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At least 19 recordsLinked to original sources

PubMed2006

Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy.

OBJECTIVES: Recently, two ion channels associated with congenital long QT syndrome, the SCN5A-encoded Nav1.5 sodium channel and the KCNH2-encoded HERG potassium channel (IKr), have been found on gastrointestinal smooth muscle and interstitial cells of Cajal. The aim of this study was to determine if the cardiac channelopathy-associated mutations in SCN5A or KCNH2 are associated with GI symptom complexes. METHODS: Mayo Clinic's Sudden Death Genomics Laboratory performed comprehensive mutational analysis on index patients referred for long QT syndrome genetic testing and their family members thus establishing a cohort of families for which the genotype status for SCN5A or KCNH2 is known. A valid GI symptom questionnaire was mailed to all family members (both genotype positive and genotype negative) in this cohort. The association between cardiac channel genotype and GI symptoms was assessed by logistic regression adjusted for age and sex. RESULTS: Two hundred and nineteen (43% of 529) subjects returned the questionnaire. Fifty percent of the subjects with an SCN5A mutation reported abdominal pain compared to only 13% of controls (OR 5.7; 95% CI 1.3-24.4). Over 65% of subjects with an SCN5A mutation reported a GI symptom complex compared to 28% of controls (OR 5.2; 95% CI 1.5-18.3). No associations with KCNH2 genotype status were detected. CONCLUSIONS: This study is the first to suggest an association between a well-defined cardiac channelopathy and GI symptoms. The role of sodium channelopathies in the pathogenesis of digestive diseases merits exploration.

Adolescent↗

PubMed2001

Disorders of membrane channels or channelopathies.

OBJECTIVE: To review the structure and function of membrane ion channels with special emphasis on inherited nervous system channel disorders or channelopathies. RESULTS: Channels are pores in the cell membrane. Through these pores ions flow across the membrane and depolarize or hyperpolarize the cell. Channels can be classified into 3 types: non-gated, directly gated and second messenger gated channels. Among the important directly gated channels are voltage gated (Na(+), K(+), Ca(2+), Cl(-)) and ligand gated (ACh, Glutamate, GABA, Glycine) channels. Channels are macromolecular protein complexes within the lipid membrane. They are divided into distinct protein units called subunits. Each subunit has a specific function and is encoded by a different gene. The following inherited channelopathies are described. (1) Sodium channelopathies: familial generalized epilepsy with febrile seizures plus, hyperkalemic periodic paralysis, paramyotonias, hypokalemic periodic paralysis; (2) potassium channelopathies: benign infantile epilepsy, episodic ataxia type 1; (3) calcium channelopathies: episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, hypokalemic periodic paralysis, central core disease, malignant hyperthermia syndrome, congenital stationary night blindness; (4) chloride channelopathies: myotonia congenitas; (5) ACh receptor channelopathies: autosomal dominant frontal lobe nocturnal epilepsy, congenital myasthenic syndromes; (6) glycine receptor channelopathies: hyperekplexia. CONCLUSIONS: Studies of human inherited channelopathies have clarified the functions of many ion channels. More than one gene may regulate a function in a channel, thus different genetic mutations may manifest with the same disorder. The complex picture of the genetic and molecular structures of channels will require frequent updates.

Animals↗

PubMed2003

The skeletal muscle channelopathies: distinct entities and overlapping syndromes.

PURPOSE OF REVIEW: This review outlines recent advances in clinical, genetic and molecular aspects of skeletal muscle channelopathies. RECENT FINDINGS: A new molecular genetic classification of skeletal muscle channelopathies has now emerged. This genetic classification complements previous clinical classifications. It is evident that there is considerable phenotypic diversity associated with dysfunction of a given muscle ion channel. Treatment response is likely to be related to genotype. DNA-based diagnosis is now achievable in most patients. SUMMARY: Ion channel dysfunction is now known to be the basis for familial variants of common neurological diseases such as migraine and epilepsy. Such discoveries were made possible through earlier work on the skeletal muscle channelopathies which remain the best understood example of all channelopathies. Classification of muscle channelopathies initially relied upon their specific clinical and neurophysiological features. This classification remains useful, but recent advances have led to a new system of classification based on the underlying molecular genetic defect. Recent advances have highlighted the broad phenotypic spectrum of muscle channelopathies and remarkable genetic heterogeneity is now recognized. DNA-based diagnosis is now available and should be achieved in all patients. Accurate genetic diagnosis is of major importance for accurate prognosis, for genetic counselling and has implications for therapeutics.

