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Amin Akbari Ahangar, Eslam Elhanafy, Hayden Blanton, Jing Li
Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms...
September 23, 2023: bioRxiv
#22
Yasir Bakhit, James Clark, Richard Cowell
No abstract text is available yet for this article.
September 2023: HeartRhythm Case Reports
#23
REVIEW
Mohammad N Almohammal
Neonates can have ion channel abnormalities known as channelopathies, which can impact any organ system. These abnormalities cause seizures, which can result in developmental delays and lead to early death. For a child's long-term neurodevelopment, early identification as a channelopathy is essential to avoid any brain damage. Therefore, this review aims to focus on early diagnostic criteria. Since it might be difficult for doctors to interpret the presenting symptoms of channelopathies, a thorough diagnostic examination that follows a methodical step-by-step procedure is essential...
August 2023: Curēus
#24
JOURNAL ARTICLE
Simon Loose, Annette Lischka, Samuel Kuehs, Carla Nau, Stefan H Heinemann, Ingo Kurth, Enrico Leipold
The voltage-gated sodium channel NaV 1.8 is prominently expressed in the soma and axons of small-caliber sensory neurons, and pathogenic variants of the corresponding gene SCN10A are associated with peripheral pain and autonomic dysfunction. While most disease-associated SCN10A variants confer gain-of-function properties to NaV 1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygous SCN10A missense variant resulting in alteration p...
September 11, 2023: Pflügers Archiv: European Journal of Physiology
#25
JOURNAL ARTICLE
Jenny Sun, Don Daniel Ocay, Meghan Halpin, Kimberly Lobo, Dafni F T Frohman, Carolina Donado, Catherine A Brownstein, Casie A Genetti, Anna Madden, Charles B Berde
Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates...
July 26, 2023: Children
#26
REVIEW
Arnaud Monteil, Nathalie C Guérineau, Antonio Gil-Nagel, Paloma Parra-Diaz, Philippe Lory, Adriano Senatore
Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of membrane proteins, especially ion channels. Unique complements of co-expressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intra-cellular concentrations of ions, mainly Na+ , K+ , and Cl- , and their passive permeation across the cell membrane through leak ion channels...
August 24, 2023: Physiological Reviews
#27
JOURNAL ARTICLE
Kyung Mi Chung, Joshua Hack, Jennifer Andrews, Maureen Galindo-Kelly, John Schreiber, Joseph Watkins, Michael F Hammer
OBJECTIVES: Genetic variants in the SCN8A gene underlie a wide spectrum of neurodevelopmental phenotypes including several distinct seizure types and a host of comorbidities. One of the major challenges facing clinicians and researchers alike is to identify genotype-phenotype (G-P) correlations that may improve prognosis, guide treatment decisions, and lead to precision medicine approaches. METHODS: We investigated genotype-phenotype correlations among 270 participants harboring gain-of-function (GOF) variants enrolled in the International SCN8A Registry, a patient-driven online database...
August 16, 2023: Epilepsia
#28
REVIEW
Vinojini Vivekanandam, Dipa Jayaseelan, Michael G Hanna
Muscle channelopathies encompass a wide range of mainly episodic conditions that are characterized by muscle stiffness and weakness. The myotonic conditions, characterized predominantly by stiffness, include myotonia congenita, paramyotonia congenita, and sodium channel myotonia. The periodic paralysis conditions include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome. Clinical history is key, and diagnosis is confirmed by next-generation genetic sequencing of a panel of known genes but can also be supplemented by neurophysiology studies and MRI...
2023: Handbook of Clinical Neurology
#29
REVIEW
Evelina Carapancea, Maria Roberta Cilio
THE CHALLENGE OF SEIZURE RECOGNITION: Recognition of seizures in neonates remains the foremost challenge to overcome. All neonates at risk for seizures, especially the critically ill, should undergo video-EEG monitoring. The initial step toward an accurate diagnosis is the accurate description and interpretation of the electro-clinical phenotype. THE IMPORTANCE OF SEIZURE SEMIOLOGY AND ASSOCIATION WITH ETIOLOGY: The early distinction between acute provoked seizures and neonatal-onset epilepsies serves as the primary determinant for guiding management, treatment choices, and duration...
