WorldWideScience

Sample records for channelopathies

  1. Potassium Channelopathies and Gastrointestinal Ulceration

    Science.gov (United States)

    Han, Jaeyong; Lee, Seung Hun; Giebisch, Gerhard; Wang, Tong

    2016-01-01

    Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract. PMID:27784845

  2. Channelopathy Pathogenesis in Autism Spectrum Disorders

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    Galina eSchmunk

    2013-11-01

    Full Text Available Autism spectrum disorder (ASD is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole- genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders, and animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.

  3. Action potential broadening in a presynaptic channelopathy

    Science.gov (United States)

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

    2016-07-01

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

  4. Pathophysiological role of omega pore current in channelopathies

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    Karin eJurkat-Rott

    2012-06-01

    Full Text Available In voltage-gated cation channels, a recurrent pattern for mutations is the neutralization of positively charged residues in the voltage-sensing S4 transmembrane segments. These mutations cause dominant ion channelopathies affecting many tissues such as brain, heart, and skeletal muscle. Recent studies suggest that the pathogenesis of associated phenotypes is not limited to alterations in the gating of the ion-conducting alpha pore. Instead, aberrant so-called omega currents facilitated by the movement of the S4 segments during activation and during recovery are thought to cause symptoms. Surprisingly, these omega currents display uni- or bi-directionality and conduct cations with varying ion selectivity. Additionally, the voltage-sensitivity enables the channels to conduct different omega currents in the various voltage ranges. This review gives an overview of voltage sensor channelopathies in general and focuses on pathogenesis of skeletal muscle S4 disorders for which current knowledge is most advanced.

  5. Ion channelopathy and hyperphosphorylation contributing to cardiac arrhythmias

    Institute of Scientific and Technical Information of China (English)

    De-zai DAI; Feng YU

    2005-01-01

    The occurrence of cardiac arrhythmias is related to the abnormality of ion channels not only in sarcolemma but also in the sarcoplasmic reticulum, which regulates the process of calcium release and up-take intracellularly. Patterns of ion channelopathy in the sarcolemma can be divided into single channel disorder from gene mutations and multiple channels disorder in a diseased hypertrophied heart. Abnormal RyR2, FKBP12.6, SERCA2a, and PLB are also involved in the initiation of cardiac arrhythmias. Maladjustment by hyperphosphorylation on the ion channels in the sarcolemma and RyR2-FKBP12.6 and SERCA2a-PLB is discussed. Hyperphosphorylation, which is the main abnormality upstream to ion channels, can be targeted for suppressing the deterioration of ion channelopathy in terms of new drug discovery in the treatment and prevention of malignant cardiac arrhythmias.

  6. Canalopatías epilépticas Epileptic channelopathies

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    Jaime Carrizosa Moog

    2003-03-01

    Full Text Available Se hace una revisión actualizada sobre las epilepsias debidas a alteraciones de los diferentes canales iónicos, con énfasis en su presentación clínica y genotipificación. Se plantean someramente las bases del enfoque farmacológico del tratamiento. Thies an up to date review of the genotypic and phenotypic characteristics of epileptic channelopathies is presented and the bases for a pharmacologic approach to treatment are briefly described.

  7. Voltage-gated sodium channels: biophysics, pharmacology, and related channelopathies

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    Eleonora eSavio Galimberti

    2012-07-01

    Full Text Available Voltage-gated sodium channels (VGSC are multi-molecular protein complexes expressed in both excitable and non-excitable cells. They are primarily formed by a pore-forming multi-spanning integral membrane glycoprotein (α-subunit that can be associated with one or more regulatory β-subunits. The latter are single-span integral membrane proteins that modulate the sodium current (INa and can also function as cell-adhesion molecules (CAMs. In-vitro some of the cell-adhesive functions of the β-subunits may play important physiological roles independently of the α-subunits. Other endogenous regulatory proteins named channel partners or channel interacting proteins (ChiPs like caveolin-3 and calmodulin/calmodulin kinase II (CaMKII can also interact and modulate the expression and/or function of VGSC. In addition to their physiological roles in cell excitability and cell adhesion, VGSC are the site of action of toxins (like tetrodotoxin and saxitoxin, and pharmacologic agents (like antiarrhythmic drugs, local anesthetics, antiepileptic drugs, and newly developed analgesics. Mutations in genes that encode α- and/or β-subunits as well as the ChiPs can affect the structure and biophysical properties of VGSC, leading to the development of diseases termed sodium channelopathies. This review will outline the structure, function and biophysical properties of VGSC as well as their pharmacology and associated channelopathies and highlight some of the recent advances in this field

  8. Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

    Institute of Scientific and Technical Information of China (English)

    Konstantinos Dean BOUDOULAS; Peter J MOHLER

    2011-01-01

    Over the past fifteen years, our understanding of the molecular mechanisms underlying human disease has flourished in large part due to the discovery of gene mutations linked with membrane ion channels and transporters. In fact, ion channel defects ("channelopathies" - the focus of this review series) have been associated with a spectrum of serious human disease phenotypes including cystic fibrosis, cardiac arrhythmia, diabetes, skeletal muscle defects, and neurological disorders. However, we now know that human disease, particularly excitable cell disease, may be caused by defects in non-ion channel polypeptides including in cellular components residing well beneath the plasma membrane. For example, over the past few years, a new class of potentially fatal cardiac arrhythmias has been linked with cytoplasmic proteins that include sub-membrane adapters such as ankyrin-B (ANK2),ankyrin-G (ANK3), and alpha-1 syntrophin, membrane coat proteins including caveolin-3 (CAV3), signaling platforms including yotiao (AKAPg), and cardiac enzymes (GPD1L). The focus of this review is to detail the exciting role of lamins, yet another class of gene products that have provided elegant new insight into human disease.

  9. Neural network modelling of the influence of channelopathies on reflex visual attention.

    Science.gov (United States)

    Gravier, Alexandre; Quek, Chai; Duch, Włodzisław; Wahab, Abdul; Gravier-Rymaszewska, Joanna

    2016-02-01

    This paper introduces a model of Emergent Visual Attention in presence of calcium channelopathy (EVAC). By modelling channelopathy, EVAC constitutes an effort towards identifying the possible causes of autism. The network structure embodies the dual pathways model of cortical processing of visual input, with reflex attention as an emergent property of neural interactions. EVAC extends existing work by introducing attention shift in a larger-scale network and applying a phenomenological model of channelopathy. In presence of a distractor, the channelopathic network's rate of failure to shift attention is lower than the control network's, but overall, the control network exhibits a lower classification error rate. The simulation results also show differences in task-relative reaction times between control and channelopathic networks. The attention shift timings inferred from the model are consistent with studies of attention shift in autistic children. PMID:26834861

  10. Molecular basis of inherited calcium Channelopathies: role of mutations in pore-forming subunits

    Institute of Scientific and Technical Information of China (English)

    Lynn MCKEOWN; Philip ROBINSON; Owen T JONES

    2006-01-01

    The pore-forming alpha subunits of voltage-gated calcium channels contain the essential biophysical machinery that underlies calcium influx in response to cell depolarization.In combination with requisite auxiliary subunits,these pore subunits form calcium channel complexes that are pivotal to the physiology and pharmacology of diverse cells ranging from sperm to neurons.Not surprisingly,mutations in the pore subunits generate diverse pathologies,termed channelopathies,that range from failures in excitation-contraction coupling to night blindness.Over the last decade, major insights into the mechanisms of pathogenesis have been derived from animals showing spontaneous or induced mutations.In parallel,there has been considerable growth in our understanding of the workings of voltage-gated ion channels from a structure-function,regulation and cell biology perspective.Here we document our current understanding of the mutations underlying channelopathies involving the voltage-gated calcium channel alpha subunits in humans and other species.

  11. Modelling Human Channelopathies Using Induced Pluripotent Stem Cells: A Comprehensive Review

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    Martin Müller

    2013-01-01

    Full Text Available The generation of induced pluripotent stem cells (iPS cells has pioneered the field of regenerative medicine and developmental biology. They can be generated by overexpression of a defined set of transcription factors in somatic cells derived from easily accessible tissues such as skin or plucked hair or even human urine. In case of applying this tool to patients who are classified into a disease group, it enables the generation of a disease- and patient-specific research platform. iPS cells have proven a significant tool to elucidate pathophysiological mechanisms in various diseases such as diabetes, blood disorders, defined neurological disorders, and genetic liver disease. One of the first successfully modelled human diseases was long QT syndrome, an inherited cardiac channelopathy which causes potentially fatal cardiac arrhythmia. This review summarizes the efforts of reprogramming various types of long QT syndrome and discusses the potential underlying mechanisms and their application.

  12. MLC1 protein: a likely link between leukodystrophies and brain channelopathies

    Science.gov (United States)

    Brignone, Maria S.; Lanciotti, Angela; Camerini, Serena; De Nuccio, Chiara; Petrucci, Tamara C.; Visentin, Sergio; Ambrosini, Elena

    2015-01-01

    Megalencephalic leukoencephalopathy with subcortical cysts (MLCs) disease is a rare inherited, autosomal recessive form of childhood-onset spongiform leukodystrophy characterized by macrocephaly, deterioration of motor functions, epileptic seizures and mental decline. Brain edema, subcortical fluid cysts, myelin and astrocyte vacuolation are the histopathological hallmarks of MLC. Mutations in either the MLC1 gene (>75% of patients) or the GlialCAM gene (<20% of patients) are responsible for the disease. Recently, the GlialCAM adhesion protein was found essential for the membrane expression and function of the chloride channel ClC-2 indicating MLC disease caused by mutation in GlialCAM as the first channelopathy among leukodystrophies. On the contrary, the function of MLC1 protein, which binds GlialCAM, its functional relationship with ClC-2 and the molecular mechanisms underlying MLC1 mutation-induced functional defects are not fully understood yet. The human MLC1 gene encodes a 377-amino acid membrane protein with eight predicted transmembrane domains which shows very low homology with voltage-dependent potassium (K+) channel subunits. The high expression of MLC1 in brain astrocytes contacting blood vessels and meninges and brain alterations observed in MLC patients have led to hypothesize a role for MLC1 in the regulation of ion and water homeostasis. Recent studies have shown that MLC1 establishes structural and/or functional interactions with several ion/water channels and transporters and ion channel accessory proteins, and that these interactions are affected by MLC1 mutations causing MLC. Here, we review data on MLC1 functional properties obtained in in vitro and in vivo models and discuss evidence linking the effects of MLC1 mutations to brain channelopathies. PMID:25883547

  13. Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment.

    Science.gov (United States)

    Tanaka, Naoto; Dutrow, Emily V; Miyadera, Keiko; Delemotte, Lucie; MacDermaid, Christopher M; Reinstein, Shelby L; Crumley, William R; Dixon, Christopher J; Casal, Margret L; Klein, Michael L; Aguirre, Gustavo D; Tanaka, Jacqueline C; Guziewicz, Karina E

    2015-01-01

    Cyclic nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM). ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivo and channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD) simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ) domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis of in vivo channels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients. PMID:26407004

  14. Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment.

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    Naoto Tanaka

    Full Text Available Cyclic nucleotide-gated (CNG ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM. ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivo and channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis of in vivo channels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients.

  15. Cardiac sodium channelopathies

    NARCIS (Netherlands)

    A.S. Amin; A. Asghari-Roodsari; H.L. Tan

    2010-01-01

    Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (I-Na) during phase 0 of the cardiac action potential. The importance of I-Na for normal cardiac electrical activity is reflected by the high incidence of

  16. Recent advance in inherited arrhythmogenic disease-associated ion channelopathies%遗传性心律失常疾病相关离子通道病变的研究进展

    Institute of Scientific and Technical Information of China (English)

    陈明颢; 胡峻岩

    2013-01-01

    Sudden cardiac death of young people is mainly caused by arrhythmia with genetic defects, which is called inherited arrhythmogenic diseases (IADs). The most common kinds of IADs are long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Abnormal cardiac-electrical activities caused by the mutation of the subunit genes coding the ion channels in myocardial cells are the major cause of IADs. In this review, we focus on the advances in pathophysiological and genetic research of the channelopathies mentioned above.

  17. Muscle channelopathies and electrophysiological approach

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    Cherian Ajith

    2008-01-01

    Full Text Available Myotonic syndromes and periodic paralyses are rare disorders of skeletal muscle characterized mainly by muscle stiffness or episodic attacks of weakness. Familial forms are caused by mutation in genes coding for skeletal muscle voltage ionic channels. Familial periodic paralysis and nondystrophic myotonias are disorders of skeletal muscle excitability caused by mutations in genes coding for voltage-gated ion channels. These diseases are characterized by episodic failure of motor activity due to muscle weakness (paralysis or stiffness (myotonia. Clinical studies have identified two forms of periodic paralyses: hypokalemic periodic paralysis (hypoKPP and hyperkalemic periodic paralysis (hyperKPP, based on changes in serum potassium levels during the attacks, and three distinct forms of myotonias: paramyotonia congenita (PC, potassium-aggravated myotonia (PAM, and myotonia congenita (MC. PC and PAM have been linked to missense mutations in the SCN4A gene, which encodes α subunit of the voltage-gated sodium channel, whereas MC is caused by mutations in the chloride channel gene (CLCN1. Exercise is known to trigger, aggravate, or relieve symptoms. Therefore, exercise can be used as a functional test in electromyography to improve the diagnosis of these muscle disorders. Abnormal changes in the compound muscle action potential can be disclosed using different exercise tests. Five electromyographic (EMG patterns (I-V that may be used in clinical practice as guides for molecular diagnosis are discussed.

  18. Cardiac channelopathies and sudden infant death syndrome

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Jacob; Winkel, Bo Gregers; Grunnet, Morten;

    2011-01-01

    Sudden infant death syndrome (SIDS) is always a devastating and unexpected occurrence. SIDS is the leading cause of death in the first 6 months after birth in the industrialized world. Since the discovery in 1998 of long QT syndrome as an underlying substrate for SIDS, around 10-20% of SIDS cases...

  19. Channelopathy Pathogenesis in Autism Spectrum Disorders

    OpenAIRE

    Galina eSchmunk; J. Jay eGargus

    2013-01-01

    Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting bod...

  20. Channelopathy pathogenesis in autism spectrum disorders

    OpenAIRE

    Schmunk, Galina; Gargus, J. Jay

    2013-01-01

    Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting bod...

  1. Diseases of the nervous system associated with calcium channelopathies

    NARCIS (Netherlands)

    Todorov, Boyan Bogdanov

    2010-01-01

    The aim of the studies described in this thesis was to investigate how abnormal CaV2.1 channel function can cause disease, in particular motor coordination dysfunction. The chapters illustrate how various neuronal cell types in the periphery (peripheral nervous system) and the central nervous system

  2. HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications

    OpenAIRE

    Reid, Christopher A.; Phillips, A. Marie; Petrou, Steven

    2012-01-01

    Hyperpolarization-activated cyclic nucleotide-gated channels (HCN) can act as pacemakers in the brain making them strong candidates for driving aberrant hypersynchronous network activity seen in epilepsy. Transcriptional changes in HCN channels occur in several animal models of epilepsy. However, only recently have genetic studies demonstrated sequence variation in HCN1 and HCN2 genes associated with human epilepsy. These include a triple proline deletion in HCN2 that increases channel functi...

  3. Channelopathies and drug discovery in the postgenomic era

    Institute of Scientific and Technical Information of China (English)

    Dayue Darrel DUAN; Tong-hui MA

    2011-01-01

    @@ Ion channels are a diverse group of pore-forming proteins that provide selective pathways for the movement of ions (Na+, K+,Ca2+, C1-,etc) across the lipid membrane barrier.Aquaporins facilitate water movement across cell membranes in response to osmotic gradients.There is an increasing body of information on the molecular structure and functional roles of ion and water channels in health and disease, linking channel function at the molecular level to organ physiology.

  4. Multifocal Ectopic Purkinje-Related Premature Contractions: A New SCN5A-Related Cardiac Channelopathy. : MEPPC: a new SCN5A-related cardiac channelopathy

    OpenAIRE

    Amarouch, Mohamed Yassine; Barc, Julien; Bar, Isabelle; Baron, Estelle; Barthez, Olivier; Bertaux, Geraldine; Béziau, Delphine M.; Charpentier, Flavien; Charron, Philippe; Coudière, Yves; Dina, Christian; Faivre, Laurence; Fressart, Véronique; Kyndt, Florence; Laurent, Gabriel

    2012-01-01

    OBJECTIVES: The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease. BACKGROUND: Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias. METHODS: Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and r...

  5. Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy

    OpenAIRE

    Saito, Yuri A; Strege, Peter R.; Tester, David J.; Locke, G. Richard; Talley, Nicholas J; Bernard, Cheryl E.; Rae, James L.; Makielski, Jonathan C.; Ackerman, Michael J.; Farrugia, Gianrico

    2008-01-01

    The SCN5A-encoded Nav1.5 Na+ channel is expressed in interstitial cells of Cajal and smooth muscle in the circular layer of the human intestine. Patients with mutations in SCN5A are more likely to report gastrointestinal symptoms, especially abdominal pain. Twin and family studies of irritable bowel syndrome (IBS) suggest a genetic basis for IBS, but no genes have been identified to date. Therefore, our aims were to evaluate SCN5A as a candidate gene involved in the pathogenesis of IBS and to...

  6. Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system?

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    Marijke eDe Bock

    2013-09-01

    Full Text Available The coordination of tissue function is mediated by gap junctions (GJs that enable direct cell-cell transfer of metabolic and electric signals. GJs are formed by connexins of which Cx43 is most widespread in the human body. In the brain, Cx43 GJs are mostly found in astroglia where they coordinate the propagation of Ca2+ waves, spatial K+ buffering and distribution of glucose. Beyond its role in direct intercellular communication, Cx43 also forms unapposed, non-junctional hemichannels in the plasma membrane of glial cells. These allow the passage of several neuro- and gliotransmitters that may, combined with downstream paracrine signaling, complement direct GJ communication among glial cells and sustain glial-neuronal signaling. Mutations in the GJA1 gene encoding Cx43 have been identified in a rare, mostly autosomal dominant syndrome called oculodentodigital dysplasia (ODDD. ODDD patients display a pleiotropic phenotype reflected by eye, hand, teeth and foot abnormalities, as well as craniofacial and bone malformations. Remarkably, neurological symptoms such as dysarthria, neurogenic bladder (manifested as urinary incontinence, spasticity or muscle weakness, ataxia, and epilepsy are other prominent features observed in ODDD patients. Over 10 mutations detected in patients diagnosed with neurological disorders are associated with altered functionality of Cx43 GJs/hemichannels, but the link between ODDD-related abnormal channel activities and neurologic phenotype is still elusive. Here, we present an overview on the nature of the mutants conveying structural and functional changes of Cx43 channels and discuss available evidence for aberrant Cx43 GJ and hemichannel function. In a final step, we examine the possibilities of how channel dysfunction may lead to some of the neurological manifestations of ODDD.