Animals↗

PubMed2001

Acquired channelopathies in nerve injury and MS.

Although neurophysiologic doctrine has traditionally referred to "the" voltage-gated sodium channel, it is now clear that there are at least nine genes that encode molecularly and physiologically distinct sodium channels. Mutations of sodium channel genes provide a basis for genetic channelopathies. Dysregulated expression of sodium channels due to alterations in activity of nonmutated channel genes, on the other hand, can produce acquired channelopathies. Two examples of acquired channelopathies are discussed in this article. Recent research has established that peripheral nerve injury can provoke an acquired channelopathy in spinal sensory neurons; axonal transection triggers the turning-off of some previously active sodium channel genes and the turning-on of at least one previously silent sodium channel gene, a set of molecular changes that can result in hyperexcitability of these cells. Emerging evidence also suggests that an acquired channelopathy, characterized by abnormal expression of sensory neuron specific sodium channels that can alter impulse trafficking within Purkinje cells, may contribute to the pathophysiology of MS. Subtype-specific drugs that selectively modulate various types of channels probably will soon be developed. The acquired channelopathies associated with nerve injury and MS may thus represent prototype disorders that present therapeutic opportunities.

Axons↗

PubMed2026

Genetic Research on Cardiac Channelopathies in African and African-Descent Populations: A Scoping Review.

Cardiac channelopathies are inherited arrhythmias that can lead to sudden cardiac death. Despite Africa's extensive genomic diversity, African and African-descent populations remain underrepresented in genetic research, creating gaps in variant interpretation and clinical care. This scoping review aims to map the extent, range, and nature of genetic research on cardiac channelopathies in these populations and to identify key geographic, thematic, and methodological gaps. Using the Joanna Briggs Institute scoping review methodology and the Population-Concept-Context framework, systematic searches in PubMed, Embase, and Web of Science identified original human studies on cardiac channelopathies with genetic data. Extracted variables included study characteristics, populations, types of channelopathies, and reported genes and variants. Forty-four studies met the inclusion criteria. Most studies originated from the United States and South Africa, while West, Central, and East Africa were largely underrepresented. US Black individuals and South African individuals of continental African or African-descended ancestry (excluding populations of European descent such as Cape Afrikaner people) were the most studied groups, with other continental African groups rarely included. Long QT syndrome was the predominant focus, and SCN5A, KCNQ1, and KCNH2 were the most frequently analyzed genes. Many of the genetic variants discussed remained of uncertain significance due to limited functional validation and the underrepresentation of African genomes in reference databases. Genetic research on cardiac channelopathies in populations of African ancestry is limited, restricting variant interpretation, counseling, and risk prediction. Broader African inclusion, expanded gene screening, and functional studies are essential to improve diagnostics and promote equity in genomic medicine.

Humans↗

PubMed2004

Acquired neuronal channelopathies in HIV-associated dementia.

A gene expression profile of the human brain cortex was performed in people with HIV-1-associated dementia (HAD) using Affymetrix HG-U133 chips. Messenger RNA transcripts in middle frontal gyrus from subjects with HAD or milder neurocognitive dysfunction were compared to HIV-negative people. The analysis focused on ionic conductance carriers that control membrane excitation. Overexpressed ionic channel genes in brain cortex of subjects with dementia included (1) a calcium-driven K+ channel that prolongs afterhyperpolarization (AHP) current, (2) a leak type of K+ channel that prolongs the AHP, (3) an adenosine receptor that modulates cationic current via G proteins, (4) a G protein-coupled serotonin receptor that modulates cyclic AMP-linked current transduction, (5) a G protein-coupled dopamine receptor, (6) a GABA receptor subunit that conducts chloride current. Underexpressed current generators in the demented subjects included (1) two voltage-gated K+ channels that influence refractory periods and the onset of AHP, (2) a Na+ channel subunit that modifies current inactivation and the onset of the AHP, (3) a neuronal type of voltage-sensitive Ca+ channel that controls postsynaptic membrane excitability, (4) a metabotropic glutamate receptor that regulates cationic gating via G protein coupling, (5) A specific Galpha protein that transduces metabotropic cationic current, (6) an NMDA receptor subunit, (7) a glycine receptor subunit that modulates chloride current. These gene expression shifts probably occurred in neurons because they were not present in gyral white matter. Acquired neuronal channelopathies were not associated with a generalized shift of neuronal or glial cell markers, which suggest that they were not an artifact produced by neurodegeneration and/or glial cell proliferation. Channelopathies were not correlated with a generalized increase of inflammatory cell transcripts and were present in demented people without, and with HIV encephalitis (HIVE). We surveyed experimentally induced perturbations of these channels to determine the implications for brain function. Eleven experimental channelopathies produced decreased neuronal firing frequencies and pacemaker rates in model neurons; seven channelopathies increase neuronal firing rates experimentally. The implied disruption of neuronal excitability is consistent with some features of HAD, including its potential reversibility after HIV-1 replication is suppressed, the abnormal electroencephalographic recordings, the lack of clear-cut correlation with neurodegeneration and the lack of strict correlation with brain inflammation. The channelopathy concept may have wide relevance to the subcortical dementias.