September 2023: European Journal of Paediatric Neurology: EJPN
#30
JOURNAL ARTICLE
Sophia Kriegeskorte, Raya Bott, Martin Hampl, Alon Korngreen, Ralf Hausmann, Angelika Lampert
Voltage-gated sodium channels (Nav) are key players in excitable tissues with the capability to generate and propagate action potentials. Mutations in the genes encoding Navs can lead to severe inherited diseases, and some of these so-called channelopathies show temperature-sensitive phenotypes, for example, paramyotonia congenita, Brugada syndrome, febrile seizure syndromes, and inherited pain syndromes like erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Nevertheless, most investigations of mutation-induced gating effects have been conducted at room temperature, and thus the role of cooling or warming in channelopathies remains poorly understood...
September 4, 2023: Journal of General Physiology
#31
JOURNAL ARTICLE
Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, Peter J Schwartz
AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients...
August 2, 2023: European Heart Journal
#32
Zainab Gilitwala, Shalmali Satpute, Sumant Patil
Non-dystrophic myotonia (NDM) is a group of rare mono-genetic muscle disorders caused by skeletal muscle sodium or chloride channelopathies. These disorders are characterized by high muscle tone and the inability of the muscles to relax spontaneously after voluntary contraction. Myotonia congenita refers to a form of NDM that typically manifests during the later stages of childhood. It occurs as a result of genetic mutations affecting the chloride channels found in the sarcolemma membrane of skeletal muscles...
June 2023: Curēus
#33
REVIEW
Fatima Maqoud, Domenico Tricarico, Rosanna Mallamaci, Antonella Orlando, Francesco Russo
Several gastrointestinal (GI) tract abnormalities, including visceral hypersensitivity, motility, and intestinal permeability alterations, have been implicated in functional GI disorders (FGIDs). Ion channels play a crucial role in all the functions mentioned above. Hormones and natural molecules modulate these channels and represent targets of drugs and bacterial toxins. Mutations and abnormal functional expression of ion channel subunits can lead to diseases called channelopathies. These channelopathies in gastroenterology are gaining a strong interest, and the evidence of co-relationships is increasing...
July 4, 2023: International Journal of Molecular Sciences
#34
Yukimune Okubo, Moriei Shibuya, Haruhiko Nakamura, Aritomo Kawashima, Kaori Kodama, Wakaba Endo, Takehiko Inui, Noriko Togashi, Yu Aihara, Matsuyuki Shirota, Ryo Funayama, Tetsuya Niihori, Atsushi Fujita, Keiko Nakayama, Yoko Aoki, Naomichi Matsumoto, Shigeo Kure, Atsuo Kikuchi, Kazuhiro Haginoya
Variants of SCN1A represent the archetypal channelopathy associated with several epilepsy syndromes. The clinical phenotypes have recently expanded from Dravet syndrome. CASE REPORT: We present a female patient with the de novo SCN1A missense variant, c.5340G > A (p. Met1780Ile). The patient had various clinical features with neonatal onset SCN1A epileptic encephalopathy, arthrogryposis multiplex congenita, thoracic hypoplasia, thoracic scoliosis, and hyperekplexia. CONCLUSION: Our findings are compatible with neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis; the most severe phenotype probably caused by gain-of-function variant of SCN1A...
July 11, 2023: Brain & Development
#35
JOURNAL ARTICLE
Judith A Pijpers, Ping Yee Billie Au, Lauren C Weeke, Alla A Vein, Liesbeth S Smit, Ana Vilan, Elke Jacobs, Linda S de Vries, Sylke J Steggerda, Maria Roberta Cilio, Evelina Carapancea, Marie-Coralie Cornet, Juan P Appendino, Cacha M P C D Peeters-Scholte
PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions...
