo SCN2A mutation...
October 18, 2016: Pediatric Neurology
Yashwant Agrawal, Sourabh Aggarwal, Jagadeesh K Kalavakunta, Vishal Gupta
Brugada syndrome (BS), a life-threatening channelopathy associated with reduced inward sodium current due to dysfunctional sodium channels, is characterized by ST-segment elevation with downsloping "coved type" (type 1) or "saddle back" (type 2) pattern in V1-V3 precordial chest leads (1, 2). Brugada phenocopy, a term describing conditions inducing Brugada-like pattern of electrocardiogram (EKG) manifestations in patients without true BS, is an emerging condition (3). We describe a case series of Brugada phenocopy with hyponatremia...
October 2016: Journal of the Saudi Heart Association
Fiona M Baumer, Jurriaan M Peters, Christelle M El Achkar, Phillip L Pearl
Voltage-gated sodium channels (Nav) are critical regulators of neuronal excitability. Genes for the α-subunits of three sodium channel subtypes-SCN1A, SCN2A, and SCN3A-are all located on chromosome 2q24. A full-term boy with an unremarkable birth history presented at 1 month of age with unusual movements that had started on day of life 2. Exam was notable for lack of visual attention, hypotonia, and hyperreflexia. Electroencephalogram (EEG) showed an invariant burst suppression with multifocal spikes, ictal episodes with bicycling movements associated with buildups of rhythmic activity, and epileptic spasms...
March 2016: Journal of Pediatric Epilepsy
C E Morris, B Joos
Sick excitable cells (ie, Nav channel-expressing cells injured by trauma, ischemia, inflammatory, and other conditions) typically exhibit "acquired sodium channelopathies" which, we argue, reflect bleb-damaged membranes rendering their Nav channels "leaky." The situation is excitotoxic because untreated Nav leak exacerbates bleb damage. Fast Nav inactivation (a voltage-independent process) is so tightly coupled, kinetically speaking, to the inherently voltage-dependent process of fast activation that when bleb damage accelerates and thus left-shifts macroscopic fast activation, fast inactivation accelerates to the same extent...
2016: Current Topics in Membranes
E G Moczydlowski
This review glances at the voltage-gated sodium (Na(+)) channel (NaV) from the skewed perspective of natural history and the history of ideas. Beginning with the earliest natural philosophers, the objective of biological science and physiology was to understand the basis of life and discover its intimate secrets. The idea that the living state of matter differs from inanimate matter by an incorporeal spirit or mystical force was central to vitalism, a doctrine based on ancient beliefs that persisted until the last century...
2016: Current Topics in Membranes
Arthur Beyder, Gianrico Farrugia
In the gastrointestinal (GI) tract, abnormalities in secretion, absorption, motility, and sensation have been implicated in functional gastrointestinal disorders (FGIDs). Ion channels play important roles in all these GI functions. Disruptions of ion channels' ability to conduct ions can lead to diseases called ion channelopathies. Channelopathies can result from changes in ion channel biophysical function or expression due to mutations, posttranslational modification, and accessory protein malfunction. Channelopathies are strongly established in the fields of cardiology and neurology, but ion channelopathies are only beginning to be recognized in gastroenterology...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Paola Imbrici, Antonella Liantonio, Giulia M Camerino, Michela De Bellis, Claudia Camerino, Antonietta Mele, Arcangela Giustino, Sabata Pierno, Annamaria De Luca, Domenico Tricarico, Jean-Francois Desaphy, Diana Conte
In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies...
2016: Frontiers in Pharmacology
Mert Karakaya, Raoul Heller, Volkmar Kunde, Klaus-Peter Zimmer, Cho-Ming Chao, Peter Nürnberg, Sebahattin Cirak
Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of disorders. Mostly myopathic and neurogenic defects have been described, but many patients remain without genetic diagnosis. We are elaborating on the clinical presentation of neonatal cases with DA who carry novel mutations in the nonselective sodium leak channel (NALCN). Two patients reported herein were remarkable for central hypertonicity in addition to DA. By trio-whole exome sequencing, two undescribed de novo mutations in NALCN were revealed...
August 2016: Neuropediatrics
Heather M Byers, Christopher W Beatty, Si Houn Hahn, Sidney M Gospe
BACKGROUND: Channelopathies are a group of monogenic disorders that affect a single ion channel and can result in neurological disease. While a rare cause of epilepsy, channelopathies offer unique insight to the molecular basis of epilepsy and treatment opportunities. Calcium homeostasis is tightly regulated by a series of interacting subunits. CACNA1A encodes the principal pore-forming subunit of the voltage-gated P/Q-type calcium channel, alpha1. Patients with epileptic encephalopathy due to pathogenic variants in CACNA1A have been previously described and are challenging to treat...
July 2016: Pediatric Neurology
Roberta Gualdani, Maria Maddalena Cavalluzzi, Giovanni Lentini
Voltage-gated sodium channels (VGSC) are responsible for the selective influx of sodium ions in excitable cells. A number of physiological phenomena such as muscle contraction, pain sensation, processing of neuronal information in the brain as well as neuronal regulation of peripheral tissues rely on the activity of these channels. On the other hand, abnormal activity of VGSC are implicated in several pathological processes (e.g., cardiac arrhythmias, epilepsy, and chronic pain) which in some cases (e.g., channelopathies such as myotonias) are linked to specific gene mutations...