AIDS Dementia Complex↗

PubMed2004

[Electrophysiological testing in muscle channelopathies].

Electrodiagnostic testing should always be tailored to the clinical setting; in the muscle channelopathies, provocative tests are essential to demonstrate the modifications of the muscle excitability. When a permanent muscle weakness is present, a post-exercise (or post-tetanic) potentiation should be search to demonstrate a presynaptic neuromuscular channelopathy; when the weakness is fluctuating it is useful to perform repetitive nerve stimulation to see if a decrement is present or if the jitter is prolonged, indicative of a postsynaptic neuromuscular channelopathy; when the weakness is episodic, the prolonged exercise test is the only test to demonstrate the appearance of a late post-exercise decrement (sodium and calcium channelopathies), and when a myotonic reaction is seen to search the myotonic discharges by needle emg. The concomitant presence of myotonic discharges and abnormal decrement of the motor responses during repetitive nerve stimulation train depend on the type of mutations in the chloride gene and the amount of CTG repeats in myotonic dystrophy type 1. In paramyotonia congenita there a prolonged decrement when the tests are carried out with cooling the recorded muscle. Electrophysiological testings appear therefore useful to diagnose muscle channelopathies but also give information about the prognosis of the disorder; they could also be viewed as useful tests to predict response to treatments.

Electrophysiology↗

PubMed1999

Neurological channelopathies: diagnosis and therapy in the new millennium.

Rapid progress in the complementary fields of molecular genetics and cellular electrophysiology has led to a better understanding of many disorders which are caused by ion channel dysfunction. These channelopathies may manifest in a multitude of ways depending on the tissue specificity of the channel that is affected. Several important general medical conditions are now known to be channelopathies but the neurological members of this family are amongst the best characterized. Over recent years, ion channel dysfunction in skeletal muscle in particular has emerged as a paradigm for understanding neurological ion channel disorders. This review concentrates mainly on the diseases caused by dysfunction of the voltage-gated ion channels. We initially focus on the skeletal muscle channelopathies (the periodic paralyses, malignant hyperthermia, paramyotonia congenita and myotonia congenita). The central nervous system channelopathies are then explored, with particular reference to the advances which have implications for understanding the mechanisms of common neurological disorders such as epilepsy and migraine. Looking towards the new millennium, DNA-based diagnosis will become a realistic proposition for most neurological channelopathies. Furthermore, it seems likely that new therapies will be designed based on genotype and mode of ion channel dysfunction.

Animals↗

PubMed2006

Genetic neurological channelopathies.

Ion channels are crucial for the normal function of excitable tissues such as neurons and skeletal muscle. Since the discovery that the paroxysmal muscle disorder periodic paralysis is caused by mutations in genes that encode voltage-gated ion channels, many genetic neurological channelopathies have been defined. These channelopathies include epilepsy syndromes that show a mendelian pattern of inheritance, certain forms of migraine and disorders of cerebellar function, as well as periodic paralysis. The clinical diversity of these disorders relates in part to the tissue-specific expression of the dysfunctional channel, but is probably influenced by other, as yet unidentified, genetic and non-genetic factors. The complementary disciplines of molecular genetics and cellular and in vitro electrophysiology have resulted in significant advances in understanding of the basic molecular pathophysiology of some of these disorders. The single-gene neurological channelopathies are generally regarded as a paradigm for understanding common human paroxysmal disorders, such as epilepsy and migraine. This article reviews the clinical and molecular features of some of the single-gene channelopathies that affect muscle and brain. The possible role of ion-channel functional and genetic variation in predisposing individuals to common forms of human epilepsy and migraine are also considered. The implications for accurate genetic diagnosis and therapeutic intervention are highlighted.

Humans↗

PubMed2001

The skeletal muscle channelopathies: basic science, clinical genetics and treatment.