  7. Screening for, and management of, possible arrhythmogenic syndromes (channelopathies/ion channel diseases)

    DEFF Research Database (Denmark)

    Svendsen, Jesper Hastrup; Geelen, Peter

    2010-01-01

    This survey assesses the current management strategies for individuals with electrocardiographic features, suggesting an arrhythmogenic syndrome [including long QT syndrome (LQTS), Brugada syndrome (BS), catecholaminergic polymorphic ventricular tachycardia (CPVT) or short QT syndrome] or family...

  8. Diabetic Dead-in-Bed Syndrome: A Possible Link to a Cardiac Ion Channelopathy

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    Jonathan R. Skinner

    2014-01-01

    Full Text Available Sudden unexpected nocturnal death among patients with diabetes occurs approximately ten times more commonly than in the general population. Malignant ventricular arrhythmia due to Brugada syndrome has been postulated as a cause, since a glucose-insulin bolus can unmask the Brugada electrocardiographic signature in genetically predisposed individuals. In this report we present a 16-year-old male with insulin-dependent diabetes who died suddenly at night. His diabetes had been well controlled, without significant hypoglycaemia. At autopsy, he had a full stomach and a glucose level of 7 mmol/L in vitreous humor, excluding hypoglycaemia. Genetic analysis of autopsy DNA revealed a missense mutation, c.370A>G (p.Ile124Val, in the GPD1L gene. A parent carried the same mutation and has QT prolongation. Mutations in this gene have been linked to Brugada syndrome and sudden infant death. The patient may have died from a ventricular arrhythmia, secondary to occult Brugada syndrome, triggered by a full stomach and insulin. The data suggest that molecular autopsies are warranted to investigate other cases of the diabetic dead-in-bed syndrome.

  9. The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.

    Science.gov (United States)

    Kharade, Sujay V; Nichols, Colin; Denton, Jerod S

    2016-05-01

    ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators.

  10. Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies.

    Science.gov (United States)

    Amarouch, Mohamed-Yassine; Kasimova, Marina A; Tarek, Mounir; Abriel, Hugues

    2014-01-01

    The p.I141V mutation of the voltage-gated sodium channel is associated with several clinical hyper-excitability phenotypes. To understand the structural bases of the p.I141V biophysical alterations, molecular dynamics simulations were performed. These simulations predicted that the p.I141V substitution induces the formation of a hydrogen bond between the Y168 residue of the S2 segment and the R225 residue of the S4 segment. We generated a p.I141V-Y168F double mutant for both the Nav1.4 and Nav1.5 channels. The double mutants demonstrated the abolition of the functional effects of the p.I141V mutation, consistent with the formation of a specific interaction between Y168-S2 and R225-S4. The single p.Y168F mutation, however, positively shifted the activation curve, suggesting a compensatory role of these residues on the stability of the voltage-sensing domain.

  11. Na(v)1.8 channelopathy in mutant mice deficient for myelin protein zero is detrimental to motor axons

    DEFF Research Database (Denmark)

    Alvarez Herrero, Susana; Pinchenko, Volodymyr; Klein, Dennis;

    2011-01-01

    Myelin protein zero mutations were found to produce Charcot-Marie-Tooth disease phenotypes with various degrees of myelin impairment and axonal loss, ranging from the mild 'demyelinating' adult form to severe and early onset forms. Protein zero deficient homozygous mice ( ) show a severe...... be considered as a novel therapeutic target for Charcot-Marie-Tooth disease....

  12. Combined use of in silico and in vitro splicing assays for interpretation of genomic variants of unknown significance in cardiomyopathies and channelopathies

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    Hervé Crehalet

    2012-06-01

    Full Text Available The identification of molecular anomalies in patients with inherited arrhythmias or cardiomyopathies is a multi challenge due to: i the number of genes involved; ii the number of polymorphisms and the fact that most mutations are private; and iii the variable degree of penetrance which complicates family segregation study. Consequently, a number of unclassified variants (UV are found in patients’ DNA and some (outside the canonical GT/AG may affect splicing. Mutational screening on the most prevalent genes involved in arrythmias syndromes or in cardiomyopathies was performed on a cohort made up of 740 unrelated French index probands. To identify splice variants among the identified UVs, a combination of available in silico and in vitro tools were used since transcript is not available. Using this approach, 10 previously identified UVs were reclassified as disease-causing mutations and, more precisely, as haploinsufficiency mutations rather than dominant-negative mutations. Most of them (7 of 10 were observed in MYBPC3. Our study highlighted the importance of the combined use of in silico and in vitro splicing assays to improve the prediction of the functional impact of identified genetic variants. The primary challenge now, with new sequencing technologies, is to distinguish between background polymorphisms and pathogenic mutations. Since splice site mutations can account for almost 50% of disease-causing mutations, recognizing them from among other variations is essential.

  13. Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy.

    Science.gov (United States)

    Kano, S; Yuan, M; Cardarelli, R A; Maegawa, G; Higurashi, N; Gaval-Cruz, M; Wilson, A M; Tristan, C; Kondo, M A; Chen, Y; Koga, M; Obie, C; Ishizuka, K; Seshadri, S; Srivastava, R; Kato, T A; Horiuchi, Y; Sedlak, T W; Lee, Y; Rapoport, J L; Hirose, S; Okano, H; Valle, D; O'Donnell, P; Sawa, A; Kai, M

    2015-01-01

    Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies. PMID:25732146

  14. [Idiopathic ventricular tachycardia, an arrhythmia with good prognosis].

    NARCIS (Netherlands)

    Camaro, C.; Bos, H.S.; Smeets, J.L.R.M.

    2010-01-01

    Three patients, one experiencing palpitations and two complaining of chest pain in stressful situations, appeared to have monomorphic wide complex tachycardia. After excluding channelopathy, structural abnormalities and ischaemia of the heart, this arrhythmia was classified as idiopathic. Symptoms d

  15. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

    DEFF Research Database (Denmark)

    Nunn, Laurence M; Lopes, Luis R; Syrris, Petros;

    2016-01-01

    ). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency

  16. A review of potassium channels in bipolar disorder

    Directory of Open Access Journals (Sweden)

    Jennifer Toolan Judy

    2013-06-01

    Full Text Available Although bipolar disorder (BP is one of the most heritable psychiatric conditions, susceptibility genes for the disorder have yet to be conclusively identified. It is likely that variants in multiple genes across multiple pathways contribute to the genotype-phenotype relationship. Recent evidence from genome-wide association studies (GWAS implicates an entire class of genes related to the structure and regulation of ion channels, suggesting that the etiology of BP may arise from a channelopathy. In this review, we examine the evidence for this hypothesis, with a focus on the potential role of voltage gated potassium channels. We consider evidence from genetic and expression studies, and discuss the potential underlying biology. We consider animal models and treatment implications of the involvement of potassium ion channelopathy in BP. Finally, we explore intriguing parallels between BP and epilepsy, the signature channelopathy of the CNS.

  17. Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Pilar eMartinez-Martinez

    2013-09-01

    Full Text Available Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the CNS, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand–activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.

  18. Disease: H00774 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available n all of the neurons in which this channel is expressed. Nervous system disease SCN9A [HSA:6335] [KO:K04841]...rall WA, Dib-Hajj S, Meisler MH, Pietrobon D Inherited neuronal ion channelopathies: new windows on complex neurological disea

  19. A Salbutamol responsive myopathy

    LENUS (Irish Health Repository)

    Fitzpatrick, A

    2011-05-01

    Background: Reversibility of weakness is rare in inherited muscle disease and suggests a channelopathy as the underlying pathology. Improvement in muscle strength after treatment with beta-adrenergic agonists has been documented in hyperkalaemic periodic paralysis and only very recently in the congenital myasthenic syndromes. The exact mechanism of action is not understood. \\r\

  20. Genetic and environmental factors in cardiac sodium channel disease

    NARCIS (Netherlands)

    Y. Mizusawa

    2016-01-01

    Cardiac sodium channelopathies, such as long QT syndrome type3 (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD), are heritable diseases associated with mutations in the SCN5A gene and sudden cardiac death. They were classically thought to be a monogenic disease. However, while LQT

  1. Channels Active in the Excitability of Nerves and Skeletal Muscles across the Neuromuscular Junction: Basic Function and Pathophysiology

    Science.gov (United States)

    Goodman, Barbara E.

    2008-01-01

    Ion channels are essential for the basic physiological function of excitable cells such as nerve, skeletal, cardiac, and smooth muscle cells. Mutations in genes that encode ion channels have been identified to cause various diseases and disorders known as channelopathies. An understanding of how individual ion channels are involved in the…

  2. Fever-Induced Life-Threatening Arrhythmias in Children Harboring an SCN5A Mutation

    NARCIS (Netherlands)

    P. Chockalingam; L.A. Rammeloo; P.G. Postema; J. Hruda; S.A.B. Clur; N.A. Blom; A.A. Wilde

    2011-01-01

    Cardiac channelopathies caused by SCN5A mutation are well tolerated by most patients. However, the dramatic presentation of a previously healthy 4-month-old girl with life-threatening arrhythmias and the subsequent findings in the child and her family provide evidence that loss-of-function sodium ch

  3. Disease: H01258 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H01258 Generalized epilepsy and paroxysmal dyskinesia (GEPD) Epilepsy is one of the...ment often requiring life-long treatment. GEPD is a syndrome of coexistent generalized epilepsy...icherson GB, Wang QK Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 37:733-8 (2005) ...

  4. Chloride : The queen of electrolytes?

    NARCIS (Netherlands)

    Berend, Kenrick; van Hulsteijn, Leonard Hendrik; Gans, Rijk O. B.

    2012-01-01

    Background: Channelopathies, defined as diseases that are caused by mutations in genes encoding ion channels, are associated with a wide variety of symptoms and have been documented extensively over the past decade. In contrast, despite the important role of chloride in serum, textbooks in general d

  5. Automated external defibrillator rescues among children with diagnosed and treated long QT syndrome.

    NARCIS (Netherlands)

    Pundi, K.N.; Bos, J.M.; Cannon, B.C.; Ackerman, M.J.

    2015-01-01

    BACKGROUND: Long QT syndrome (LQTS) is a potentially lethal yet highly treatable cardiac channelopathy. A comprehensive LQTS-directed treatment program often includes an automated external defibrillator (AED). OBJECTIVE: The purpose of this study was to determine the incidence of AED rescues among c

  6. Disease: H00746 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00746 Hypokalemic periodic paralysis (HypoPP) The periodic paralyses are a group o...racterized by episodes of muscle weakness associated with variations in serum potassium concentration. Hypokalemic periodic paralysis...Raja Rayan DL, Hanna MG Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis. Cur

  7. Advanced Genetic Testing Comes to the Pain Clinic to Make a Diagnosis of Paroxysmal Extreme Pain Disorder

    Directory of Open Access Journals (Sweden)

    Ashley Cannon

    2016-01-01

    Full Text Available Objective. To describe the use of an advanced genetic testing technique, whole exome sequencing, to diagnose a patient and their family with a SCN9A channelopathy. Setting. Academic tertiary care center. Design. Case report. Case Report. A 61-year-old female with a history of acute facial pain, chronic pain, fibromyalgia, and constipation was found to have a gain of function SCN9A mutation by whole exome sequencing. This mutation resulted in an SCN9A channelopathy that is most consistent with a diagnosis of paroxysmal extreme pain disorder. In addition to the patient being diagnosed, four siblings have a clinical diagnosis of SCN9A channelopathy as they have consistent symptoms and a sister with a known mutation. For treatment, gabapentin was ineffective and carbamazepine was not tolerated. Nontraditional therapies improved symptoms and constipation resolved with pelvic floor retraining with biofeedback. Conclusion. Patients with a personal and family history of chronic pain may benefit from a referral to Medical Genetics. Pelvic floor retraining with biofeedback should be considered for patients with a SCN9A channelopathy and constipation.

  8. Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in Brugada syndrome

    DEFF Research Database (Denmark)

    Holst, Anders Gaarsdal; Jensen, Henrik Kjærulf; Eschen, Ole;

    2012-01-01

    Brugada syndrome (BrS) is an inherited channelopathy that predisposes to malignant ventricular arrhythmias and thereby syncope and sudden cardiac death. Prior studies characterizing BrS patients have used highly selected referral populations from tertiary centres and prevalence estimates have bee...

  9. Phobic memory and somatic vulnerabilities in anorexia nervosa: a necessary unity?

    Directory of Open Access Journals (Sweden)

    Myslobodsky Michael

    2005-09-01

    Full Text Available Abstract Anorexia nervosa is a clinically significant illness that may be associated with permanent medical complications involving almost every organ system. The paper raises a question whether some of them are associated with premorbid vulnerability such as subcellular ion channel abnormalities ('channelopathy' that determines the clinical expression of the bodily response to self-imposed malnutrition. Aberrant channels emerge as a tempting, if rather speculative alternative to the notion of cognitively-driven neurotransmitter modulation deficit in anorexia nervosa. The concept of channelopathies is in keeping with some characteristics of anorexia nervosa, such as a genetically-based predisposition to hypophagia, early onset, cardiac abnormalities, an appetite-enhancing efficacy of some antiepileptic drugs, and others. The purpose of this article is to stimulate further basic research of ion channel biophysics in relation to restrictive anorexia.

  10. Cell model for efficient simulation of wave propagation in human ventricular tissue under normal and pathological conditions

    Energy Technology Data Exchange (ETDEWEB)

    Tusscher, K H W J Ten; Panfilov, A V [Department of Theoretical Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht (Netherlands)

    2006-12-07

    In this paper, we formulate a model for human ventricular cells that is efficient enough for whole organ arrhythmia simulations yet detailed enough to capture the effects of cell level processes such as current blocks and channelopathies. The model is obtained from our detailed human ventricular cell model by using mathematical techniques to reduce the number of variables from 19 to nine. We carefully compare our full and reduced model at the single cell, cable and 2D tissue level and show that the reduced model has a very similar behaviour. Importantly, the new model correctly produces the effects of current blocks and channelopathies on AP and spiral wave behaviour, processes at the core of current day arrhythmia research. The new model is well over four times more efficient than the full model. We conclude that the new model can be used for efficient simulations of the effects of current changes on arrhythmias in the human heart.

  11. Cardiac ryanodine receptor gene (hRyR2) mutation underlying catecholaminergic polymorphic ventricular tachycardia in a Chinese adolescent presenting with sudden cardiac arrest and cardiac syncope

    Institute of Scientific and Technical Information of China (English)

    Ngai-Shing Mok; Ching-Wan Lam; Nai-Chung Fong; Yim-Wo Hui; Yuen-Choi Choi; Kwok-Yin Chan

    2006-01-01

    @@ Sudden cardiac death (SCD) in children and adolescents is uncommon and yet it is devastating for both victim's family and the society.Recently, it was increasingly recognized that SCD in young patients with structurally normal heart may be caused by inheritable primary electrical diseases due to the malfunction of cardiac ion channels, a disease entity known as the ion channelopathies.Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a specific form of ion channelopathy which can cause cardiac syncope or SCD in young patients by producing catecholamine-induced bi-directional ventricular tachycardia (BiVT), polymorphic VT and ventricular fibrillation (VF) during physical exertion or emotion.1-7 We reported here an index case of CPVT caused by cardiac ryanodine receptor gene (hRyR2)mutation which presented as cardiac syncope and sudden cardiac arrest in a Chinese adolescent female.

  12. Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases

    DEFF Research Database (Denmark)

    Hertz, Christin Løth; Christiansen, Sofie Lindgren; Ferrero-Miliani, Laura;

    2015-01-01

    Sudden cardiac death (SCD) is responsible for a large proportion of sudden deaths in young individuals. In forensic medicine, many cases remain unexplained after routine postmortem autopsy and conventional investigations. These cases are called sudden unexplained deaths (SUD). Genetic testing has...... been suggested useful in forensic medicine, although in general with a significantly lower success rate compared to the clinical setting. The purpose of the study was to estimate the frequency of pathogenic variants in the genes most frequently associated with SCD in SUD cases and compare the frequency...... to that in patients with inherited cardiac channelopathies. Fifteen forensic SUD cases and 29 patients with channelopathies were investigated. DNA from 34 of the genes most frequently associated with SCD were captured using NimbleGen SeqCap EZ library build and were sequenced with next-generation sequencing (NGS...

  13. [Sudden cardiac death in individuals with normal hearts: an update].

    Science.gov (United States)

    González-Melchor, Laila; Villarreal-Molina, Teresa; Iturralde-Torres, Pedro; Medeiros-Domingo, Argelia

    2014-01-01

    Sudden death (SD) is a tragic event and a world-wide health problem. Every year, near 4-5 million people experience SD. SD is defined as the death occurred in 1h after the onset of symptoms in a person without previous signs of fatality. It can be named "recovered SD" when the case received medical attention, cardiac reanimation effective defibrillation or both, surviving the fatal arrhythmia. Cardiac channelopathies are a group of diseases characterized by abnormal ion channel function due to genetic mutations in ion channel genes, providing increased susceptibility to develop cardiac arrhythmias and SD. Usually the death occurs before 40 years of age and in the autopsy the heart is normal. In this review we discuss the main cardiac channelopathies involved in sudden cardiac death along with current management of cases and family members that have experienced such tragic event.

  14. Neurotoxins and Their Binding Areas on Voltage-Gated Sodium Channels

    OpenAIRE

    Stevens, Marijke; Peigneur, Steve; Tytgat, Jan

    2011-01-01

    Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called “channelopathies.” The f...

  15. Transient loss of consciousness in a patient with a Brugada like ECG

    OpenAIRE

    Belinda Sandler; Steve Furniss; Eric McWilliams

    2011-01-01

    Syncope in a patient with a Brugada syndrome channelopathy carries significant prognostic implications and warrants consideration of implantable cardioverter defibrillator (ICD) implantation. We report a case of a 62- year-old gentleman who presented with a transient loss of consciousness and an electrocardiogram (ECG) suggestive of type 1 Brugada syndrome. Further investigation revealed evidence of a silent myocardial infarction and negative ventricular tachycardia stimulation and Ajmaline t...

  16. Disease: H00747 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00747 Thyrotoxic hypokalemic periodic paralysis (TPP) Thyrotoxic hypokalemic periodic paralysis... (TPP) is characterized by thyrotoxicosis in combination with typical episodes of hypokalemic periodic paralysis... with TPP. Hypokalemia is typical during paralysis, but is not always detected; a...gene) Raja Rayan DL, Hanna MG Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis...Silva MR Novel etiopathophysiological aspects of thyrotoxic periodic paralysis. Nat Rev Endocrinol 7:657-67 (2011) ...

  17. Disease: H00745 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00745 Hyperkalemic periodic paralysis (HyperPP) The periodic paralyses are a group... genetically undefined, suggesting genetic heterogeneity. HyperPP is characterized by attacks of flaccid limb paralysis...ayan DL, Hanna MG Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis. Curr Opin...haracterized by episodes of muscle weakness associated with variations in serum potassium concentration. Hyperkalemic periodic paraly...sis (HyperPP) is caused by gain-of-function mutations in

  18. From syncope to ICD: clinical paths of the Brugada syndrome

    OpenAIRE

    Ivan Comelli; Gianfranco Cervellin; Tiziana Meschi; Loris Borghi

    2010-01-01

    This review summarizes the evidences in the literature on the management of the Brugada syndrome (BS), an arrhythmogenic disease caused by genetic channelopathies, predisposing to syncope and sudden cardiac death in young, apparently healthy, typically male subjects, in the third and fourth decade of their life. Sudden cardiac death (SCD) is defined as natural death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of symptoms. It ranks among the main ...