August 2023: Seizure: the Journal of the British Epilepsy Association
#36
JOURNAL ARTICLE
Shiva Barforoshi, Jenica Thangathurai, Houman Khakpour, Sonia Shah
Brugada syndrome is a rare sodium channelopathy that predisposes to an increased risk of malignant arrythmias and sudden cardiac death. Previous studies have reported that metabolic disturbances can uncover a Brugada ECG pattern. Given the risk of malignant arrhythmias, it is important to correctly diagnose and treat Brugada syndrome. We report a case of Brugada syndrome uncovered by hyperkalaemia precipitated in a patient with pseudohypoaldosteronism.
June 30, 2023: BMJ Case Reports
#37
JOURNAL ARTICLE
Marwa Elamin, Fouad Lemtiri-Chlieh, Tiwanna M Robinson, Eric S Levine
OBJECTIVE: Duplication of the maternal chromosome 15q11.2-q13.1 region causes Dup15q syndrome, a highly penetrant neurodevelopmental disorder characterized by severe autism and refractory seizures. Although UBE3A, the gene encoding the ubiquitin ligase E3A, is thought to be the main driver of disease phenotypes, the cellular and molecular mechanisms that contribute to the development of the syndrome are yet to be determined. We previously established the necessity of UBE3A overexpression for the development of cellular phenotypes in human Dup15q neurons, including increased action potential firing and increased inward current density, which prompted us to further investigate sodium channel kinetics...
June 16, 2023: Epilepsia
#38
Nicolò Salvarani, Giovanni Peretto, Crasto Silvia, Andrea Villatore, Cecilia Thairi, Anna Santoni, Camilla Galli, Paola Carrera, Simone Sala, Sara Benedetti, Elisa Di Pasquale, Chiara Di Resta
Brugada syndrome (BrS) is an inherited autosomal dominant cardiac channelopathy. Pathogenic rare mutations in the SCN5A gene, encoding the alpha-subunit of the voltage-dependent cardiac Na+ channel protein (Nav1.5), are identified in 20% of BrS patients, affecting the correct function of the channel. To date, even though hundreds of SCN5A variants have been associated with BrS, the underlying pathogenic mechanisms are still unclear in most cases. Therefore, the functional characterization of the SCN5A BrS rare variants still represents a major hurdle and is fundamental to confirming their pathogenic effect...
May 31, 2023: International Journal of Molecular Sciences
#39
JOURNAL ARTICLE
Juan Lorenzo B Pablo, Savannah L Cornett, Lei A Wang, Sooyeon Jo, Tobias Brünger, Nikita Budnik, Mudra Hegde, Jean-Marc DeKeyser, Christopher H Thompson, John G Doench, Dennis Lal, Alfred L George, Jen Q Pan
It is challenging to apply traditional mutational scanning to voltage-gated sodium channels (NaV s) and functionally annotate the large number of coding variants in these genes. Using a cytosine base editor and a pooled viability assay, we screen a library of 368 guide RNAs (gRNAs) tiling NaV 1.2 to identify more than 100 gRNAs that change NaV 1.2 function. We sequence base edits made by a subset of these gRNAs to confirm specific variants that drive changes in channel function. Electrophysiological characterization of these channel variants validates the screen results and provides functional mechanisms of channel perturbation...
June 1, 2023: Cell Reports
#40
Judah A Kreinbrook, Annalia Foster, Luis Paulino, Fabio Leonelli
COVID-19 has been associated with an increased risk of both atrial and ventricular arrhythmias. Brugada syndrome (BrS), an inherited sodium channelopathy presenting with a characteristic ECG morphology, confers a baseline risk of ventricular arrhythmias such as ventricular fibrillation (VF), especially during febrile illnesses. However, mimics of BrS, termed Brugada phenocopies (BrP), have been noted in association with fever, electrolyte abnormalities, and toxidromes outside of viral illness. Such presentations manifest the same ECG pattern, the type-I Brugada pattern (type-I BP)...
April 2023: Curēus
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