The human neurological channelopathies are a rapidly expanding group of mainly genetic conditions that are characterized by dysfunction of membrane-bound glycoproteins (ion channels). The skeletal muscle channelopathies were the first to be characterized in this group. In recent years significant progress has been made in our understanding of the molecular genetic and cellular electrophysiological bases of these disorders. DNA-based diagnosis is now a reality for many of the channelopathies. The advances made have implications for both genetic counselling and for tailoring treatment to specific channelopathies.

Humans↗

PubMed2003

Channelopathies as a genetic cause of epilepsy.

PURPOSE OF REVIEW: This review describes the significant number of new gene associations with epilepsy syndromes that have emerged during the past year, together with additional mutations and new electrophysiological data relating to previously known gene associations. RECENT FINDINGS: Autosomal dominant juvenile myoclonic epilepsy was demonstrated to be a channelopathy associated with a GABA(A) receptor, alpha1 subunit mutation. Benign familial neonatal infantile seizures were delineated as another channelopathy of infancy, by molecular characterization of sodium channel, alpha2 subunit defects. A sodium channel, alpha2 subunit defect was previously found to be associated with generalized epilepsy with febrile seizures plus. Similarly, the clinical spectrum associated with potassium channel, KQT-like mutations was extended to include the channelopathy myokymia and neonatal epilepsy. Mutations in the non-ion channel genes, leucine-rich, glioma inactivated 1 gene and Aristaless related homeobox gene, have emerged as important causes of their specific syndromes, with mutations in the latter gene frequently underlying X-linked mental retardation with epilepsy. SUMMARY: All but one of the idiopathic epilepsies with a known molecular basis are channelopathies. Where the ion channel defects have been identified, however, they generally account for a minority of families and sporadic cases with the syndrome in question. The data suggest that ion channel mutations of large effect are a common cause of rare monogenic idiopathic epilepsies, but are rare causes of common epilepsies. Additive effects of genetic variation, perhaps within the same ion channel gene families, are likely to underlie the common idiopathic generalized epilepsies with complex inheritance. The genetics of epilepsy is progressing rapidly toward a more detailed molecular dissection and definition of syndromes.

Calcium Channels↗

PubMed2003

Muscle biopsy and cell cultures: potential diagnostic tools in hereditary skeletal muscle channelopathies.

Hereditary muscle channelopathies are caused by dominant mutations in the genes encoding for subunits of muscle voltage-gated ion channels. Point mutations on the human skeletal muscle Na+ channel (Nav1.4) give rise to hyperkalemic periodic paralysis, potassium aggravated myotonia, paramyotonia congenita and hypokalemic periodic paralysis type 2. Point mutations on the human skeletal muscle Ca2+ channel give rise to hypokalemic periodic paralysis and malignant hyperthermia. Point mutations in the human skeletal chloride channel CIC-1 give rise to myotonia congenita. Point mutations in the inwardly rectifying K+ channel Kir2.1 give rise to a syndrome characterized by periodic paralysis, severe cardiac arrhythmias and skeletal alterations (Andersen's syndrome). Involvement of the same ion channel can thus give rise to different phenotypes. In addition, the same mutation can lead to different phenotypes or similar phenotypes can be caused by different mutations on the same or on different channel subtypes. Bearing in mind, the complexity of this field, the growing number of potential channelopathies (such as the myotonic dystrophies), and the time and cost of the genetic procedures, before a biomolecular approach is addressed, it is mandatory to apply strict diagnostic protocols to screen the patients. In this study we propose a protocol to be applied in the diagnosis of the hereditary muscle channelopathies and we demonstrate that muscle biopsy studies and muscle cell cultures may significantly contribute towards the correct diagnosis of the channel involved. DNA-based diagnosis is now a reality for many of the channelopathies. This has obvious genetic counselling, prognostic and therapeutic implications.

Adult↗

PubMed2005

[The spectrum of hereditary skeletal-muscle channelopathies].

Channelopathies are a heterogeneous group of genetic diseases in which a defective ion channel is responsible for the symptoms. They manifest as diseases of the heart, brain or skeletal muscle. Hereditary skeletal-muscle channelopathies are characterised by myotonia, periodic paralysis or a combination of both and can be categorised as chloride, sodium and calcium channelopathies. When there is myotonia, the skeletal-muscle membrane is overexcited. In cases of periodic paralysis, the skeletal-muscle membrane is inactive. It is difficult to classify hereditary muscle channelopathies on the basis of clinical criteria only. A more reliable diagnosis is made using DNA analysis. Scientific research should focus on genotype-phenotype relationships.