  19. in a Family of South Indian Descent

    Directory of Open Access Journals (Sweden)

    Muthiah Subramanian

    2015-01-01

    Full Text Available Inherited channelopathies are a heterogeneous group of disorders resulting from dysfunction of ion channels in cellular membranes. They may manifest as diseases affecting skeletal muscle contraction, the conduction system of the heart, nervous system function, and vision syndromes. We describe a family of South Indian descent with hypokalemic periodic paralysis in which four members also have idiopathic generalized epilepsy. Hypokalemic periodic paralysis is a genetically heterogeneous channelopathy that has been linked to mutations in genes encoding three ion channels CACNIAS, SCN4A, and KCNJ2 predominantly. Although data on specific gene in idiopathic generalized epilepsy is relatively scarce, mutations of voltage gated sodium channel subunit genes (CACNB4 and nonsense mutations in voltage gated calcium channels (CACNA1A have been linked to idiopathic generalized epilepsy in two families. We speculate that gene mutations altering the ability of the beta subunit to interact with the alpha subunit of the CaV1.1 channel and mutations in the pore-forming potassium channel subunit may be possible explanations for the combined manifestation of both diseases. Functional analysis of voltage gated calcium channel and other ion channels mutations may provide additional support and insight for the causal role of these mutations. The understanding of mutations in ion-channel genes will lead to improved diagnosis and treatment of such inherited channelopathies.

  20. Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases.

    Science.gov (United States)

    Hertz, C L; Christiansen, S L; Ferrero-Miliani, L; Fordyce, S L; Dahl, M; Holst, A G; Ottesen, G L; Frank-Hansen, R; Bundgaard, H; Morling, N

    2015-07-01

    Sudden cardiac death (SCD) is responsible for a large proportion of sudden deaths in young individuals. In forensic medicine, many cases remain unexplained after routine postmortem autopsy and conventional investigations. These cases are called sudden unexplained deaths (SUD). Genetic testing has been suggested useful in forensic medicine, although in general with a significantly lower success rate compared to the clinical setting. The purpose of the study was to estimate the frequency of pathogenic variants in the genes most frequently associated with SCD in SUD cases and compare the frequency to that in patients with inherited cardiac channelopathies. Fifteen forensic SUD cases and 29 patients with channelopathies were investigated. DNA from 34 of the genes most frequently associated with SCD were captured using NimbleGen SeqCap EZ library build and were sequenced with next-generation sequencing (NGS) on an Illumina MiSeq. Likely pathogenic variants were identified in three out of 15 (20%) forensic SUD cases compared to 12 out of 29 (41%) patients with channelopathies. The difference was not statistically significant (p = 0.1). Additionally, two larger deletions of entire exons were identified in two of the patients (7%). The frequency of likely pathogenic variants was >2-fold higher in the clinical setting as compared to SUD cases. However, the demonstration of likely pathogenic variants in three out of 15 forensic SUD cases indicates that NGS investigations will contribute to the clinical investigations. Hence, this has the potential to increase the diagnostic rate significantly in the forensic as well as in the clinical setting.

  1. Development of heart failure is independent of K+ channel-interacting protein 2 expression

    DEFF Research Database (Denmark)

    Speerschneider, Tobias; Grubb, Søren; Metoska, Artina;

    2013-01-01

    Abstract  Abnormal ventricular repolarization in ion channelopathies and heart disease is a major cause of ventricular arrhythmias and sudden cardiac death. K(+) channel-interacting protein 2 (KChIP2) expression is significantly reduced in human heart failure (HF), contributing to a loss of the...... before and every 2 weeks after the operation. Ten weeks post-surgery, surface ECG was recorded and we paced the heart in vivo to induce arrhythmias. Afterwards, tissue from the left ventricle was used for immunoblotting. Time courses of HF development were comparable in TAC-operated WT and KChIP2...

  2. KCNK3: new gene target for pulmonary hypertension?

    Science.gov (United States)

    Girerd, Barbara; Perros, Frédéric; Antigny, Fabrice; Humbert, Marc; Montani, David

    2014-08-01

    Recently, KCNK3 has been identified as a new predisposing gene for pulmonary arterial hypertension (PAH) by whole-exome sequencing. Mutation in KCNK3 gene is responsible for the first channelopathy identified in PAH. PAH due to KCNK3 mutations is an autosomal dominant disease with an incomplete penetrance as previously described in PAH due to BMPR2 mutations. This discovery represents an important advance for genetic counselling, allowing identification of high risk relatives for PAH and possible screening for PAH in KCNK3 mutation carriers. PMID:24742047

  3. Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases

    DEFF Research Database (Denmark)

    Hertz, Christin Loeth; Christiansen, Sofie Lindgren; Larsen, Maiken Kudahl;

    2016-01-01

    -generation sequencing (NGS), the coding regions of 100 genes associated with inherited channelopathies and cardiomyopathies were captured and sequenced on the Illumina MiSeq platform. Sixteen (34%) of the SUDI cases had variants with likely functional effects, based on conservation, computational prediction and allele...... victims is important in the forensic setting and a valuable supplement to the clinical investigation in all cases of sudden death.European Journal of Human Genetics advance online publication, 9 September 2015; doi:10.1038/ejhg.2015.198....

  4. On the multiple roles of the voltage gated sodium channel β1 subunit in genetic diseases

    Directory of Open Access Journals (Sweden)

    Debora eBaroni

    2015-05-01

    Full Text Available Voltage-gated sodium channels are intrinsic plasma membrane proteins that initiate the action potential in electrically excitable cells. They are composed of a pore-forming α-subunit and associated β-subunits. The β1-subunit was the first accessory subunit to be cloned. It can be important for controlling cell excitability and modulating multiple aspects of sodium channel physiology. Mutations of β1 are implicated in a wide variety of inherited pathologies, including epilepsy and cardiac conduction diseases. This review summarizes β1-subunit related channelopathies pointing out the current knowledge concerning their genetic background and their underlying molecular mechanisms.

  5. BRUGADA SYNDROME: FROM PRIMARY ELECTRIC HEART DISEASE TO MORPHOLOGICAL SUBSTRATE

    Directory of Open Access Journals (Sweden)

    T. A. Pavlenko

    2016-01-01

    Full Text Available Nowadays interest in channelopathies is growing, and developing diagnostic capabilities make Brugada syndrome much more actual problem than ever. Conception of «primary electric heart disease», which earlier was so popular, now couldn’t explain the absence of single genetic syndromes’ substrate, its’ common combinations with another arrhythmias and the presence of Brugada phenocopy. Conjunction of Brugada syndrome with morphological changes in myocardium , especially myocarditis, is an area of special interest. Infl ammation associates with clinical manifestation of the syndrome, and this situation forces to think about channelopathies’ primacy and to look for another possible mechanisms of Brugada syndrome.

  6. Disease: H00215 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00215 Periodic paralysis, including: ; Hyperkalemic periodic paralysis (HyperPP) [...DS:H00745]; Hypokalemic periodic paralysis (HypoPP) [DS:H00746]; Andersen-Tawil syndrome (ATS) [DS:H00748] T...include hyperkalaemic periodic paralysis (HyperPP), hypokalaemic periodic paralysis...Meola G, Links TP, Panzeri M, Rose MR Treatment for periodic paralysis. Cochrane Database Syst Rev CD005045 ...8-17 (2006) PMID:20634695 Raja Rayan DL, Hanna MG Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis. Curr Opin Neurol 23:466-76 (2010) ...

  7. Transient loss of consciousness in a patient with a Brugada like ECG

    Directory of Open Access Journals (Sweden)

    Belinda Sandler

    2011-11-01

    Full Text Available Syncope in a patient with a Brugada syndrome channelopathy carries significant prognostic implications and warrants consideration of implantable cardioverter defibrillator (ICD implantation. We report a case of a 62- year-old gentleman who presented with a transient loss of consciousness and an electrocardiogram (ECG suggestive of type 1 Brugada syndrome. Further investigation revealed evidence of a silent myocardial infarction and negative ventricular tachycardia stimulation and Ajmaline testing. Careful review of the ECG’s subsequently showed the type 1 pattern was present in only V1.

  8. An 11-year retrospective experience of antibodies against the voltage-gated potassium channel (VGKC) complex from a tertiary neurological centre.

    Science.gov (United States)

    Huda, S; Wong, S H; Pettingill, P; O'Connell, D; Vincent, A; Steiger, M

    2015-02-01

    Acquired diseases classically associated with VGKC-complex antibodies include peripheral nerve hyperexcitability (PNH), Morvan's syndrome, limbic encephalitis (LE), and epilepsy. However, not all such patients have VGKC-complex antibodies and antibodies have been reported in patients without a defined immune-mediated syndrome. To analyse the clinical relevance of positive VGKC-complex antibodies requested on the basis of initial clinical suspicion. We retrospectively analysed patients with positive VGKC-complex antibodies (>100 pM) referred to our institution between 2001 and 2011. 1,614 VGKC-complex assays were performed in 1,298 patients. Titres >100 pM were detected in 57/1,298 (4 %) patients. A classic VGKC-complex channelopathy (60 %) was associated with VGKC-complex antibody titres >400 pM (p = 0.0004). LGI1 or CASPR2 antibodies were only detected in classic VGKC-complex channelopathies (LE; n = 3/4 and PNH; n = 1/5). VGKC-complex antibody titres VGKC-complex antibodies was higher than the age-matched national incidence of malignancy (OR 19.9, 95 % CI 8.97-44.0 p400 pM can help determine VGKC-complex antibody relevance. Antibody titres <400 pM are associated with PNH but also a more heterogeneous clinical spectrum. The antibody association in the latter is of doubtful clinical relevance. The rate of malignancy was significantly higher than the national incidence irrespective of titre.

  9. Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias.

    Science.gov (United States)

    Park, David S; Cerrone, Marina; Morley, Gregory; Vasquez, Carolina; Fowler, Steven; Liu, Nian; Bernstein, Scott A; Liu, Fang-Yu; Zhang, Jie; Rogers, Christopher S; Priori, Silvia G; Chinitz, Larry A; Fishman, Glenn I

    2015-01-01

    SCN5A encodes the α subunit of the major cardiac sodium channel Na(V)1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A(E558X/+) pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A(E558X/+) hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.

  10. Motivation to pursue genetic testing in individuals with a personal or family history of cardiac events or sudden cardiac death.

    Science.gov (United States)

    Erskine, Kathleen E; Hidayatallah, Nadia Z; Walsh, Christine A; McDonald, Thomas V; Cohen, Lilian; Marion, Robert W; Dolan, Siobhan M

    2014-10-01

    Genetic testing is becoming increasingly available for cardiac channelopathies, such as long QT syndrome and Brugada syndrome, which can lead to sudden cardiac death. Test results can be used to shape an individual's medical management and to identify at-risk family members. In our qualitative study, all participants had a personal or family history of a diagnosed cardiac arrhythmia syndrome or sudden cardiac death. Open-ended interviews were conducted individually and in focus groups. Interviews were audio recorded, transcribed verbatim, and analyzed using a qualitative grounded-theory approach. Of 50 participants, 37 described their motivations for pursuing genetic testing for long QT syndrome or another cardiac channelopathy. Participants' motivations included: to find an explanation for a family member's sudden death, to relieve uncertainty regarding a diagnosis, to guide future medical management, to allay concern about children or other family members, and to comply with recommendations of physicians or family members. Perceived reasons not to pursue genetic testing included denial, fear, and lack of information. The genetic counseling and informed consent process can be enhanced by understanding and addressing an individual's internal and external motivations either for or against pursuing genetic testing.

  11. Seropositive myasthenia and autoimmune autonomic ganglionopathy: cross reactivity or subclinical disease?

    Science.gov (United States)

    Miglis, Mitchell G; Racela, Rikki; Kaufmann, Horacio

    2011-10-28

    Autoimmune autonomic ganglionopathy (AAG) and myasthenia gravis (MG) are both autoimmune channelopathies mediated by antibodies directed against nicotinic acetylcholine receptors. While both diseases target acetylcholine receptors, skeletal muscle and ganglionic receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. We report a patient with antibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG. We presume that his skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the patient's ganglionic nAChR antibodies with skeletal nAChR subtypes. PMID:21745762

  12. Understanding autoimmunity: The ion channel perspective.

    Science.gov (United States)

    RamaKrishnan, Anantha Maharasi; Sankaranarayanan, Kavitha

    2016-07-01

    Ion channels are integral membrane proteins that orchestrate the passage of ions across the cell membrane and thus regulate various key physiological processes of the living system. The stringently regulated expression and function of these channels hold a pivotal role in the development and execution of various cellular functions. Malfunction of these channels results in debilitating diseases collectively termed channelopathies. In this review, we highlight the role of these proteins in the immune system with special emphasis on the development of autoimmunity. The role of ion channels in various autoimmune diseases is also listed out. This comprehensive review summarizes the ion channels that could be used as molecular targets in the development of new therapeutics against autoimmune disorders.

  13. Republished: A straightforward guide to the basic science behind arrhythmogenesis.

    Science.gov (United States)

    Dumotier, Berengere M

    2015-04-01

    The underlying mechanisms behind cardiac arrhythmias are described in this manuscript. In clinical practice, significant arrhythmias are unpredictable, and under some conditions, potentially life-threatening. How can basic science help improve our understanding of molecular entities and factors behind the arrhythmia to advance, develop, adapt or deliver available medications? Structural heart disease and remodelling (e.g., heart failure, cardiomyopathy), the presence of modulating factors (i.e., diabetes mellitus, autonomic nervous system), genetic predispositions (i.e., channelopathies) are considerable preconditions, and influence the development of an arrhythmia. Cardiac arrhythmias may indeed share common basic mechanisms, while elements and substrates perpetuating these may be different and ultimately manifest as various ECG abnormalities. This article lists cellular and subcellular iatrogenic disorders responsible for abnormal impulse generation, or conduction disturbances, including the latest development in theories and biological research, for a better understanding of cellular disorders behind arrhythmogenesis. PMID:25862707

  14. From exercise intolerance to functional improvement: the second wind phenomenon in the identification of McArdle disease

    Directory of Open Access Journals (Sweden)

    Renata Siciliani Scalco

    2014-07-01

    Full Text Available McArdle disease is the most common of the glycogen storage diseases. Onset of symptoms is usually in childhood with muscle pain and restricted exercise capacity. Signs and symptoms are often ignored in children or put down to ‘growing pains’ and thus diagnosis is often delayed. Misdiagnosis is not uncommon because several other conditions such as muscular dystrophy and muscle channelopathies can manifest with similar symptoms. A simple exercise test performed in the clinic can however help to identify patients by revealing the second wind phenomenon which is pathognomonic of the condition. Here a patient is reported illustrating the value of using a simple 12 minute walk test.

  15. Towards a hierarchy of mechanisms in CaMKII-mediated arrhythmia

    Directory of Open Access Journals (Sweden)

    Kevin P Vincent

    2014-05-01

    Full Text Available CaMKII activity has been shown to contribute to arrhythmogenesis in a remarkably broad range of cardiac pathologies. Several of these involve significant structural and electrophysiologic remodeling, whereas others are due to specific channelopathies, and are not typically associated with arrhythmogenic changes to protein expression or cellular and tissue structure. The ability of CaMKII to contribute to arrhythmia across such a broad range of phenotypes suggests one of two interpretations regarding the role of CaMKII in cardiac arrhythmia: (1 some CaMKII-dependent mechanism is a common driver of arrhythmia irrespective of the specific etiology of the disease, or (2 these different etiologies expose different mechanisms by which CaMKII is capable of promoting arrhythmia. In this review, we dissect the available mechanistic evidence to explore these two possibilities and discuss how the various molecular actions of CaMKII promote arrhythmia in different pathophysiologic contexts.

  16. High throughput electrophysiology: new perspectives for ion channel drug discovery

    DEFF Research Database (Denmark)

    Willumsen, Niels J; Bech, Morten; Olesen, Søren-Peter;

    2003-01-01

    Proper function of ion channels is crucial for all living cells. Ion channel dysfunction may lead to a number of diseases, so-called channelopathies, and a number of common diseases, including epilepsy, arrhythmia, and type II diabetes, are primarily treated by drugs that modulate ion channels. A...... introduction of new powerful HTS electrophysiological techniques is predicted to cause a revolution in ion channel drug discovery....... cornerstone in current drug discovery is high throughput screening assays which allow examination of the activity of specific ion channels though only to a limited extent. Conventional patch clamp remains the sole technique with sufficiently high time resolution and sensitivity required for precise and direct...... characterization of ion channel properties. However, patch clamp is a slow, labor-intensive, and thus expensive, technique. New techniques combining the reliability and high information content of patch clamping with the virtues of high throughput philosophy are emerging and predicted to make a number of ion...

  17. The Myotonic Plot Thickens: Electrical Myotonia in Antimuscle-Specific Kinase Myasthenia Gravis

    Directory of Open Access Journals (Sweden)

    Marcus Magnussen

    2015-01-01

    Full Text Available Electrical myotonia is known to occur in a number of inherited and acquired disorders including myotonic dystrophies, channelopathies, and metabolic, toxic, and inflammatory myopathies. Yet, electrical myotonia in myasthenia gravis associated with antibodies against muscle-specific tyrosine kinase (MuSK has not been previously reported. We describe two such patients, both of whom had a typical presentation of proximal muscle weakness with respiratory failure in the context of a significant electrodecrement in repetitive nerve stimulation. In both cases, concentric needle examination revealed electrical myotonia combined with myopathic motor unit morphology and early recruitment. These findings suggest that MuSK myasthenia should be included within the differential diagnosis of disorders with electrical myotonia.

  18. SÍNDROME DE BRUGADA: DESDE LOS GENES HASTA LA TERAPÉUTICA / Brugada syndrome: from genes to therapeutics

    Directory of Open Access Journals (Sweden)

    Raimundo Carmona Puerta

    2010-06-01

    Full Text Available The increasing number of ion channelopathies discovered in the heart, with fatal consequences, implies that the specialists involved in the management of these patients must strive to reach a better understanding of basic cardiac electrophysiology. In the Brugada syndrome, up to six genotypes have already been described with affectations in the sodium, calcium and potassium (Ito type channels. In all cases there is a typical electrocardiogram which shows right precordial leads due to the transmural dispersion of repolarization, more pronounced in the region of the outflow tract of the right ventricle. The disease may be asymptomatic or have sudden death as its first manifestation. The implantable defibrillator is considered the most effective treatment, but it can be combined with quinidine to space the shocks and abort electrical storms.