2016: Current Medicinal Chemistry
Roman V Frolov, Matti Weckström
Cellular signaling in both excitable and nonexcitable cells involves several classes of ion channels. Some of them are of minor importance, with very specialized roles in physiology, but here we concentrate on three major channel classes: TRP (transient receptor potential channels), voltage-gated sodium channels (Nav), and voltage-gated calcium channels (Cav). Here, we first propose a conceptual framework binding together all three classes of ion channels, a "flow-of-excitation model" that takes into account the inputs mediated by TRP and other similar channels, the outputs invariably provided by Cav channels, and the regenerative transmission of signals in the neural networks, for which Nav channels are responsible...
2016: Advances in Protein Chemistry and Structural Biology
Mohammad Mehdi Heidari, Mehri Khatami, Shahriar Nafissi, Faezeh Hesami-Zokai, Afshin Khorrami
BACKGROUND: Non-dystrophic myotonias are a heterogeneous set of skeletal, muscular channelopathies, which have been associated with point mutations within sodium channel α-subunit (SCN4A) gene. Because exons 22 and 24 of SCN4A gene are recognized as hot spots for this disease, the purpose of the study is to identify mutation in exons 22 and 24 of SCN4A gene in Iranian non-dystrophic myotonias patients. METHODS: In this study, 28 Iranian patients with non-dystrophic myotonia analyzed for the mutation scanning in exons 22 and 24 of SCN4A gene by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and sequencing...
October 7, 2015: Iranian Journal of Neurology
Marco Daverio, Ornella Ciccone, Clementina Boniver, Luca De Palma, Domenico Corrado, Marilena Vecchi
BACKGROUND: The possibility that epileptic seizures and arrhythmias are different clinical manifestations of a common channelopathy is an interesting but unproved hypothesis. Patients with Dravet syndrome show heart rate variability and affected individuals with arrhythmias have also been documented. The possibility that a genetic mutation affecting sodium channel functions may predispose to both Dravet syndrome and arrhythmogenic disorders is an interesting hypothesis. PATIENT PRESENTATION: We describe a 5-month-old girl with Dravet syndrome who presented with paroxysmal supraventricular tachycardia during status epilepticus...
March 2016: Pediatric Neurology
Emile G Daoud
No abstract text is available yet for this article.
February 16, 2016: Circulation
Gabriella A Horvath, Michelle Demos, Casper Shyr, Allison Matthews, Linhua Zhang, Simone Race, Sylvia Stockler-Ipsiroglu, Margot I Van Allen, Ogan Mancarci, Lilah Toker, Paul Pavlidis, Colin J Ross, Wyeth W Wasserman, Natalie Trump, Simon Heales, Simon Pope, J Helen Cross, Clara D M van Karnebeek
We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism...
January 2016: Molecular Genetics and Metabolism
M K Chaykovskaya, E A Fetisova, M V Yakoleva, V V Kalinin, E V Zaklyazminskaya
Patient P., 50 years old, male, with type I Brugada syndrome was examined. The patient had aborted sudden death event (2006) in his clinical history, ICD Gem III VR was implanted in 2006, ICDLumax DR was reimplanted in 2012. The patient had coved type pattern in right precordial ECG-leads. The p.E553X mutation in SCN5A gene, whish encodes the sodium channel α-subunit, was found. Noninvasive electrocardiographic mapping was performed. Significant changes of local unipolar electrograms including QRS fragmentation, ST segment elevation and late ventricular potentials were identified in the epicardium of the right ventricle outflow tract...
2015: Kardiologiia
Ami Mankodi, Christopher Grunseich, Martin Skov, Lisa Cook, Georg Aue, Enkhtsetseg Purev, Dara Bakar, Tanya Lehky, Karin Jurkat-Rott, Thomas H Pedersen, Richard W Childs
We report a patient with paramyotonia congenita/hyperkalemic periodic paralysis due to Nav1.4 I693T mutation who had worsening of myotonia and muscle weakness in the setting of hypomagnesemia and hypocalcemia with marked recovery after magnesium administration. Computer simulations of the effects of the I693T mutation were introduced in the muscle fiber model by both hyperpolarizing shifts in the Nav1.4 channel activation and a faster recovery from slow channel inactivation. A further shift in the Nav1.4 channel activation in the hyperpolarizing direction as expected with low divalent cations resulted in myotonia that progressed to membrane inexcitability...
November 2015: Neuromuscular Disorders: NMD
Zhaoli Tang, Zhao Chen, Beisha Tang, Hong Jiang
Primary erythromelalgia (PE ORPHA90026) is a rare autosomal dominant neuropathy characterized by the combination of recurrent burning pain, warmth and redness of the extremities. The incidence rate of PE ranges from 0.36 to 1.1 per 100,000 persons. Gender ratio differs according to different studies and no evidence showed a gender preference. Clinical onset of PE is often in the first decade of life. Burning pain is the most predominant symptom and is usually caused and precipitated by warmth and physical activities...
2015: Orphanet Journal of Rare Diseases
Jessica R Gilbert, Mkael Symmonds, Michael G Hanna, Raymond J Dolan, Karl J Friston, Rosalyn J Moran
Clinical assessments of brain function rely upon visual inspection of electroencephalographic waveform abnormalities in tandem with functional magnetic resonance imaging. However, no current technology proffers in vivo assessments of activity at synapses, receptors and ion-channels, the basis of neuronal communication. Using dynamic causal modeling we compared electrophysiological responses from two patients with distinct monogenic ion channelopathies and a large cohort of healthy controls to demonstrate the feasibility of assaying synaptic-level channel communication non-invasively...
January 1, 2016: NeuroImage
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