Humans↗

PubMed2006

Channeling studies in yeast: yeast as a model for channelopathies?

Regulation of the concentration of ions within a cell is mediated by their specific transport and sequestration across cellular membranes. This regulation constitutes a major factor in the maintenance of correct cellular homeostasis, with the transport occurring through the action of a large number of different channel proteins localized to the plasma membrane as well as to various organelles. These ion channels vary in specificity from broad (cationic vs anionic) to highly selective (chloride vs sodium). Mutations in many of these channels result in a large number of human diseases, collectively termed channelopathies. Characterization of many of these channels has been undertaken in a variety of both prokaryotic and eukaryotic organisms. Among these organisms is the budding yeast Saccharomyces cerevisiae. Possessing a fully annotated genome, S. cerevisiae would appear to be an ideal organism in which to study this class of proteins associated to diseases. We have compiled and reviewed a list of yeast ion channels, each possessing a human homolog implicated in a channelopathy. Although yeast has been used for the study of other human disease, it has been under utilized for channelopathy research. The utility of using yeast as a model system for studying ion channels associated to human disease is illustrated using yeast lacking the GEF1 gene product that encodes the human homolog to the chloride channel CLC-3.

Animals↗

PubMed2000

Exercise test in muscle channelopathies and other muscle disorders.

We studied the percentage change in compound muscle action potential (CMAP) amplitude and area during and after a 5-min maximal contraction of the muscle. The exercise test (ET) was performed on 64 patients with different muscle disorders and on 46 normal controls. The range of normal ET values was defined as the mean + 2 SD of the control values. The mean sensitivity of the test was 63% in the whole group with ion channel muscle disorders, the highest sensitivity being seen in primary periodic paralysis (81%) and the lowest in chloride channelopathies (17%). In thyrotoxic periodic paralysis, the ET was abnormal in the three of the four patients studied. In patients with myotonic dystrophy, a smaller than normal increase in CMAP amplitude occurred during and after exercise, whereas in proximal myotonic myopathy a normal initial increase in CMAP amplitude was followed by an abnormal decrement. We conclude that the ET can be of use in confirming abnormal muscle membrane excitability in patients with calcium and sodium channelopathies and thyrotoxic periodic paralysis. In chloride channelopathy, the test may also be abnormal, but shows no, or only a small, increase in amplitude or area in the immediate postexercise period. The test may also be abnormal in proximal myotonic myopathy, but is normal in myotonic dystrophy.

Action Potentials↗

PubMed2004

L-type Ca2+ channels in Ca2+ channelopathies.

Voltage-gated L-type Ca2+ channels (LTCCs) mediate depolarization-induced Ca2+ entry in electrically excitable cells, including muscle cells, neurons, and endocrine and sensory cells. In this review we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within pore-forming alpha1 subunits causing incomplete congenital stationary night blindness, malignant hyperthermia sensitivity or hypokalemic periodic paralysis. However, studies in mice revealed that LTCC dysfunction also contributes to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Ca(v)2.1 alpha1 in tottering mice. Ca2+ channelopathies provide exciting molecular tools to elucidate the contribution of different LTCC isoforms to human diseases.

Animals↗

PubMed2006

Autoimmune channelopathies and related neurological disorders.

Ion channels are crucial elements in neuronal signaling and synaptic transmission, and defects in their function are known to underlie rare genetic disorders, including some forms of epilepsy. A second class of channelopathies, characterized by autoantibodies against ligand- and voltage-gated ion channels, cause a variety of defects in peripheral neuromuscular and ganglionic transmission. There is also emerging evidence for autoantibody-mediated mechanisms in subgroups of patients with central nervous system disorders, particularly those involving defects in cognition or sleep and often associated with epilepsy. In all autoimmune channelopathies, the relationship between autoantibody specificity and clinical phenotype is complex. But with this new information, autoimmune channelopathies are detected and treated with increasing success, and future research promises new insights into the mechanisms of dysfunction at neuronal synapses and the determinants of clinical phenotype.

Animals↗

PubMed2004

Sudden cardiac death and channelopathies: a review of implantable defibrillator therapy.

This article focuses on implantable cardioverter-defibrillator (ICD) therapy in the child/adolescent who is predisposed to sudden cardiac death because of an underlying channelopathy. As such, the primary channelopathies are reviewed briefly. Next, the history of the ICD device and the technological advancements that have enabled its use in pediatrics are discussed. Finally, the clinical experience with ICDs in the young is summarized and general indications for device therapy in young patients who have a channelopathy are provided.

Adolescent↗