  19. Venom-based biotoxins as potential analgesics.

    Science.gov (United States)

    Gazerani, Parisa; Cairns, Brian Edwin

    2014-11-01

    Chronic pain is a common debilitating condition with negative social and economic consequences. Management of chronic pain is challenging and the currently available medications do not yet yield satisfactory outcomes for many patients. Venom-derived biotoxins from various venomous species consist of several substances with different structures and compositions that include peptides. A unique characteristic of some venom-based biotoxins is the ability to block essential components of the pain signaling system, notably ion channels. This property is leading to the evaluation of the potential of biotoxins as analgesics to manage chronic pain. In addition to their therapeutic potential, biotoxins have also been essential tools to probe mechanisms underlying pain signaling, channelopathies and receptor expression. This review discusses venom-derived peptidergic biotoxins that are in preclinical stages or already in clinical trials. Some promising results from preliminary in vitro studies, ongoing challenges and unmet needs will also be discussed. PMID:25234848

  20. Physiological and pathophysiological insights of Nav1.4 and Nav1.5 comparison

    Directory of Open Access Journals (Sweden)

    Gildas eLoussouarn

    2016-01-01

    Full Text Available Mutations in Nav1.4 and Nav1.5 α-subunits have been associated with muscular and cardiac channelopathies, respectively. Despite intense research on the structure and function of these channels, a lot of information is still missing to delineate the various physiological and pathophysiological processes underlying their activity at the molecular level. Nav1.4 and Nav1.5 sequences are similar, suggesting structural and functional homologies between the two orthologous channels. This also suggests that any characteristics described for one channel subunit may shed light on the properties of the counterpart channel subunit. In this review article, after a brief clinical description of the muscular and cardiac channelopathies related to Nav1.4 and Nav1.5 mutations, respectively, we compare the knowledge accumulated in different aspects of the expression and function of Nav1.4 and Nav1.5 α-subunits: the regulation of the two encoding genes (SCN4A and SCN5A, the associated/regulatory proteins and at last, the functional effect of the same missense mutations detected in Nav1.4 and Nav1.5. First, it appears that more is known on Nav1.5 expression and accessory proteins. Because of the high homologies of Nav1.5 binding sites and equivalent Nav1.4 sites, Nav1.5-related results may guide future investigations on Nav1.4. Second, the analysis of the same missense mutations in Nav1.4 and Nav1.5 revealed intriguing similarities regarding their effects on membrane excitability and alteration in channel biophysics. We believe that such comparison may bring new cues to the physiopathology of cardiac and muscular diseases.

  1. Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series.

    Science.gov (United States)

    Narula, Nupoor; Tester, David J; Paulmichl, Anna; Maleszewski, Joseph J; Ackerman, Michael J

    2015-04-01

    Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes. Here, we set out to determine whether post-mortem whole exome sequencing (WES) is an efficient strategy to detect ultra-rare, potentially pathogenic variants. We performed post-mortem WES and gene-specific analysis of 117 sudden death-susceptibility genes for 14 consecutively referred Caucasian SUDY victims (average age at death 17.4 ± 8.6 years) to identify putative SUDY-associated mutations. On average, each SUDY case had 12,758 ± 2,016 non-synonymous variants, of which 79 ± 15 localized to these 117 genes. Overall, eight ultra-rare variants (seven missense, one in-frame insertion) absent in three publically available exome databases were identified in six genes (three in TTN, and one each in CACNA1C, JPH2, MYH7, VCL, RYR2) in seven of 14 cases (50 %). Of the seven missense alterations, two (T171M-CACNA1C, I22160T-TTN) were predicted damaging by three independent in silico tools. Although WES and gene-specific surveillance is an efficient means to detect rare genetic variants that might underlie the pathogenic cause of death, accurate interpretation of each variant is challenging. Great restraint and caution must be exercised otherwise families may be informed prematurely and incorrectly that the root cause has been found.

  2. Deadly proposal: a case of catecholaminergic polymorphic ventricular tachycardia.

    Science.gov (United States)

    Heiner, Jason D; Bullard-Berent, Jeffrey H; Inbar, Shmuel

    2011-11-01

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood. Catecholaminergic polymorphic ventricular tachycardia is a genetic cardiac channelopathy with known mutations involving genes affecting intracellular calcium regulation. We present a case of a 14-year-old boy who had cardiopulmonary arrest after an emotionally induced episode of CPVT while attempting to invite a girl to the school dance. Review of his presenting cardiac rhythm, induction of concerning ventricular arrhythmias during an exercise stress test, and genetic testing confirmed the diagnosis of CPVT. He recovered fully and was treated with β-blocker therapy and placement of an implantable cardioverter-defibrillator. In this report, we discuss this rare but important entity, including its molecular foundation, clinical presentation, basics of diagnosis, therapeutic options, and implications of genetic testing for family members. We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome. PMID:22068070

  3. Electro-mechanical dysfunction in long QT syndrome: Role for arrhythmogenic risk prediction and modulation by sex and sex hormones.

    Science.gov (United States)

    Lang, C N; Menza, M; Jochem, S; Franke, G; Perez Feliz, S; Brunner, M; Koren, G; Zehender, M; Bugger, H; Jung, B A; Foell, D; Bode, C; Odening, K E

    2016-01-01

    Long QT syndrome (LQTS) is a congenital arrhythmogenic channelopathy characterized by impaired cardiac repolarization. Increasing evidence supports the notion that LQTS is not purely an "electrical" disease but rather an "electro-mechanical" disease with regionally heterogeneously impaired electrical and mechanical cardiac function. In the first part, this article reviews current knowledge on electro-mechanical (dys)function in LQTS, clinical consequences of the observed electro-mechanical dysfunction, and potential underlying mechanisms. Since several novel imaging techniques - Strain Echocardiography (SE) and Magnetic Resonance Tissue Phase Mapping (TPM) - are applied in clinical and experimental settings to assess the (regional) mechanical function, advantages of these non-invasive techniques and their feasibility in the clinical routine are particularly highlighted. The second part provides novel insights into sex differences and sex hormone effects on electro-mechanical cardiac function in a transgenic LQT2 rabbit model. Here we demonstrate that female LQT2 rabbits exhibit a prolonged time to diastolic peak - as marker for contraction duration and early relaxation - compared to males. Chronic estradiol-treatment enhances these differences in time to diastolic peak even more and additionally increases the risk for ventricular arrhythmia. Importantly, time to diastolic peak is particularly prolonged in rabbits exhibiting ventricular arrhythmia - regardless of hormone treatment - contrasting with a lack of differences in QT duration between symptomatic and asymptomatic LQT2 rabbits. This indicates the potential added value of the assessment of mechanical dysfunction in future risk stratification of LQTS patients. PMID:26718598

  4. ICEPO: the ion channel electrophysiology ontology.

    Science.gov (United States)

    Hinard, V; Britan, A; Rougier, J S; Bairoch, A; Abriel, H; Gaudet, P

    2016-01-01

    Ion channels are transmembrane proteins that selectively allow ions to flow across the plasma membrane and play key roles in diverse biological processes. A multitude of diseases, called channelopathies, such as epilepsies, muscle paralysis, pain syndromes, cardiac arrhythmias or hypoglycemia are due to ion channel mutations. A wide corpus of literature is available on ion channels, covering both their functions and their roles in disease. The research community needs to access this data in a user-friendly, yet systematic manner. However, extraction and integration of this increasing amount of data have been proven to be difficult because of the lack of a standardized vocabulary that describes the properties of ion channels at the molecular level. To address this, we have developed Ion Channel ElectroPhysiology Ontology (ICEPO), an ontology that allows one to annotate the electrophysiological parameters of the voltage-gated class of ion channels. This ontology is based on a three-state model of ion channel gating describing the three conformations/states that an ion channel can adopt: closed, open and inactivated. This ontology supports the capture of voltage-gated ion channel electrophysiological data from the literature in a structured manner and thus enables other applications such as querying and reasoning tools. Here, we present ICEPO (ICEPO ftp site:ftp://ftp.nextprot.org/pub/current_release/controlled_vocabularies/), as well as examples of its use.

  5. Application of Massively Parallel Sequencing in the Clinical Diagnostic Testing of Inherited Cardiac Conditions

    Directory of Open Access Journals (Sweden)

    Ivone U. S. Leong

    2014-06-01

    Full Text Available Sudden cardiac death in people between the ages of 1–40 years is a devastating event and is frequently caused by several heritable cardiac disorders. These disorders include cardiac ion channelopathies, such as long QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome and cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Through careful molecular genetic evaluation of DNA from sudden death victims, the causative gene mutation can be uncovered, and the rest of the family can be screened and preventative measures implemented in at-risk individuals. The current screening approach in most diagnostic laboratories uses Sanger-based sequencing; however, this method is time consuming and labour intensive. The development of massively parallel sequencing has made it possible to produce millions of sequence reads simultaneously and is potentially an ideal approach to screen for mutations in genes that are associated with sudden cardiac death. This approach offers mutation screening at reduced cost and turnaround time. Here, we will review the current commercially available enrichment kits, massively parallel sequencing (MPS platforms, downstream data analysis and its application to sudden cardiac death in a diagnostic environment.

  6. Impaired cardiac sympathetic innervation in symptomatic patients with long QT syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Kies, Peter; Stegger, Lars; Schober, Otmar [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Paul, Matthias; Moennig, Gerold [University Hospital Muenster, Department for Cardiology and Angiology, Muenster (Germany); Gerss, Joachim [University of Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany); Wichter, Thomas [Marienhospital Osnabrueck, Department of Cardiology, Niels-Stensen-Kliniken, Osnabrueck (Germany); Schaefers, Michael [University of Muenster, European Institute of Molecular Imaging - EIMI, Muenster (Germany); Schulze-Bahr, Eric [University Hospital Muenster, Department for Cardiology and Angiology, Muenster (Germany); University Hospital Muenster, Institute for Genetics of Heart Diseases, Muenster (Germany)

    2011-10-15

    Increased sympathetic activation is a key modifier for arrhythmogenesis in patients with long QT syndrome (LQTS), a congenital channelopathy. Therefore, we investigated cardiac sympathetic function using {sup 123}I-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) in a cohort of symptomatic LQTS patients and correlated these findings with the underlying genotype. [{sup 123}I]MIBG SPECT was performed in 28 LQTS patients. Among these, 18 patients (64%) had a previous syncope and 10 patients (36%) survived sudden cardiac arrest. Patients were characterized in terms of genetic subtypes and QTc interval on surface ECGs. SPECT images were analysed for regional [{sup 123}I]MIBG uptake in a 33-segment bullseye scheme and compared to those obtained from 10 age-matched healthy control subjects (43 {+-} 12 years). An abnormal {sup 123}I-MIBG scan was found in 17 of 28 LQTS patients (61%) with a tracer reduction mainly located in the anteroseptal segments of the left ventricle. This finding was independent of the genetic LQTS subtype. In addition, no differences were found between LQTS patients with a QTc >500 ms vs <500 ms or those suffering from syncope vs VF (p > 0.05). A distinct regional pattern of impaired cardiac sympathetic function was identified in the majority of symptomatic LQTS patients. This innervation defect was independent of the underlying genotype and clinical disease expression. (orig.)

  7. Experimental evidence for the functional relevance of anion-π interactions

    Science.gov (United States)

    Dawson, Ryan E.; Hennig, Andreas; Weimann, Dominik P.; Emery, Daniel; Ravikumar, Velayutham; Montenegro, Javier; Takeuchi, Toshihide; Gabutti, Sandro; Mayor, Marcel; Mareda, Jiri; Schalley, Christoph A.; Matile, Stefan

    2010-07-01

    Attractive in theory and confirmed to exist, anion-π interactions have never really been seen at work. To catch them in action, we prepared a collection of monomeric, cyclic and rod-shaped naphthalenediimide transporters. Their ability to exert anion-π interactions was demonstrated by electrospray tandem mass spectrometry in combination with theoretical calculations. To relate this structural evidence to transport activity in bilayer membranes, affinity and selectivity sequences were recorded. π-acidification and active-site decrowding increased binding, transport and chloride > bromide > iodide selectivity, and supramolecular organization inverted acetate > nitrate to nitrate > acetate selectivity. We conclude that anion-π interactions on monomeric surfaces are ideal for chloride recognition, whereas their supramolecular enhancement by π,π-interactions appears perfect to target nitrate. Chloride transporters are relevant to treat channelopathies, and nitrate sensors to monitor cellular signaling and cardiovascular diseases. A big impact on organocatalysis can be expected from the stabilization of anionic transition states on chiral π-acidic surfaces.

  8. HIV-1gp120 induces neuronal apoptosis through enhancement of 4-aminopyridine-senstive outward K+ currents.

    Directory of Open Access Journals (Sweden)

    Lina Chen

    Full Text Available Human immunodeficiency virus type 1 (HIV-1-associated dementia (HAD usually occurs late in the course of HIV-1 infection and the mechanisms underlying HAD pathogenesis are not well understood. Accumulating evidence indicates that neuronal voltage-gated potassium (Kv channels play an important role in memory processes and acquired neuronal channelopathies in HAD. To examine whether Kv channels are involved in HIV-1-associated neuronal injury, we studied the effects of HIV-1 glycoprotein 120 (gp120 on outward K+ currents in rat cortical neuronal cultures using whole-cell patch techniques. Exposure of cortical neurons to gp120 produced a dose-dependent enhancement of A-type transient outward K+ currents (IA. The gp120-induced increase of IA was attenuated by T140, a specific antagonist for chemokine receptor CXCR4, suggesting gp120 enhancement of neuronal IA via CXCR4. Pretreatment of neuronal cultures with a protein kinase C (PKC inhibitor, GF109203X, inhibited the gp120-induced increase of IA. Biological significance of gp120 enhancement of IA was demonstrated by experimental results showing that gp120-induced neuronal apoptosis, as detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assay and caspase-3 staining, was attenuated by either an IA blocker 4-aminopyridine or a specific CXCR4 antagonist T140. Taken together, these results suggest that gp120 may induce caspase-3 dependent neuronal apoptosis by enhancing IA via CXCR4-PKC signaling.

  9. On the Natural and Unnatural History of the Voltage-Gated Na(+) Channel.

    Science.gov (United States)

    Moczydlowski, E G

    2016-01-01

    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. Experimental electrophysiology played a major role in the abandonment of vitalism by elucidating physiochemical mechanisms that explained the electrical excitability of muscle and nerve. Indeed, as a principal biomolecule underlying membrane excitability, the NaV channel may be considered as the physical analog or surrogate for the vital spirit once presumed to animate higher forms of life. NaV also epitomizes the "other secret of life" and functions as a quantal transistor element of biological intelligence. Subplots of this incredible but true story run the gamut from electric fish to electromagnetism, invention of the battery, venomous animals, neurotoxins, channelopathies, arrhythmia, anesthesia, astrobiology, etc. PMID:27586279

  10. Intensive Care Unit Acquired Weakness (ICU-AW: a brief and practical review

    Directory of Open Access Journals (Sweden)

    Daniel Agustin Godoy

    2015-01-01

    Full Text Available Intensive care unit-acquired weakness (ICU-AW is an increasingly complication of survivors of critical illness. It should be suspected in the presence of  a patient with a flaccid  tetraparesis or tetraplegia with hyporeflexia or absent deep tendon reflexes and difficult to weaning from mechanical ventilation in the absence of different diagnoses. Important risk factors are age, sepsis, illness duration and severity, some drugs (neuromuscular blockers, steroids. Electrophysiological studies have shown an axonal damage of involved peripheral nerves (critical illness polyneuropathy. However, muscle can also be primitively affected (critical illness myopathy leading to ICUAW with inconstant myopathic damage patterns in electromyographic studies. Mixed forms can are present (critical illness polyneuromyopathy. Although the pathophysiology remains obscure, the hypothesis of an acquired channelopathy is substantial.Electroneuromyography is crucial for diagnosis. Muscular and nerve biopsy are necessary for diagnosis confirmation. Aggressive treatment of baseline disease, prevention, through avoiding or minimizing precipitating factors, strict glycemic control, and early rehabilitation combining mobilization with physiotherapy and muscle electrical muscle stimulation, are the keys to improving recovery of the affected individuals. This narrative review highlights the current literature regarding the etiology and diagnosis of ICU-AW.http://dx.doi.org/10.7175/rhc.v6i1.1037

  11. Genetics of inherited primary arrhythmia disorders

    Directory of Open Access Journals (Sweden)

    Spears DA

    2015-09-01

    Full Text Available Danna A Spears, Michael H Gollob Division of Cardiology – Electrophysiology, University Health Network, Toronto General Hospital, Toronto, ON, Canada Abstract: A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening. Keywords: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, short QT syndrome, genetics

  12. Imaging of thalamocortical dysrhythmia in neuropsychiatry.

    Science.gov (United States)

    Schulman, Joshua J; Cancro, Robert; Lowe, Sandlin; Lu, Feng; Walton, Kerry D; Llinás, Rodolfo R

    2011-01-01

    Abnormal brain activity dynamics, in the sense of a thalamocortical dysrhythmia (TCD), has been proposed as the underlying mechanism for a subset of disorders that bridge the traditional delineations of neurology and neuropsychiatry. In order to test this proposal from a psychiatric perspective, a study using magnetoencephalography (MEG) was implemented in subjects with schizophrenic spectrum disorder (n = 14), obsessive-compulsive disorder (n = 10), or depressive disorder (n = 5) and in control individuals (n = 18). Detailed CNS electrophysiological analysis of these patients, using MEG, revealed the presence of abnormal theta range spectral power with typical TCD characteristics, in all cases. The use of independent component analysis and minimum-norm-based methods localized such TCD to ventromedial prefrontal and temporal cortices. The observed mode of oscillation was spectrally equivalent but spatially distinct from that of TCD observed in other related disorders, including Parkinson's disease, central tinnitus, neuropathic pain, and autism. The present results indicate that the functional basis for much of these pathologies may relate most fundamentally to the category of calcium channelopathies and serve as a model for the cellular substrate for low-frequency oscillations present in these psychiatric disorders, providing a basis for therapeutic strategies.

  13. A novel deletion-frameshift mutation in the S1 region of HERG gene in a Chinese family with long QT syndrome

    Institute of Scientific and Technical Information of China (English)

    GAO Ying; ZHANG Ping; LI Xue-bin; WU Cun-cao; GUO Ji-hong

    2013-01-01

    Background The congenital Long QT syndrome (LQTS) is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval,syncope,ventricular arrhythmias,and sudden death.The chromosome 7-linked type 2 congenital LQTS (LQT2) is caused by gene mutations in the human ether-a-go-go-related gene (HERG).Methods A Chinese family diagnosed with LQTS were screened for KCNQ1,HERG and SCN5A,using polymerase chain reaction (PCR),direct sequencing,and clong sequencing.We also investigated the mRNA expression of the HERG gene.Results We identified a novel i414fs+98X mutation in the HERG gene.The deletion mutation of 14-bp in the first transmembrane segment (S1) introduced premature termination codons (PTCs) at the end of exon 6.This mutation would result in a serious phenotype if the truncated proteins co-assembled with normal subunit to form the defective channels.But only the proband was symptomatic.Conclusions We found that the mRNA level of the HERG gene was significantly lower in 1414fs+98X carriers than in noncarriers.We found a novel 1414fs+98X mutation.The mRNA level supports that NMD mechanism might regulate the novel mutation.

  14. Cardiac voltage-gated calcium channel macromolecular complexes.

    Science.gov (United States)

    Rougier, Jean-Sébastien; Abriel, Hugues

    2016-07-01

    Over the past 20years, a new field of research, called channelopathies, investigating diseases caused by ion channel dysfunction has emerged. Cardiac ion channels play an essential role in the generation of the cardiac action potential. Investigators have largely determined the physiological roles of different cardiac ion channels, but little is known about the molecular determinants of their regulation. The voltage-gated calcium channel Cav1.2 shapes the plateau phase of the cardiac action potential and allows the influx of calcium leading to cardiomyocyte contraction. Studies suggest that the regulation of Cav1.2 channels is not uniform in working cardiomyocytes. The notion of micro-domains containing Cav1.2 channels and different calcium channel interacting proteins, called macro-molecular complex, has been proposed to explain these observations. The objective of this review is to summarize the currently known information on the Cav1.2 macromolecular complexes in the cardiac cell and discuss their implication in cardiac function and disorder. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID:26707467

  15. Imaging of thalamocortical dysrhythmia in neuropsychiatry

    Directory of Open Access Journals (Sweden)

    Joshua J Schulman

    2011-07-01

    Full Text Available Abnormal brain activity dynamics, in the sense of a thalamocortical dysrhythmia (TCD, has been proposed as the underlying mechanism for a subset of disorders that bridge the traditional delineations of neurology and neuropsychiatry. In order to test this proposal from a psychiatric perspective, a study using magnetoencephalography (MEG was implemented in subjects with schizophrenic spectrum disorder (SSD (n=14, obsessive-compulsive disorder (OCD (n = 10, or depressive disorder (DD (n=5 and in control individuals (n = 18. Detailed CNS electrophysiological analysis of these patients, using MEG, revealed the presence of abnormal theta range spectral power with typical TCD characteristics, in all cases. The use of independent component analysis (ICA and minimum-norm-based methods localized such TCD to ventromedial prefrontal and temporal cortices. The observed mode of oscillation was spectrally equivalent but spatially distinct from that of TCD observed in other related disorders, including Parkinson’s disease, central tinnitus, neuropathic pain, and autism. The present results indicate that the functional basis for much of these pathologies may relate most fundamentally to the category of calcium channelopathies and serve as a model for the cellular substrate for low frequency oscillations present in these psychiatric disorders, providing a basis for therapeutic strategies.

  16. KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps

    Science.gov (United States)

    Barro-Soria, Rene; Rebolledo, Santiago; Liin, Sara I.; Perez, Marta E.; Sampson, Kevin J.; Kass, Robert S.; Larsson, H. Peter

    2014-04-01

    The functional properties of KCNQ1 channels are highly dependent on associated KCNE-β subunits. Mutations in KCNQ1 or KCNE subunits can cause congenital channelopathies, such as deafness, cardiac arrhythmias and epilepsy. The mechanism by which KCNE1-β subunits slow the kinetics of KCNQ1 channels is a matter of current controversy. Here we show that KCNQ1/KCNE1 channel activation occurs in two steps: first, mutually independent voltage sensor movements in the four KCNQ1 subunits generate the main gating charge movement and underlie the initial delay in the activation time course of KCNQ1/KCNE1 currents. Second, a slower and concerted conformational change of all four voltage sensors and the gate, which opens the KCNQ1/KCNE1 channel. Our data show that KCNE1 divides the voltage sensor movement into two steps with widely different voltage dependences and kinetics. The two voltage sensor steps in KCNQ1/KCNE1 channels can be pharmacologically isolated and further separated by a disease-causing mutation.

  17. Catecholaminergic polymorphic ventricular tachycardia: An exciting new era.

    Science.gov (United States)

    Behere, Shashank P; Weindling, Steven N

    2016-01-01

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant inheritable cardiac channelopathy. The past decade and a half has provided exciting new discoveries elucidating the genetic etiology and pathophysiology of CPVT. This review of the current literature on CPVT aims to summarize the state of the art in our understanding of the genetic etiology and the molecular pathogenesis of CPVT, and how these relate to our current approach to diagnosis and management. We will also shed light on groundbreaking new work that will continue to refine the management of CPVT in the future. As our knowledge of CPVT continues to grow, further studies will yield a better understanding of the efficacy and pitfalls of established diagnostic approaches and therapies as well as help shape newer diagnostic and treatment strategies. Two separate searches were run on the National Center for Biotechnology Information's (NCBI) website. The first used the medical subject headings (MeSH) database using the term "catecholaminergic polymorphic ventricular tachycardia" that was run on the PubMed database using the age filter (birth to 18 years), and it yielded 58 results. The second search using the MeSH database with the search term "catecholaminergic polymorphic ventricular tachycardia," applying no filters yielded 178 results. The abstracts of all these articles were studied and the articles were categorized and organized. Articles of relevance were read in full. As and where applicable, relevant references and citations from the primary articles were further explored and read in full.

  18. High throughput electrophysiology: new perspectives for ion channel drug discovery.

    Science.gov (United States)

    Willumsen, Niels J; Bech, Morten; Olesen, Søren-Peter; Jensen, Bo Skaaning; Korsgaard, Mads P G; Christophersen, Palle

    2003-01-01

    Proper function of ion channels is crucial for all living cells. Ion channel dysfunction may lead to a number of diseases, so-called channelopathies, and a number of common diseases, including epilepsy, arrhythmia, and type II diabetes, are primarily treated by drugs that modulate ion channels. A cornerstone in current drug discovery is high throughput screening assays which allow examination of the activity of specific ion channels though only to a limited extent. Conventional patch clamp remains the sole technique with sufficiently high time resolution and sensitivity required for precise and direct characterization of ion channel properties. However, patch clamp is a slow, labor-intensive, and thus expensive, technique. New techniques combining the reliability and high information content of patch clamping with the virtues of high throughput philosophy are emerging and predicted to make a number of ion channel targets accessible for drug screening. Specifically, genuine HTS parallel processing techniques based on arrays of planar silicon chips are being developed, but also lower throughput sequential techniques may be of value in compound screening, lead optimization, and safety screening. The introduction of new powerful HTS electrophysiological techniques is predicted to cause a revolution in ion channel drug discovery.

  19. Functional characterization of a CRH missense mutation identified in an ADNFLE family.

    Directory of Open Access Journals (Sweden)

    Veronica Sansoni

    Full Text Available Nocturnal frontal lobe epilepsy has been historically considered a channelopathy caused by mutations in subunits of the neuronal nicotinic acetylcholine receptor or in a recently reported potassium channel. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In 2005, we detected two nucleotide variations in the promoter of the CRH gene coding for the corticotropin releasing hormone in 7 patients. These variations cosegregated with the disease and were demonstrated to alter the cellular levels of this hormone. Here, we report the identification in an Italian affected family of a novel missense mutation (hpreproCRH p.Pro30Arg located in the region of the CRH coding for the protein pro-sequence. The mutation was detected in heterozygosity in the two affected individuals. In vitro assays demonstrated that this mutation results in reduced levels of protein secretion in the short time thus suggesting that mutated people could present an altered capability to respond immediately to stress agents.

  20. Management of survivors of cardiac arrest - the importance of genetic investigation.

    Science.gov (United States)

    Schwartz, Peter J; Dagradi, Federica

    2016-09-01

    Management of survivors of cardiac arrest is largely based on a traditional approach. However, during the past decade, arrhythmias of genetic origin have increasingly been recognized as contributing to many more cases than previously appreciated. This realization is forcing physicians managing the survivors of cardiac arrest also to consider family members. In this Perspectives article, we examine the appropriate management approaches for survivors of cardiac arrests related to channelopathies, cardiomyopathies, or ischaemic heart disease, and for their families. Important implications for families of individuals who have experienced sudden cardiac death as part of sudden infant death syndrome or during sport activity are also discussed. Congenital long QT syndrome provides a paradigm of the logical sequence of the steps that should be performed. When a diagnosis of the cause of the cardiac arrest is certain or probable, every effort should be made to identify the genetic basis of disease, because this approach will enable the identification and early protection of similarly affected family members. Accordingly, the availability in hospitals of at least one cardiologist with cardiovascular genetics expertise would improve the management of survivors of cardiac arrest as well as of their families. PMID:27383078

  1. Generation Mechanism of Alternans in Luo-Rudy Model

    Science.gov (United States)

    Kitajima, Hiroyuki; Ioka, Eri; Yazawa, Toru

    Electrical alternans is the alternating amplitude from beat to beat in the action potential of the cardiac cell. It has been associated with ventricular arrhythmias in many clinical studies; however, its dynamical mechanisms remain unknown. The reason is that we do not have realistic network models of the heart system. Recently, Yazawa clarified the network structure of the heart and the central nerve system in the crustacean heart. In this study, we construct a simple model of the heart system based on Yazawa’s experimental data. Using this model, we clarify that two parameters (the conductance of sodium ions and free concentration of potassium ions in the extracellular compartment) play the key roles of generating alternans. In particular, we clarify that the inactivation gate of the time-independent potassium channel is the most important parameter. Moreover, interaction between the membrane potential and potassium ionic currents is significant for generating alternate rhythms. This result indicates that if the muscle cell has problems such as channelopathies, there is great risk of generating alternans.

  2. Concomitant presentation of Anderson-Tawil syndrome and myasthenia gravis in an adult patient: A case report

    Science.gov (United States)

    Fan, Rui; Ji, Ruirui; Zou, Wenxin; Wang, Guoliang; Wang, Hu; Penney, Daniel James; Luo, Jin Jun; Fan, Yuxin

    2016-01-01

    Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies. Laboratory results revealed hypokalemia and an elevated anti-AChR antibody expression levels. Electrocardiography demonstrated prolonged QT-interval, ST-elevation, and subsequent third-degree atrioventricular block. Neurological examination revealed bilateral ptosis, horizontal diplopia, dysarthria and generalized weakness. No mutations in the potassium channel inwardly rectifying subfamily J member 2 gene were detected in the present case. The patient was treated with oral potassium supplementation and an acetylcholinesterase inhibitor (pyridostigmine), after which the symptoms were improved. To the best of our knowledge, the present case report was the first to describe concomitant presentation of both ATS and MG, which represents a diagnostic and therapeutic challenge.

  3. Common pediatric epilepsy syndromes.

    Science.gov (United States)

    Park, Jun T; Shahid, Asim M; Jammoul, Adham

    2015-02-01

    Benign rolandic epilepsy (BRE), childhood idiopathic occipital epilepsy (CIOE), childhood absence epilepsy (CAE), and juvenile myoclonic epilepsy (JME) are some of the common epilepsy syndromes in the pediatric age group. Among the four, BRE is the most commonly encountered. BRE remits by age 16 years with many children requiring no treatment. Seizures in CAE also remit at the rate of approximately 80%; whereas, JME is considered a lifelong condition even with the use of antiepileptic drugs (AEDs). Neonates and infants may also present with seizures that are self-limited with no associated psychomotor disturbances. Benign familial neonatal convulsions caused by a channelopathy, and inherited in an autosomal dominant manner, have a favorable outcome with spontaneous resolution. Benign idiopathic neonatal seizures, also referred to as "fifth-day fits," are an example of another epilepsy syndrome in infants that carries a good prognosis. BRE, CIOE, benign familial neonatal convulsions, benign idiopathic neonatal seizures, and benign myoclonic epilepsy in infancy are characterized as "benign" idiopathic age-related epilepsies as they have favorable implications, no structural brain abnormality, are sensitive to AEDs, have a high remission rate, and have no associated psychomotor disturbances. However, sometimes selected patients may have associated comorbidities such as cognitive and language delay for which the term "benign" may not be appropriate.

  4. A novel mutation in CLCN1 associated with feline myotonia congenita.

    Directory of Open Access Journals (Sweden)

    Barbara Gandolfi

    Full Text Available Myotonia congenita (MC is a skeletal muscle channelopathy characterized by inability of the muscle to relax following voluntary contraction. Worldwide population prevalence in humans is 1:100,000. Studies in mice, dogs, humans and goats confirmed myotonia associated with functional defects in chloride channels and mutations in a skeletal muscle chloride channel (CLCN1. CLCN1 encodes for the most abundant chloride channel in the skeletal muscle cell membrane. Five random bred cats from Winnipeg, Canada with MC were examined. All cats had a protruding tongue, limited range of jaw motion and drooling with prominent neck and proximal limb musculature. All cats had blepharospasm upon palpebral reflex testing and a short-strided gait. Electromyograms demonstrated myotonic discharges at a mean frequency of 300 Hz resembling the sound of a 'swarm of bees'. Muscle histopathology showed hypertrophy of all fiber types. Direct sequencing of CLCN1 revealed a mutation disrupting a donor splice site downstream of exon 16 in only the affected cats. In vitro translation of the mutated protein predicted a premature truncation and partial lack of the highly conserved CBS1 (cystathionine β-synthase domain critical for ion transport activity and one dimerization domain pivotal in channel formation. Genetic screening of the Winnipeg random bred population of the cats' origin identified carriers of the mutation. A genetic test for population screening is now available and carrier cats from the feral population can be identified.

  5. The β1-subunit of Na(v1.5 cardiac sodium channel is required for a dominant negative effect through α-α interaction.

    Directory of Open Access Journals (Sweden)

    Aurélie Mercier

    Full Text Available Brugada syndrome (BrS is an inherited autosomal dominant cardiac channelopathy. Several mutations on the cardiac sodium channel Na(v1.5 which are responsible for BrS lead to misfolded proteins that do not traffic properly to the plasma membrane. In order to mimic patient heterozygosity, a trafficking defective mutant, R1432G was co-expressed with Wild Type (WT Na(v1.5 channels in HEK293T cells. This mutant significantly decreased the membrane Na current density when it was co-transfected with the WT channel. This dominant negative effect did not result in altered biophysical properties of Na(v1.5 channels. Luminometric experiments revealed that the expression of mutant proteins induced a significant reduction in membrane expression of WT channels. Interestingly, we have found that the auxiliary Na channel β(1-subunit was essential for this dominant negative effect. Indeed, the absence of the β(1-subunit prevented the decrease in WT sodium current density and surface proteins associated with the dominant negative effect. Co-immunoprecipitation experiments demonstrated a physical interaction between Na channel α-subunits. This interaction occurred only when the β(1-subunit was present. Our findings reveal a new role for β(1-subunits in cardiac voltage-gated sodium channels by promoting α-α subunit interaction which can lead to a dominant negative effect when one of the α-subunits shows a trafficking defective mutation.

  6. Rare Titin (TTN Variants in Diseases Associated with Sudden Cardiac Death

    Directory of Open Access Journals (Sweden)

    Oscar Campuzano

    2015-10-01

    Full Text Available A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death.

  7. Novel SCN5A mutation associated with idiopathic ventricular fibrillation due to subclinical Brugada syndrome

    Directory of Open Access Journals (Sweden)

    Juan Jiménez-Jáimez

    2011-12-01

    Full Text Available Idiopathic ventricular fibrillation can be caused by subclinical channelopathies such as Brugada syndrome. Our objective is to study the clinical behaviour of a new SCN5A mutation found in a woman with idiopathic ventricular fibrillation. A 53-year-old woman presented with multiple episodes of ventricular fibrillation, a structurally normal heart and normal baseline electrocardiogram. Genetic testing included KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 and KCNJ2 and identified a mutation in SCN5A (D1816fs/g98747-98748insT. We studied 15 immediate family members by means of electrocardiogram, echocardiogram, flecainide challenge test and genetic study. Eight subjects had the mutation. The flecainide challenge test was positive for Brugada syndrome in two subjects in the case group and none in the control group. The PR and QRS intervals on the baseline electrocardiogram were longer in the case group. The left atrial volume indexed to body surface was higher in the case group, likely due to the fact that two patients with the mutation had atrial fibrillation and none had it in the control group. The D1816fs/g98747-98748insT mutation in SCN5A may be associated with idiopathic ventricular fibrillation and Brugada syndrome with a broad phenotypic spectrum and incomplete penetrance. Genetic testing may be useful to identify the etiology of idiopathic ventricular fibrillation in patients with a negative thorough clinical evaluation.

  8. DDESC: Dragon database for exploration of sodium channels in human

    Directory of Open Access Journals (Sweden)

    Radovanovic Aleksandar

    2008-12-01

    Full Text Available Abstract Background Sodium channels are heteromultimeric, integral membrane proteins that belong to a superfamily of ion channels. The mutations in genes encoding for sodium channel proteins have been linked with several inherited genetic disorders such as febrile epilepsy, Brugada syndrome, ventricular fibrillation, long QT syndrome, or channelopathy associated insensitivity to pain. In spite of these significant effects that sodium channel proteins/genes could have on human health, there is no publicly available resource focused on sodium channels that would support exploration of the sodium channel related information. Results We report here Dragon Database for Exploration of Sodium Channels in Human (DDESC, which provides comprehensive information related to sodium channels regarding different entities, such as "genes and proteins", "metabolites and enzymes", "toxins", "chemicals with pharmacological effects", "disease concepts", "human anatomy", "pathways and pathway reactions" and their potential links. DDESC is compiled based on text- and data-mining. It allows users to explore potential associations between different entities related to sodium channels in human, as well as to automatically generate novel hypotheses. Conclusion DDESC is first publicly available resource where the information related to sodium channels in human can be explored at different levels. This database is freely accessible for academic and non-profit users via the worldwide web http://apps.sanbi.ac.za/ddesc.

  9. Exciting Cells: Modeling Genetic Epilepsies with Patient-Derived Induced Pluripotent Stem Cells

    Science.gov (United States)

    Tidball, Andrew M.; Parent, Jack M.

    2016-01-01

    Human induced pluripotent stem cell (iPSC) models of epilepsy are becoming a revolutionary platform for mechanistic studies and drug discovery. The skyrocketing pace of epilepsy gene discovery is vastly outstripping the development of in vivo animal models. Currently, antiepileptic drug prescribing to patients with specific genetic epilepsies is based on small-scale clinical trials and empiricism; however, rapid production of patient-derived iPSC models will allow for precision therapy. We review iPSC-based studies that have already afforded novel discoveries in diseases with epileptic phenotypes, as well as challenges to using iPSC-based neurological disease models. We also discuss iPSC-derived cardiomyocyte studies of arrhythmia-inducing ion channelopathies that exemplify novel drug discovery and use of multielectrode array technology that can be translated to epilepsy research. Beyond initial studies of Rett, Timothy, Phelan-McDermid and Dravet syndromes, the stage is set for groundbreaking iPSC-based mechanistic and therapeutic discoveries in genetic epilepsies with the potential to impact patient treatment and quality of life. PMID:26373465

  10. Cardiovascular science: opportunities for translating research into improved care.

    Science.gov (United States)

    Braunwald, Eugene

    2013-01-01

    Cardiovascular research is progressing on many fronts, as highlighted in the collection of Reviews in this issue of the JCI. MicroRNAs that regulate cardiac function have been implicated in cardiac disorders, and efforts to develop therapeutic antagomirs are underway. The genetic bases of several cardiac disorders, including cardiomyopathies that cause heart failure and channelopathies that underlie cardiac arrhythmias, have been elucidated. Genetic testing can identify asymptomatic individuals at risk, potentially leading to effective preventative measures. Growing evidence supports the role of chronic inflammation in atherosclerosis, providing new opportunities for therapeutic intervention. For heart failure, recent work suggests that cardiac regeneration using stem/progenitor cells, gene transfer, new drugs that restore normal Ca2+ cycling, and agents that reduce reperfusion injury following myocardial infarction are all viable new approaches to managing disease. Cumulatively, it seems likely that the clinical advances emerging from ongoing research will, in the foreseeable future, reduce the number of deaths in the industrialized world from cardiovascular disease. PMID:23281404

  11. NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.

    Science.gov (United States)

    Conroy, J; Allen, N M; Gorman, K M; Shahwan, A; Ennis, S; Lynch, S A; King, M D

    2016-02-01

    Next-generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early-onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes. The identification of a disease-causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE. PMID:26235277

  12. Impaired cardiac sympathetic innervation in symptomatic patients with long QT syndrome

    International Nuclear Information System (INIS)

    Increased sympathetic activation is a key modifier for arrhythmogenesis in patients with long QT syndrome (LQTS), a congenital channelopathy. Therefore, we investigated cardiac sympathetic function using 123I-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) in a cohort of symptomatic LQTS patients and correlated these findings with the underlying genotype. [123I]MIBG SPECT was performed in 28 LQTS patients. Among these, 18 patients (64%) had a previous syncope and 10 patients (36%) survived sudden cardiac arrest. Patients were characterized in terms of genetic subtypes and QTc interval on surface ECGs. SPECT images were analysed for regional [123I]MIBG uptake in a 33-segment bullseye scheme and compared to those obtained from 10 age-matched healthy control subjects (43 ± 12 years). An abnormal 123I-MIBG scan was found in 17 of 28 LQTS patients (61%) with a tracer reduction mainly located in the anteroseptal segments of the left ventricle. This finding was independent of the genetic LQTS subtype. In addition, no differences were found between LQTS patients with a QTc >500 ms vs 0.05). A distinct regional pattern of impaired cardiac sympathetic function was identified in the majority of symptomatic LQTS patients. This innervation defect was independent of the underlying genotype and clinical disease expression. (orig.)

  13. Catecholaminergic polymorphic ventricular tachycardia: An exciting new era

    Directory of Open Access Journals (Sweden)

    Shashank P Behere

    2016-01-01

    Full Text Available Catecholaminergic polymorphic ventricular tachycardia (CPVT is a highly malignant inheritable cardiac channelopathy. The past decade and a half has provided exciting new discoveries elucidating the genetic etiology and pathophysiology of CPVT. This review of the current literature on CPVT aims to summarize the state of the art in our understanding of the genetic etiology and the molecular pathogenesis of CPVT, and how these relate to our current approach to diagnosis and management. We will also shed light on groundbreaking new work that will continue to refine the management of CPVT in the future. As our knowledge of CPVT continues to grow, further studies will yield a better understanding of the efficacy and pitfalls of established diagnostic approaches and therapies as well as help shape newer diagnostic and treatment strategies. Two separate searches were run on the National Center for Biotechnology Information's (NCBI website. The first used the medical subject headings (MeSH database using the term “catecholaminergic polymorphic ventricular tachycardia” that was run on the PubMed database using the age filter (birth to 18 years, and it yielded 58 results. The second search using the MeSH database with the search term “catecholaminergic polymorphic ventricular tachycardia,” applying no filters yielded 178 results. The abstracts of all these articles were studied and the articles were categorized and organized. Articles of relevance were read in full. As and where applicable, relevant references and citations from the primary articles were further explored and read in full.

  14. Electro-mechanical dysfunction in long QT syndrome: Role for arrhythmogenic risk prediction and modulation by sex and sex hormones.

    Science.gov (United States)

    Lang, C N; Menza, M; Jochem, S; Franke, G; Perez Feliz, S; Brunner, M; Koren, G; Zehender, M; Bugger, H; Jung, B A; Foell, D; Bode, C; Odening, K E

    2016-01-01

    Long QT syndrome (LQTS) is a congenital arrhythmogenic channelopathy characterized by impaired cardiac repolarization. Increasing evidence supports the notion that LQTS is not purely an "electrical" disease but rather an "electro-mechanical" disease with regionally heterogeneously impaired electrical and mechanical cardiac function. In the first part, this article reviews current knowledge on electro-mechanical (dys)function in LQTS, clinical consequences of the observed electro-mechanical dysfunction, and potential underlying mechanisms. Since several novel imaging techniques - Strain Echocardiography (SE) and Magnetic Resonance Tissue Phase Mapping (TPM) - are applied in clinical and experimental settings to assess the (regional) mechanical function, advantages of these non-invasive techniques and their feasibility in the clinical routine are particularly highlighted. The second part provides novel insights into sex differences and sex hormone effects on electro-mechanical cardiac function in a transgenic LQT2 rabbit model. Here we demonstrate that female LQT2 rabbits exhibit a prolonged time to diastolic peak - as marker for contraction duration and early relaxation - compared to males. Chronic estradiol-treatment enhances these differences in time to diastolic peak even more and additionally increases the risk for ventricular arrhythmia. Importantly, time to diastolic peak is particularly prolonged in rabbits exhibiting ventricular arrhythmia - regardless of hormone treatment - contrasting with a lack of differences in QT duration between symptomatic and asymptomatic LQT2 rabbits. This indicates the potential added value of the assessment of mechanical dysfunction in future risk stratification of LQTS patients.

  15. Primary erythromelalgia: a review.

    Science.gov (United States)

    Tang, Zhaoli; Chen, Zhao; Tang, Beisha; Jiang, Hong

    2015-01-01

    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. Reported cases of PE contain both inherited and sporadic forms. Genetic etiology of PE is mutations on SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Diagnosis of PE is made upon clinical manifestations and screening for mutations on SCN9A. Exclusion of several other treatable diseases/secondary erythromelalgia is also necessary because of the lack of biomarkers specifically for PE. Differential diagnoses can include Fabry disease, cellulites, Raynaud phenomenon, vasculitis and so on. Diagnostic methods often involve complete blood count, imaging studies and thermograph. Treatment for PE is unsatisfactory and highly individualized. Frequently used pain relieving drugs involve sodium channel blockers such as lidocaine, carbamazepine and mexiletine. Novel drugs such as PF-05089771 and TV-45070 could be promising in ameliorating pain symptoms due to their Nav1.7 selectivity. Patients' symptoms often worsen over time and many patients develop ulcerations and gangrenes caused by excessive exposure to low temperature in order to relieve pain. This review mainly focuses on PE and the causative gene SCN9A--its mutations and their effects on Nav1.7 channels' electrophysiological properties. We propose a genotype-channelopathy-phenotype correlation network underlying PE etiology which could provide guidance for future therapeutics.

  16. Transgenic rabbit models to investigate the cardiac ion channel disease long QT syndrome.

    Science.gov (United States)

    Lang, C N; Koren, G; Odening, K E

    2016-07-01

    Long QT syndrome (LQTS) is a rare inherited channelopathy caused mainly by different mutations in genes encoding for cardiac K(+) or Na(+) channels, but can also be caused by commonly used ion-channel-blocking and QT-prolonging drugs, thus affecting a much larger population. To develop novel diagnostic and therapeutic strategies to improve the clinical management of these patients, a thorough understanding of the pathophysiological mechanisms of arrhythmogenesis and potential pharmacological targets is needed. Drug-induced and genetic animal models of various species have been generated and have been instrumental for identifying pro-arrhythmic triggers and important characteristics of the arrhythmogenic substrate in LQTS. However, due to species differences in features of cardiac electrical function, these different models do not entirely recapitulate all aspects of the human disease. In this review, we summarize advantages and shortcomings of different drug-induced and genetically mediated LQTS animal models - focusing on mouse and rabbit models since these represent the most commonly used small animal models for LQTS that can be subjected to genetic manipulation. In particular, we highlight the different aspects of arrhythmogenic mechanisms, pro-arrhythmic triggering factors, anti-arrhythmic agents, and electro-mechanical dysfunction investigated in transgenic LQTS rabbit models and their translational application for the clinical management of LQTS patients in detail. Transgenic LQTS rabbits have been instrumental to increase our understanding of the role of spatial and temporal dispersion of repolarization to provide an arrhythmogenic substrate, genotype-differences in the mechanisms for early afterdepolarization formation and arrhythmia maintenance, mechanisms of hormonal modification of arrhythmogenesis and regional heterogeneities in electro-mechanical dysfunction in LQTS. PMID:27210307

  17. A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family.

    Science.gov (United States)

    Ackerman, M J; Schroeder, J J; Berry, R; Schaid, D J; Porter, C J; Michels, V V; Thibodeau, S N

    1998-08-01

    After identifying a 10-year-old boy with inherited long QT syndrome (LQTS) after a near-drowning that required defibrillation from torsades de pointes, evaluation of first degree relatives revealed a four-generation kindred comprising 26 individuals with four additional symptomatic and eight asymptomatic members harboring an abnormally prolonged QTc (defined as > or =0.46 s1/2). We set out to determine the molecular basis of their LQTS. The inherited LQTS represents a collection of genetically distinct ion channelopathies with over 40 mutations in four fundamental cardiac ion channels identified. Molecular studies, including linkage analysis and identification of the disease-associated mutation, were performed on genomic DNA isolated from peripheral blood samples from 29 available family members. Genetic linkage analysis excluded the regions for LQT2, LQT3, and LQT5. However, the chromosome 11p15.5 region (LQT1) showed evidence of linkage with a maximum lod score of 3.36. Examination of the KVLQT1 gene revealed a novel 3-bp deletion resulting in an in-frame deltaF339 (phenylalanine) deletion in the proband. This deltaF339 mutation was confirmed in nine additional family members who shared both an assigned affected phenotype and the disease-associated linked haplotype. Importantly, three asymptomatic family members, with a tentative clinical diagnosis based on their QTc, did not have this mutation and could be reclassified as unaffected. It is noteworthy that the proband's ECG suggested the sodium channel-based LQT3 genotype. These findings show the potential importance of establishing a molecular diagnosis rather than initiating genotype-specific interventions based upon inspection of a patient's ECG.

  18. Neurotoxins and their binding areas on voltage-gated sodium channels.

    Science.gov (United States)

    Stevens, Marijke; Peigneur, Steve; Tytgat, Jan

    2011-01-01

    Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called "channelopathies." The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963. These concepts still form the basis for understanding the function of VGSCs. When VGSCs sense a sufficient change in membrane potential, they are activated and consequently generate a massive influx of sodium ions. Immediately after, channels will start to inactivate and currents decrease. In the inactivated state, channels stay refractory for new stimuli and they must return to the closed state before being susceptible to a new depolarization. On the other hand, studies with neurotoxins like tetrodotoxin (TTX) and saxitoxin (STX) also contributed largely to our today's understanding of the structure and function of ion channels and of VGSCs specifically. Moreover, neurotoxins acting on ion channels turned out to be valuable lead compounds in the development of new drugs for the enormous range of diseases in which ion channels are involved. A recent example of a synthetic neurotoxin that made it to the market is ziconotide (Prialt(®), Elan). The original peptide, ω-MVIIA, is derived from the cone snail Conus magus and now FDA/EMA-approved for the management of severe chronic pain by blocking the N-type voltage-gated calcium channels in pain fibers. This review focuses on the current status of research on neurotoxins acting on VGSC, their contribution to further unravel the structure and function of

  19. Opposite Effects of the S4-S5 Linker and PIP(2) on Voltage-Gated Channel Function: KCNQ1/KCNE1 and Other Channels.

    Science.gov (United States)

    Choveau, Frank S; Abderemane-Ali, Fayal; Coyan, Fabien C; Es-Salah-Lamoureux, Zeineb; Baró, Isabelle; Loussouarn, Gildas

    2012-01-01

    Voltage-gated potassium (Kv) channels are tetramers, each subunit presenting six transmembrane segments (S1-S6), with each S1-S4 segments forming a voltage-sensing domain (VSD) and the four S5-S6 forming both the conduction pathway and its gate. S4 segments control the opening of the intracellular activation gate in response to changes in membrane potential. Crystal structures of several voltage-gated ion channels in combination with biophysical and mutagenesis studies highlighted the critical role of the S4-S5 linker (S4S5(L)) and of the S6 C-terminal part (S6(T)) in the coupling between the VSD and the activation gate. Several mechanisms have been proposed to describe the coupling at a molecular scale. This review summarizes the mechanisms suggested for various voltage-gated ion channels, including a mechanism that we described for KCNQ1, in which S4S5(L) is acting like a ligand binding to S6(T) to stabilize the channel in a closed state. As discussed in this review, this mechanism may explain the reverse response to depolarization in HCN-like channels. As opposed to S4S5(L), the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP(2)), stabilizes KCNQ1 channel in an open state. Many other ion channels (not only voltage-gated) require PIP(2) to function properly, confirming its crucial importance as an ion channel cofactor. This is highlighted in cases in which an altered regulation of ion channels by PIP(2) leads to channelopathies, as observed for KCNQ1. This review summarizes the state of the art on the two regulatory mechanisms that are critical for KCNQ1 and other voltage-gated channels function (PIP(2) and S4S5(L)), and assesses their potential physiological and pathophysiological roles.

  20. A mutation in TRPV4 results in altered chondrocyte calcium signaling in severe metatropic dysplasia.

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    Hurd, Lauren; Kirwin, Susan M; Boggs, Mary; Mackenzie, William G; Bober, Michael B; Funanage, Vicky L; Duncan, Randall L

    2015-10-01

    Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a polymodal modulated non-selective cation channel required for normal development and maintenance of bone and cartilage. Heterozygous mutations of this channel cause a variety of channelopathies, including metatropic dysplasia (MD). We analyzed the effect of a novel TRPV4 mutation c.2398G>A, p.Gly800Asp on intracellular calcium ([Ca(2+) ]i ) regulation in chondrocytes and compared this response to chondrocytes with a frequently observed mutation, c.2396C>T, p.Pro799Leu. We observed temperature-dependent [Ca(2+) ]i oscillations in both intact and MD chondrocytes however, MD mutations exhibited increased peak magnitudes of [Ca(2+) ]i during oscillations. We also found increased baseline [Ca(2+) ]i in MD primary cells, as well as increased [Ca(2+) ]i response to either hypotonic swelling or the TRVP4-specific agonist, GSK1016790A. Oscillations and stimulation responses were blocked with the TRPV4-specific antagonist, GSK205. Analysis of [Ca(2+) ]i response kinetics showed that MD chondrocytes had increased frequency of temperature-sensitive oscillations, and the magnitude and duration of [Ca(2+) ]i responses to given stimuli. Duration of the response of the p.Gly800Asp mutation to stimulation was greater than for the p.Pro799Leu mutation. These experiments show that this region of the channel is essential for proper [Ca(2+) ]i regulation. These studies of primary cells from patients show how both mutant and WT TRPV4 channels regulate cartilage and bone development. © 2015 Wiley Periodicals, Inc.

  1. Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels

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    Mohamed-Yassine eAMAROUCH

    2015-02-01

    Full Text Available Voltage-gated sodium channels (Nav are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the voltage-gated sodium channels. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the voltage-gated sodium channels by shifting the voltage-dependence of steady state activation towards more negative potentials.

  2. K+ CHANNELEPSY: progress in the neurobiology of potassium channels and epilepsy

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    Maria Cristina D'Adamo

    2013-09-01

    Full Text Available K+ channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K+ channels as primary targets of genetic variations or perturbations in K+-dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K+ channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K+ channels defects underlying distinct epilepsies as K+ channelepsies, and introduce a new nomenclature (e.g. Kx.y-channelepsy, following the widely used K+ channel classification, which could be also adopted to easily identify other channelopathies involving Na+ (e.g. Navx.y-phenotype, Ca2+ (e.g. Cavx.y-phenotype, and Cl- channels. Furthermore, we discuss novel genetic defects in K+ channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K+ channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.

  3. [Evolution of Devic's neuromyelitis optica spectrum disorders].

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    Bernard-Valnet, Raphaël; Marignier, Romain

    2015-04-01

    Neuromyelitis optica (NMO) is a rare inflammatory disorder of the central nervous system affecting mostly the optic nerve and the spinal cord. These last few years have been characterized by a dramatic improvement of NMO knowledge and care. A unique feature of NMO is the presence of autoantibodies directed against aquaporin-4 (AQP4-Ab). Identification of this biomarker has enlarged the clinical spectrum of the disease to a broad variety of symptoms and syndromes including brain, brainstem and hypothalamus involvement. This modifies the acknowledged definition of NMO, switching from a clinical phenotype to a biological one and introducing the concept of "aquaporinopathy" or "autoimmune AQP4 channelopathy". AQP4-Ab plays an important role in NMO pathophysiology. In vitro and ex vivo experiments showed that AQP4-Ab can induce either direct astrocyte loss through complement activation (neuroinflammation) or astrocyte changes via internalization of AQP4 (neuromodulation). Recently, T cell involvement in NMO has been suggested. Based on relatively small retrospective and prospective case series, several treatments appear to be likely effective in preventing attacks and stabilizing disability in NMO patients. Relapse prevention in NMO is based on early and maintenance immunosuppressive treatments. Considering the antibody-driven hypothesis, treatment should target B-cells. MS-approved therapies are not currently recommended for NMO patients, several series suggesting poor efficacy or harmful effects. Despite recent improvement of the detection method, some patients remain seronegative for AQP4-Ab. This group expresses specific demographic and disease-related features different for AQP4-Ab positive ones. This raises the question of the place of seronegative AQP4-Ab NMO patients in the spectrum, of their intimate physiopathology and finally of the therapeutic strategy to adopt in such patients.

  4. Multi-electrode array study of neuronal cultures expressing nicotinic β2-V287L subunits, linked to autosomal dominant nocturnal frontal lobe epilepsy. An in vitro model of spontaneous epilepsy.

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    Francesca eGullo

    2014-07-01

    Full Text Available Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE is a partial sleep-related epilepsy which can be caused by mutant neuronal nicotinic acetylcholine receptors (nAChR. We applied multi-electrode array (MEA recording methods to study the spontaneous firing activity of neocortical cultures obtained from mice expressing or not (WT an ADNFLE-linked nAChR subunit (β2-V287L.More than 100,000 up-states were recorded during experiments sampling from several thousand neurons. Data were analyzed by using a fast sliding-window procedure which computes histograms of the up-state durations. Differently from the WT, cultures expressing β2-V287L displayed long (10-32 s synaptic-induced up-state firing events. The occurrence of such long up-states was prevented by both negative (gabazine, penicillin G and positive (benzodiazepines modulators of GABAA receptors. Carbamazepine (CBZ, a drug of choice in ADNFLE patients, also inhibited the long up-states at micromolar concentrations. In cultures expressing β2-V287L, no significant effect was observed on the action potential waveform either in the absence or in the presence of pharmacological treatment.Our results show that some aspects of the spontaneous hyperexcitability displayed by a murine model of a human channelopathy can be reproduced in neuronal cultures. In particular, our cultures represent an in vitro chronic model of spontaneous epileptiform activity, i.e. not requiring pre-treatment with convulsants. This opens the way to the study in vitro of the role of β2-V287L on synaptic formation. Moreover, our neocortical cultures on MEA platforms allow to determine the effects of prolonged pharmacological treatment on spontaneous network hyperexcitability (which is impossible in the short-living brain slices. Methods such as the one we illustrate in the present paper should also considerably facilitate the preliminary screening of antiepileptic drugs, thereby reducing the number of in vivo

  5. Clinical and biochemical spectrum of hypokalemic paralysis in North: East India

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    Ashok K Kayal

    2013-01-01

    Full Text Available Background: Acute hypokalemic paralysis, characterized by acute flaccid paralysis is primarily a calcium channelopathy, but secondary causes like renal tubular acidosis (RTA, thyrotoxic periodic paralysis (TPP, primary hyperaldosteronism, Gitelman′s syndrome are also frequent. Objective: To study the etiology, varied presentations, and outcome after therapy of patients with hypokalemic paralysis. Materials And Methods: All patients who presented with acute flaccid paralysis with hypokalemia from October 2009 to September 2011 were included in the study. A detailed physical examination and laboratory tests including serum electrolytes, serum creatine phosphokinase (CPK, urine analysis, arterial blood gas analysis, thyroid hormones estimation, and electrocardiogram were carried out. Patients were further investigated for any secondary causes and treated with potassium supplementation. Result: The study included 56 patients aged 15-92 years (mean 36.76 ± 13.72, including 15 female patients. Twenty-four patients had hypokalemic paralysis due to secondary cause, which included 4 with distal RTA, 4 with Gitelman syndrome, 3 with TPP, 2 each with hypothyroidism, gastroenteritis, and Liddle′s syndrome, 1 primary hyperaldosteronism, 3 with alcoholism, and 1 with dengue fever. Two female patients were antinuclear antibody-positive. Eleven patient had atypical presentation (neck muscle weakness in 4, bladder involvement in 3, 1 each with finger drop and foot drop, tetany in 1, and calf hypertrophy in 1, and 2 patient had respiratory paralysis. Five patients had positive family history of similar illness. All patients improved dramatically with potassium supplementation. Conclusion: A high percentage (42.9% of secondary cause for hypokalemic paralysis warrants that the underlying cause must be adequately addressed to prevent the persistence or recurrence of paralysis.

  6. From syncope to ICD: clinical paths of the Brugada syndrome

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    Ivan Comelli

    2010-09-01

    Full Text Available This review summarizes the evidences in the literature on the management of the Brugada syndrome (BS, an arrhythmogenic disease caused by genetic channelopathies, predisposing to syncope and sudden cardiac death in young, apparently healthy, typically male subjects, in the third and fourth decade of their life. Sudden cardiac death (SCD is defined as natural death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of symptoms. It ranks among the main causes of death in the western world, with an incidence ranging from 0.36 and 1.28‰ inhabitants per year, equal to 300,000 cases a year in the USA. In the majority of the cases it is due to the onset of arrhythmia in subjects with structural cardiac diseases, especially ischemic heart disease. However, in a non-negligible percentage of the cases, about 5-10%, the SCD arises in relatively young individuals in whom cardiac anomalies cannot be detected using traditional diagnostic techniques. About 20% of these cases can be attributed to SB. In spite of the many efforts produced to identify an effective pharmacological treatment, to date the only aid to reduce the mortality rate in subjects with SB is an implantable cardio-defibrillator (ICD. Since this approach often entails complications, the efforts of the scientific community is now focused on the assessment of the arrhythmic risk. The identification of high-risk subjects is one of the chief objectives in the therapeutic decision-making process. ABSTRACT clinica e terapia emergency

  7. Drosophila KCNQ channel displays evolutionarily conserved electrophysiology and pharmacology with mammalian KCNQ channels.

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    Sonia Cavaliere

    Full Text Available Of the five human KCNQ (Kv7 channels, KCNQ1 with auxiliary subunit KCNE1 mediates the native cardiac I(Ks current with mutations causing short and long QT cardiac arrhythmias. KCNQ4 mutations cause deafness. KCNQ2/3 channels form the native M-current controlling excitability of most neurons, with mutations causing benign neonatal febrile convulsions. Drosophila contains a single KCNQ (dKCNQ that appears to serve alone the functions of all the duplicated mammalian neuronal and cardiac KCNQ channels sharing roughly 50-60% amino acid identity therefore offering a route to investigate these channels. Current information about the functional properties of dKCNQ is lacking therefore we have investigated these properties here. Using whole cell patch clamp electrophysiology we compare the biophysical and pharmacological properties of dKCNQ with the mammalian neuronal and cardiac KCNQ channels expressed in HEK cells. We show that Drosophila KCNQ (dKCNQ is a slowly activating and slowly-deactivating K(+ current open at sub-threshold potentials that has similar properties to neuronal KCNQ2/3 with some features of the cardiac KCNQ1/KCNE1 accompanied by conserved sensitivity to a number of clinically relevant KCNQ blockers (chromanol 293B, XE991, linopirdine and opener (zinc pyrithione. We also investigate the molecular basis of the differential selectivity of KCNQ channels to the opener retigabine and show a single amino acid substitution (M217W can confer sensitivity to dKCNQ. We show dKCNQ has similar electrophysiological and pharmacological properties as the mammalian KCNQ channels, allowing future study of physiological and pathological roles of KCNQ in Drosophila and whole organism screening for new modulators of KCNQ channelopathies.

  8. [Immune-mediated neuromyotonia (Isaacs' syndrome)--clinical aspects and pathomechanism].

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    Arimura, Kimiyoshi; Watanabe, Osamu

    2010-04-01

    Neuromyotonia occurs due to several causes such as hereditary, immune-mediated and degenerative neurological disorders. Isaacs' syndrome (immune-mediated neuromyotonia) is an antibody-mediated potassium channel disorder (channelopathy). Clinical symptoms of Isaacs' syndrome are characterized by muscle cramp, slow relaxation following muscle contraction (pseudomyotonia), and hyperhidrosis; these symptoms are due to hyperexcitability of the peripheral nerve, including autonomic nerve. These symptoms are relieved by the administration of Na channel blocker and immunotherapy. Recent studies show that this disease is not infrequently associated with neoplasm, especially thymoma. The target channel proteins of the antigens are voltage-gated potassium channels (VGKCs), specifically dendrotoxin-sensitive fast potassium channels. The suppression of voltage-gated outward K+ current by antibodies induces the hyper- excitability of the peripheral nerve. The findings of patch clamp studies show that antibodies may not directly block the kinetics of VGKCs, but may decrease channel density. From the electrophysiologic, pharmacologic and immunologic view points, the site of origin of spontaneous discharges is located principally in the distal portion of the motor nerve and/or within the terminal arborization. Anti-VGKC antibodies were also found to be positive in patients with Morvan's syndrome, limbic encephalitis and temporal epilepsy. Thus, an increasing number of immune-mediated neurological disorders with anti-VGKC antibodies are being identified. However, except in Morvan's syndrome, it is rare to find symptoms pertaining to involvement of both the peripheral and central nervous system in the same patient with anti-VGKC antibodies. The differences in the pathomechanism of Isaacs' syndrome and limbic encephalitis are still unclear. PMID:20420181

  9. Nav Channels in Damaged Membranes.

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    Morris, C E; Joos, B

    2016-01-01

    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. The coupled g(V) and availability(V) processes and their window conductance regions consequently left-shift by the same number of millivolts. These damage-induced hyperpolarizing shifts, whose magnitude increases with damage intensity, are called coupled left shift (CLS). Based on past work and modeling, we discuss how to test for Nav-CLS, emphasizing the virtue of sawtooth ramp clamp. We explain that it is the inherent mechanosensitivity of Nav activation that underlies Nav-CLS. Using modeling of excitability, we show the known process of Nav-CLS is sufficient to predict a wide variety of "sick excitable cell" phenomena, from hyperexcitability through to depolarizing block. When living cells are mimicked by inclusion of pumps, mild Nav-CLS produces a wide array of burst phenomena and subthreshold oscillations. Dynamical analysis of mild damage scenarios shows how these phenomena reflect changes in spike thresholds as the pumps try to counteract the leaky Nav channels. Smart Nav inhibitors designed for sick excitable cells would target bleb-damaged membrane, buying time for cell-mediated removal or repair of Nav-bearing membrane that has become bleb-damaged (ie, detached from the cytoskeleton). PMID:27586295

  10. Key clinical features a general internist needs to know about Brugada syndrome: a case-based discussion

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    WuQiang Fan

    2015-06-01

    Full Text Available Introduction: Brugada syndrome (BrS is an autosomal dominant genetic disorder involving the abnormal function of cardiac voltage-gated sodium ion channels. Sodium channel loss of function can lead to early repolarization and loss of the Phase 2 action potential dome in cardiomyocytes. In BrS, this sodium channelopathy occurs in some, but not all, epicardial cells thus creating 1 juxtaposition of depolarized and repolarized cells in the epicardium and 2 a transmural voltage gradient. Together, these conditions can set up a Phase 2 reentry and resultant malignant cardiac arrhythmia. Of the three types of electrocardiogram (EKG changes seen in BrS, only the Type 1 EKG is considered diagnostic. In a controlled setting, sodium channel blockers and Brugada EKG leads may be used to unmask this diagnostic EKG finding. Fever and certain medications that interfere with the sodium channel can also trigger these changes, which can be catastrophic. Case report: A 26-year-old white male presented with febrile upper respiratory infection symptoms and had an EKG change, which was initially misinterpreted as an ST elevated myocardial infarction due to ST-T segment elevation in leads V1 and V2. The patient reported past recurrent syncopal episodes leading to a recent suspected diagnosis of BrS. A later episode of febrile illness, triggering a Type 1 EKG pattern, led to a subsequent hospital admission for continuous cardiac monitoring. On that occasion, he was placed on a wearable external defibrillator pending placement of implantable cardioverter defibrillator (ICD device. Conclusion: Due to the gravity of symptoms that can manifest in the BrS patient, it is important to recognize and treat this condition promptly and effectively. BrS patients require admission for continuous cardiac monitoring when febrile and certain medications interfering with the sodium channel should be avoided in this population. Although medications may be used as one treatment modality

  11. Playing it safe: exercise and cardiovascular health.

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    Dhutia, Harshil; Sharma, Sanjay

    2015-10-01

    Regular physical activity controls acquired cardiovascular risk factors such as obesity, diabetes mellitus, hypertension and hyperlipidaemia. Exercise is generally associated with a 50% reduction in adverse events from coronary artery disease (CAD). The benefits of exercise extend well beyond the cardiovascular system. Recent evidence suggests that exercise prevents cell senescence, and active individuals are at lower risk of developing certain malignancies including cancer of the prostate and the colon, osteoporosis, depression and dementia. Individuals who exercise regularly extend their life expectancy by three to seven years. Healthy individuals should engage in 150 minutes of moderate-intensity, aerobic exercise per week. Recent studies have demonstrated that even lower volumes of exercise below these recommendations confer health benefits, which is highly relevant to individuals with established cardiac disease including heart failure. Sudden cardiac death in athletes under 35 is rare with.estimates ranging from 1 in 50,000 to 1 in 200,000. Hereditary and congenital abnormalities of the heart are the most common cause of nontraumatic death during sport in young athletes. In middle-aged recreational athletes more than 90% of sudden cardiac deaths occur in males and more than 90% are caused by atherosclerotic CAD. The AHA and the ESC advocate pre-participation screening of young athletes. The ECG has the ability to detect congenital accessory pathways and ion channelopathies, and is frequently abnormal in individuals with cardiomyopathy. Screening with a 12-lead ECG in older athletes is of limited value given the overwhelming contribution of atherosclerotic CAD to sudden cardiac death. PMID:26738247

  12. Primary erythromelalgia: a review.

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    Tang, Zhaoli; Chen, Zhao; Tang, Beisha; Jiang, Hong

    2015-01-01

    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. Reported cases of PE contain both inherited and sporadic forms. Genetic etiology of PE is mutations on SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Diagnosis of PE is made upon clinical manifestations and screening for mutations on SCN9A. Exclusion of several other treatable diseases/secondary erythromelalgia is also necessary because of the lack of biomarkers specifically for PE. Differential diagnoses can include Fabry disease, cellulites, Raynaud phenomenon, vasculitis and so on. Diagnostic methods often involve complete blood count, imaging studies and thermograph. Treatment for PE is unsatisfactory and highly individualized. Frequently used pain relieving drugs involve sodium channel blockers such as lidocaine, carbamazepine and mexiletine. Novel drugs such as PF-05089771 and TV-45070 could be promising in ameliorating pain symptoms due to their Nav1.7 selectivity. Patients' symptoms often worsen over time and many patients develop ulcerations and gangrenes caused by excessive exposure to low temperature in order to relieve pain. This review mainly focuses on PE and the causative gene SCN9A--its mutations and their effects on Nav1.7 channels' electrophysiological properties. We propose a genotype-channelopathy-phenotype correlation network underlying PE etiology which could provide guidance for future therapeutics. PMID:26419464

  13. One hundred years of migraine research: major clinical and scientific observations from 1910 to 2010.

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    Tfelt-Hansen, Peer C; Koehler, Peter J

    2011-05-01

    Pain research, and headache research in particular, during the 20th century, has generated an enormous volume of literature promulgating theories, questions, and temporary answers. This narrative review describes the most important events in the history of migraine research between 1910 and 2010. Based on the standard textbooks of headache: Wolff's Headache (1948 and 1963) and The Headaches (1993, 2000, and 2006) topics were selected for a historical review. Most notably these included: isolation and clinical introduction of ergotamine (1918); further establishment of vasodilation in migraine and the constrictive action of ergotamine (1938); identification of pain-sensitive structures in the head (1941); Lashley's description of spreading scotoma (1941); cortical spreading depression (CSD) of Leão (1944); serotonin and the introduction of methysergide (1959); spreading oligemia in migraine with aura (1981); oligemia in the wake of CSD in rats (1982); neurogenic inflammation theory of migraine (1987); a new headache classification (1988); the discovery of sumatriptan (1988); migraine and calcitonin gene-related peptide (1990); the brainstem "migraine generator" and PET studies (1995); migraine as a channelopathy, including research from the genetic perspective (1996); and finally, meningeal sensitization, central sensitization, and allodynia (1996). Pathophysiological ideas have evolved within a limited number of paradigms, notably the vascular, neurogenic, neurotransmitter, and genetic/molecular biological paradigm. The application of various new technologies played an important role within these paradigms, in particular neurosurgical techniques, EEG, methods to measure cerebral blood flow, PET imaging, clinical epidemiological, genetic, and molecular biological methods, the latter putting migraine (at least hemiplegic migraine) within a completely new classification of diseases.

  14. Implantable cardioverter defibrillator therapy in pediatric and congenital heart disease patients: a single tertiary center experience in Korea

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    Bo Kyung Jin

    2013-03-01

    Full Text Available Purpose: The use of implantable cardioverter defibrillators (ICDs to prevent sudden cardiac death is increasing in children and adolescents. This study investigated the use of ICDs in children with congenital heart disease. Methods: This retrospective study was conducted on the clinical characteristics and effectiveness of ICD implantation at the department of pediatrics of a single tertiary center between 2007 and 2011. Results: Fifteen patients underwent ICD implantation. Their mean age at the time of implantation was 14.5±5.4 years (range, 2 to 22 years. The follow-up duration was 28.9±20.4 months. The cause of ICD implantation was cardiac arrest in 7, sustained ventricular tachycardia in 6, and syncope in 2 patients. The underlying disorders were as follows: ionic channelopathy in 6 patients (long QT type 3 in 4, catecholaminergic polymorphic ventricular tachycardia [CPVT] in 1, and J wave syndrome in 1, cardiomyopathy in 5 patients, and postoperative congenital heart disease in 4 patients. ICD coils were implanted in the pericardial space in 2 children (ages 2 and 6 years. Five patients received appropriate ICD shock therapy, and 2 patients received inappropriate shocks due to supraventricular tachycardia.During follow-up, 2 patients required lead dysfunction-related revision. One patient with CPVT suffered from an ICD storm that was resolved using sympathetic denervation surgery. Conclusion: The overall ICD outcome was acceptable in most pediatric patients. Early diagnosis and timely ICD implantation are recommended for preventing sudden death in high-risk children and patients with congenital heart disease.

  15. Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals with Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death

    Science.gov (United States)

    Boczek, Nicole J.; Ye, Dan; Jin, Fang; Tester, David J.; Huseby, April; Bos, J. Martijn; Johnson, Aaron J.; Kanter, Ronald; Ackerman, Michael J.

    2016-01-01

    Background A portion of sudden cardiac deaths (SCD) can be attributed to structural heart diseases such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long QT syndrome (LQTS); however, the underlying molecular mechanisms are quite distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, SCD, and congenital heart defects (CHDs). Methods and Results Whole exome sequencing (WES) in combination with Ingenuity Variant Analysis was completed on three affected individuals and one unaffected individual from a large pedigree with concomitant LQTS, HCM, and CHDs and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes, and identified two additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in CaV1.2, and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions Through WES and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and CHDs annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and co-segregation with disease in these pedigrees provides evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype. PMID:26253506

  16. T-Type Calcium Channel: A Privileged Gate for Calcium Entry and Control of Adrenal Steroidogenesis.

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    Rossier, Michel F

    2016-01-01

    Intracellular calcium plays a crucial role in modulating a variety of functions such as muscle contraction, hormone secretion, gene expression, or cell growth. Calcium signaling has been however shown to be more complex than initially thought. Indeed, it is confined within cell microdomains, and different calcium channels are associated with different functions, as shown by various channelopathies. Sporadic mutations on voltage-operated L-type calcium channels in adrenal glomerulosa cells have been shown recently to be the second most prevalent genetic abnormalities present in human aldosterone-producing adenoma. The observed modification of the threshold of activation of the mutated channels not only provides an explanation for this gain of function but also reminds us on the importance of maintaining adequate electrophysiological characteristics to make channels able to exert specific cellular functions. Indeed, the contribution to steroid production of the various calcium channels expressed in adrenocortical cells is not equal, and the reason has been investigated for a long time. Given the very negative resting potential of these cells, and the small membrane depolarization induced by their physiological agonists, low threshold T-type calcium channels are particularly well suited for responding under these conditions and conveying calcium into the cell, at the right place for controlling steroidogenesis. In contrast, high threshold L-type channels are normally activated by much stronger cell depolarizations. The fact that dihydropyridine calcium antagonists, specific for L-type channels, are poorly efficient for reducing aldosterone secretion either in vivo or in vitro, strongly supports the view that these two types of channels differently affect steroid biosynthesis. Whether a similar analysis is transposable to fasciculata cells and cortisol secretion is one of the questions addressed in the present review. No similar mutations on L-type or T-type channels

  17. T-type calcium channel: a privileged gate for calcium entry and control of adrenal steroidogenesis

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    Michel Florian Rossier

    2016-05-01

    Full Text Available Intracellular calcium plays a crucial role in modulating a variety of functions such as muscle contraction, hormone secretion, gene expression or cell growth. Calcium signaling has been however shown to be more complex than initially thought. Indeed, it is confined within cell microdomains and different calcium channels are associated with different functions, as shown by various channelopathies.Sporadic mutations on voltage-operated L-type calcium channels in adrenal glomerulosa cells have been shown recently to be the second most prevalent genetic abnormalities present in human aldosterone-producing adenoma. The observed modification of the threshold of activation of the mutated channels not only provides an explanation for this gain of function but reminds us on the importance of maintaining adequate electrophysiological characteristics to make channels able to exert specific cellular functions. Indeed, the contribution to steroid production of the various calcium channels expressed in adrenocortical cells is not equal and the reason has been investigated for a long time. Given the very negative resting potential of these cells, and the small membrane depolarization induced by their physiological agonists, low threshold T-type calcium channels are particularly well suited for responding under these conditions and conveying calcium into the cell, at the right place for controlling steroidogenesis. In contrast, high threshold L-type channels are normally activated by much stronger cell depolarizations. The fact that dihydropyridine calcium antagonists, specific for L-type channels, are poorly efficient for reducing aldosterone secretion either in vivo or in vitro, strongly supports the view that these two types of channels differently affect steroid biosynthesis.Whether a similar analysis is transposable to fasciculata cells and cortisol secretion is one of the questions addressed in the present review. No similar mutations on L-type or T

  18. Fisiopatologia da enxaqueca Migraine pathophysiology

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    MAURICE B. VINCENT

    1998-12-01

    various imaging procedures during migraine also support the pathophysiological role of spreading depression. Three abnormal loci (chromosomes 1 and 19 have been recently found in familial hemiplegic migraine. This produces abnormalities in the voltage-dependent P/Q Ca channel, specific for the central nervous system, which regulates the release of various neurotransmitters, probably including serotonin. It is possible that a channelopathy underlies the pathophysiology of migraine, as in other paroxysmal neurological disorders secondary to membrane hyperexcitability.

  19. Whole genome and exome sequencing realignment supports the assignment of KCNJ12, KCNJ17, and KCNJ18 paralogous genes in thyrotoxic periodic paralysis locus: functional characterization of two polymorphic Kir2.6 isoforms.

    Science.gov (United States)

    Paninka, Rolf M; Mazzotti, Diego R; Kizys, Marina M L; Vidi, Angela C; Rodrigues, Hélio; Silva, Silas P; Kunii, Ilda S; Furuzawa, Gilberto K; Arcisio-Miranda, Manoel; Dias-da-Silva, Magnus R

    2016-08-01

    Next-generation sequencing (NGS) has enriched the understanding of the human genome. However, homologous or repetitive sequences shared among genes frequently produce dubious alignments and can puzzle NGS mutation analysis, especially for paralogous potassium channels. Potassium inward rectifier (Kir) channels are important to establish the resting membrane potential and regulating the muscle excitability. Mutations in Kir channels cause disorders affecting the heart and skeletal muscle, such as arrhythmia and periodic paralysis. Recently, a susceptibility muscle channelopathy-thyrotoxic periodic paralysis (TPP)-has been related to Kir2.6 channel (KCNJ18 gene). Due to their high nucleotide sequence homology, variants found in the potassium channels Kir2.6 and Kir2.5 have been mistakenly attributable to Kir2.2 polymorphisms or mutations. We aimed at elucidating nucleotide misalignments by performing realignment of whole exome sequencing (WES) and whole genome sequencing (WGS) reads to specific Kir2.2, Kir2.5, and Kir2.6 cDNA sequences using BWA-MEM/GATK pipeline. WES/WGS reads correctly aligned 26.9/43.2, 37.6/31.0, and 35.4/25.8 % to Kir2.2, Kir2.5, and Kir2.6, respectively. Realignment was able to reduce over 94 % of misalignments. No putative mutations of Kir2.6 were identified for the three TPP patients included in the cohort of 36 healthy controls using either WES or WGS. We also distinguished sequences for a single Kir2.2, a single Kir2.5 sequence, and two Kir2.6 isoforms, which haplotypes were named RRAI and QHEV, based on changes at 39, 40, 56, and 249 residues. Electrophysiology records on both Kir2.6_RRAI and _QHEV showed typical rectifying currents. In our study, the reduction of misalignments allowed the elucidation of paralogous gene sequences and two distinct Kir2.6 haplotypes, and pointed the need for checking the frequency of these polymorphisms in other populations with different genetic background. PMID:27008341

  20. Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

    Science.gov (United States)

    Jaffer, Fatima; Avbersek, Andreja; Vavassori, Rosaria; Fons, Carmen; Campistol, Jaume; Stagnaro, Michela; De Grandis, Elisa; Veneselli, Edvige; Rosewich, Hendrik; Gianotta, Melania; Zucca, Claudio; Ragona, Francesca; Granata, Tiziana; Nardocci, Nardo; Mikati, Mohamed; Helseth, Ashley R.; Boelman, Cyrus; Minassian, Berge A.; Johns, Sophia; Garry, Sarah I.; Scheffer, Ingrid E.; Gourfinkel-An, Isabelle; Carrilho, Ines; Aylett, Sarah E.; Parton, Matthew; Hanna, Michael G.; Houlden, Henry; Neville, Brian; Kurian, Manju A.; Novy, Jan; Sander, Josemir W.; Lambiase, Pier D.; Behr, Elijah R.; Schyns, Tsveta; Arzimanoglou, Alexis; Cross, J. Helen; Kaski, Juan P.

    2015-01-01

    , compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable. PMID:26297560

  1. Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a Interacting with Voltage-Gated Sodium Channel Subtype NaV1.4

    Directory of Open Access Journals (Sweden)

    Ji Luo

    2014-07-01

    Full Text Available Voltage-gated sodium channels (VGSCs; NaV1.1–NaV1.9 have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure–function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX-V (also known as β-theraphotoxin-Cj2a is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC50 values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on NaV1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC50 value of 5.12 nM, compared with IC50 values of 61.7–2700 nM for other heterologously expressed NaV1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on NaV1.4 and demonstrate that the bioactive face of JZTX-V is composed of three hydrophobic (W5, M6, and W7 and two cationic (R20 and K22 residues. Our results establish that, consistent with previous assumptions, JZTX-V is a Janus-faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels.

  2. Self-assembled nanoparticles based on the c(RGDfk peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy

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    Liu L

    2014-07-01

    Full Text Available Li Liu,1 Xiaoxia Liu,1 Qian Xu,1 Ping Wu,2 Xialin Zuo,3 Jingjing Zhang,1 Houliang Deng,1 Zhuomin Wu,1 Aimin Ji1 1Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, People’s Republic of China; 3Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, People’s Republic of China Abstract: The clinical application of small interfering RNA (siRNA has been restricted by their poor intracellular uptake, low serum stability, and inability to target specific cells. During the last several decades, a great deal of effort has been devoted to exploring materials for siRNA delivery. In this study, biodegradable, tumor-targeted, self-assembled peptide nanoparticles consisting of cyclo(Arg–Gly–Asp–d–Phe–Lys-8–amino–3,6–dioxaoctanoic acid–β–maleimidopropionic acid (hereafter referred to as RPM were found to be an effective siRNA carrier both in vitro and in vivo. The nanoparticles were characterized based on transmission electron microscopy, circular dichroism spectra, and dynamic light scattering. In vitro analyses showed that the RPM/VEGFR2-siRNA exhibited negligible cytotoxicity and induced effective gene silencing. Delivery of the RPM/VEGFR2 (zebrafish-siRNA into zebrafish embryos resulted in inhibition of neovascularization. Administration of RPM/VEGFR2 (mouse-siRNA to tumor-bearing nude mice led to a significant inhibition of tumor growth, a marked reduction of vessels, and a downregulation of VEGFR2 (messenger RNA and protein in tumor tissue. Furthermore, the levels of IFN-α, IFN-γ, IL-12, and IL-6 in mouse serum, assayed via enzyme-linked immunosorbent assay, did not indicate any immunogenicity of the RPM/VEGFR2

  3. Cardiac HCN Channels: From Basic to Bedside%心脏HCN通道:从基础到临床

    Institute of Scientific and Technical Information of China (English)

    范新荣; 王超

    2012-01-01

    研究表明超极化激活环核苷酸门控阳离子通道(HCN通道)大量分布于心脏及神经系统的特定部位,其介导的起搏电流引起窦房结细胞舒张期去极化,从而在心脏自主搏动及心律的调节等方面发挥着十分重要的生理功能.目前,已克隆得到4种HCN亚型基因,并通过功能表达分析指出各种HCN亚型具有不同的电生理学特性.但是目前有关HCN逶道在心脏电活动中的生理及病理生理机制仍未完全阐明.本篇综述旨在详细阐述心脏HCN通道的生物物理学特性、心脏通道蛋白表达、各种HCN通道突变引起的离子通道疾病以及几种通道阻滞药物电药理学特性的研究进展.%Hyperpolarization-activated cyclic nucleotide-gated ( HCN) channels, responsible for pacemaker current, are widely expressed in heart and nervous system, and HCN mediated currents play a key role in generation and regulation of diastolic depolarization which controls the spontaneous rate in sinoatrial node myocytes. Recently, four mammalian HCN isoforms, respectively termed HCN1-4, have been cloned. When heterologously expressed, each of the four HCN subunits has different electrophysiological properties. However, the physiological and pathophysiological mechanisms of HCN channels on cardiac electric activity have not been revealed completely. In this review we summarize recent insight into the biophysical characteristics of cardiac HCN channels, distribution of channels in heart, five kinds of HCN-related ionic channelopathies and electropharmacological properties of several If blockers.

  4. Making a match for Valinomycin: steroidal scaffolds in the design of electroneutral, electrogenic anion carriers.

    Science.gov (United States)

    Valkenier, Hennie; Davis, Anthony P

    2013-12-17

    The natural product Valinomycin is a well-known transmembrane cation carrier. Despite being uncharged, this molecule can extract potassium ions from water without counterions and ferry them through a membrane interior. Because it only transports positive ions, it is electrogenic, mediating a flow of charge across the membrane. Equivalent agents for anions would be valuable research tools and may have therapeutic applications, especially in the treatment of "channelopathies" such as cystic fibrosis. However, no such molecules have been found in nature. In this Account, we describe our research toward synthetic and rationally designed "anti-Valinomycins". As our core approach to this problem, we used the steroid nucleus, provided by cholic acid, as a scaffold for the assembly of anion receptors. By positioning H-bond donors on this framework, especially urea and thiourea groups in conformationally constrained axial positions, we created binding sites capable of exceptionally high affinities (up to 10(11) M(-1) for R4N(+)Cl(-) in chloroform). The extended hydrocarbon surface of the steroid helped to maintain compatibility with nonpolar media. When we tested these "cholapods" for chloride transport in vesicles, they provided the first evidence for electrogenic anion transport mediated by electroneutral organic carriers: in other words, they are the first authenticated anti-Valinomycins. They also proved active in live cells that we grew and assayed in an Ussing chamber. In subsequent work, we have shown that the cholapods can exhibit very high activities, with transport observed down to carrier/lipid ratios of 1:250,000. We also understand some of the effects of structure on the activity of these molecules. For example, in most cases, powerful transporters also act as powerful receptors. On the other hand, some modifications which favor binding do not promote transport. We gained functional advantages by cyclizing the cholapod architecture, which encloses the anion

  5. Myokymia of lower limbs for over one year

    Directory of Open Access Journals (Sweden)

    Jing ZHAO

    2015-09-01

    . Cerebrospinal fluid (CSF contained protein 0.56 g/L (0.15-0.45 g/L, and IgG 49.8mg/L. Cytology, myelin basic protein (MBP, glucose, specific oligoclonal band (SOB, Gram staining and culture, voltage-gated potassium channel (VGKC antibody, N⁃methyl⁃D⁃aspartate receptor (NMDAR antibody, GM1 antibody and so on were all negative. Reexamination EMG showed typical fasciculations, doublets and triplets of spontaneous motor unit potentials (MUPs. Repetitive nerve stimulation (RNS and motor-evoked potential (MEP were unremarkable. This is a unique patient with clinical and electrophysiological features of Isaacs syndrome (neuromyotonia, NMT including myokymia, muscle stiffness and continuous motor unit activity in association with autonomic dysfunction. NMT is a disorder of generalized peripheral nerve hyperexcitability (PNH, manifesting as spontaneous, continuous muscle activity of peripheral nerve origin. It is characterized clinically by muscle twitching at rest (visible myokymia and cramps, which can be triggered by voluntary or induced muscle contraction, and impaired muscle relaxation, or pseudomyotonia. Patients may exhibit excessive sweating, paraesthesia or mild muscle weakness. An episodic syndrome of hyperhidrosis associated with VGKC-complex antibodies has also been described. However, this patient did not exhibit neuromuscular manifestations. Unlike acquired NMT, this patient did not respond to monotherapy of carbamazepine and phenytoin. But low dose carbamazepine combined with IVIG later showed some benefit. The patient was clinically similar to autoimmune NMT except for the paroxysmal course and marked pain, which was a notable and extreme feature. The nature of this disease exhibits frequent paroxysmal attacks since genetic channelopathies exhibit an episodic feature. However, antibodies to VGKC-complex were not identified, so the pathogenesis of the newly described clinical syndrome was still unknown. DOI: 10.3969/j.issn.1672-6731.2015.09.016

  6. Repolarización precoz: de benigna a muerte súbita

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    Guillermo Trout

    2013-11-01

    arrhythmias, which are 6-14% in patients without structural heart disease and is determined by genetic abnormalities that affect ion channels or idiopathic as early repolarization syndrome and idiopathic ventricular fibrillation that generate 10% of these deaths. The review addresses the pathophysiology of RP, in order to understand the mechanisms by which it is associated with malignant arrhythmias. In addition, to differentiate this pattern of others who also produce ST elevation and clarify the approach and current recommendations for diagnosis and management. Keywords: Arrhythmias; cardiac; channelopathies; sudden; cardiac; death. Fuente: Mesh Database

  7. New migraine preventive options: an update with pathophysiological considerations Novas opções para o tratamento preventivo da migrânea: revisão com considerações fisiopatológicas

    Directory of Open Access Journals (Sweden)

    Marcelo E. Bigal

    2002-01-01

    Full Text Available BACKGROUND: The pharmacological treatment of migraine may be acute or preventive. Frequent, severe and long-lasting migraine attacks require prophylaxis. Multiple threads of research over the last 15 years have led to the concept that migraine is generated from a hyperexcitable brain. A variety of causes for hyperexcitability of the brain in migraine have been suggested. These causes include low cerebral magnesium levels, mitochondrial abnormalities, dysfunctions related to increased nitric oxide or the existence of a P/Q type calcium channelopathy. The better knowledge about migraine pathophisiology led us to discuss new treatment options. OBJECTIVES: The aim of the present study is to present an evidence-based review of some new drugs or some agents that even though available for a long time, are not frequently used. METHODS/RESULTS: We present a review of anticonvulsants with various mechanisms of action such as lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam and zonisamide. We also review natural products, like riboflavin and magnesium, botulinum toxin A, a specific CGRP antagonist and the anti-asthma medication montelukast, with pathophysiological discussion. CONCLUSIONS: We aimed to present an update of newer or less frequently used preventive migraine therapies, drugs that might reduce the burden and the costs of a disease that should be considered as a public health problem all around the world.INTRODUÇÃO: O tratamento farmacológico da migrânea pode ser dividido em agudo e preventivo. Crises de migrânea severas, de longa duração e incapacitante requerem profilaxia. Múltiplas linhas de pesquisa ao longo dos últimos 15 anos sedimentaram o conceito de que a migrânea é gerada a partir de um cérebro hiperexcitável. Variadas causas para essa hiperexcitabilidade têm sido sugeridas e incluem baixo nível de magnésio cerebral, anormalidades mitocondriais, disfunções relacionadas ao óxido nítrico e a existência de

  8. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

    Science.gov (United States)

    2016-09-01

    -epilepsy-intellectual Disability Syndrome Due to TUD Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to KIAA0226 Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome; Autosomal Recessive Cerebellar Ataxia With Late-onset Spasticity; Autosomal Recessive Cerebellar Ataxia Due to STUB1 Deficiency; Autosomal Recessive Cerebellar Ataxia Due to a DNA Repair Defect; Autosomal Recessive Cerebellar Ataxia - Saccadic Intrusion; Autosomal Recessive Cerebellar Ataxia - Psychomotor Retardation; Autosomal Recessive Cerebellar Ataxia - Blindness - Deafness; Autosomal Recessive Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to a Polyglutamine Anomaly; Autosomal Dominant Spinocerebellar Ataxia Due to a Point Mutation; Autosomal Dominant Spinocerebellar Ataxia Due to a Channelopathy; Autosomal Dominant Spastic Ataxia Type 1; Autosomal Dominant Spastic Ataxia; Autosomal Dominant Optic Atrophy; Ataxia-telangiectasia Variant; Ataxia-telangiectasia; Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy; Autosomal Dominant Cerebellar Ataxia Type 4; Autosomal Dominant Cerebellar Ataxia Type 3; Autosomal Dominant Cerebellar Ataxia Type 2; Autosomal Dominant Cerebellar Ataxia Type 1; Autosomal Dominant Cerebellar Ataxia; Ataxia-telangiectasia-like Disorder; Ataxia-intellectual Disability-oculomotor Apraxia-cerebellar Cysts Syndrome; Ataxia-deafness-intellectual Disability Syndrome; Ataxia With Vitamin E Deficiency; Ataxia With Dementia; Ataxia Neuropathy Spectrum; Ataxia - Tapetoretinal Degeneration; Ataxia - Photosensitivity - Short Stature; Ataxia - Pancytopenia; Ataxia - Oculomotor Apraxia Type 1; Ataxia - Hypogonadism - Choroidal Dystrophy; Ataxia - Other; Ataxia - Genetic Diagnosis - Unknown; Acquired Ataxia; Adult-onset Autosomal Recessive Cerebellar Ataxia; Alcohol Related Ataxia

  9. Familial Hemiplegic Migraine and Spreading Depression

    Directory of Open Access Journals (Sweden)

    Hadi KAZEMI

    2014-07-01

    mutations. Neurology 2009 31;72(13:1178-83.Thomsen LL, Ostergaard E, Olesen J, Russell MB. Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine. Neurology 2003;60(4:595-601.van den Maagdenberg AM, Haan J, Terwindt GM, Ferrari MD. Migraine: gene mutations and functional consequences. Curr Opin Neurol 2007; 20:299–305.Gritz SM, Radcliffe RA. Genetic effects of ATP1A2 in familial hemiplegic migraine type II and animal models. Hum Genomics 2013;5;7:8.Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543–552.Gargus JJ, Tournay A. Novel Mutation Confirms Seizure Locus SCN1A is Also Familial Hemiplegic Migraine Locus FHM3.PediatrNeurol 2007;37:407-410.Tottene A, Conti R, Fabbro A, Vecchia D, Shapovalova M, Santello M, et al.Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v2.1 knockin migraine mice. Neuron 2009;61(5:762-73.Terwindt GM, Ophoff RA, Haan J, Sandkuijl LA, Frants RR, Ferrari MD. Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Dutch Migraine Genetics Research Group. Eur J Hum Genet 1998;6(4:297-307.Terwindt GM, Ophoff RA, van Eijk R, Vergouwe MN, Haan J, Frants RR, et al. Dutch Migraine Genetics Research Group. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 2001;56(8:1028-32.Franceschini A, Vilotti S, Ferrari MD, van den Maagdenberg AM, Nistri A, Fabbretti E. TNFα levels and macrophages expression reflect an inflammatory potential of trigeminal ganglia in a mouse model of familial hemiplegic migraine. PLoS One 2013;8:e52394.Kodangattil JN, Möddel G, Müller, M, Weber W, Gorji A.The inflammatory chemokine CXCL10 modulates synaptic plasticity and neuronal activity in the hippocampus. European Journal of Inflammation 2012;10(3:311-328Leao AAP