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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Potassium channel dysfunction has been implicated in a variety of genetic and acquired neurological disorders that are collectively referred to as the potassium channelopathies. These include acquired neuromyotonia, episodic ataxia type-1, hereditary deafness syndromes, benign familial neonatal convulsions and hypokalaemic periodic paralysis. Insight into potassium channel structure and function is crucial to understanding the pathophysiology of these conditions. This article describes potassium channel structure and function and then outlines what is known about the immunology and genetics of the neurological potassium channelopathies.
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PMID:Neurological potassium channelopathies. 1111 May 85

1. The conventional approach to understanding the structure and properties of ion channels has been to use physiological characterization. 2. Purification and molecular cloning of ion channel genes has enabled more detailed structure-function analyses to be undertaken. 3. An alternative approach to the identification of genes of pathophysiological importance has been the use of genetic linkage approaches and positional cloning or positional candidate analysis of ion channel genes. 4. Using genetic approaches, mutations have been described that cause inherited neurological disorders of neurons (e.g. epilepsy, migraine, deafness, ataxia and startle disease), skeletal muscle (myotonia, malignant hyperthermia, periodic paralysis and myasthenia) and cardiac muscle (long QT syndrome and ventricular fibrillation). 5. For each disease, gene structure-function analyses of the mutant alleles have provided further insights into the biology of ion channels. 6. The present brief review examines the methods used in genetic linkage studies and positional cloning of disease genes. Understanding how ion channel gene mutations give rise to dysfunctional channels will be important in defining and treating the episodic and chronic channelopathies.
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PMID:Genetics, an alternative way to discover, characterize and understand ion channels. 1115 44

Many important aspects of our life are regulated by the free cytosolic Ca2+ concentration. The intracellular Ca2+ signal is regulated both in space, frequency and amplitude. Each cell chooses a unique set of Ca2+ signals to control its function. Ca2+ signal transduction is based on rises in free cytosolic Ca2+ concentration. Ca2+ can come from the extracellular space or be released from intracellular stores. Extracellular Ca2+ enters the cell through various types of plasma-membrane Ca2+ channels and leaves the cell using Ca2+ pumps and Na+/Ca(2+)-exchangers. Ca2+ is accumulated in intracellular stores by means of Ca2+ pumps and is released via inositol 1,4,5-trisphosphate (IP3) and ryanodine receptors. Mutations or abnormalities in one of the above mentioned Ca(2+)-transporting proteins can lead to disease. Skeletal-muscle pathology can be caused by abnormal ryanodine receptors (malignant hyperthermia, porcine stress syndrome, central core disease), plasma-membrane Ca2+ channels (hypokalemic periodic paralysis, muscular dysgenesis mice, paraneoplastic Lambert-Eaton myasthenia syndrome) or Ca2+ pumps (Brody disease). Neurologic disorders can be related to altered function of plasma-membrane Ca2+ channels (episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, glutamate excitotoxicity, tottering, leaner, lethargic and stargazer mice), IP3 receptors (Lowe's oculocerebrorenal syndrome, manic depression, Alzheimer's disease, opisthotonos mice) and Ca2+ pumps (deafwaddler mouse and wriggle mouse sagami). Two skin diseases are caused by Ca(2+)-pump mutations (Darier disease and Hailey-Hailey disease). Incomplete X-linked congenital stationary night blindness is caused by a mutation in the plasma-membrane Ca2+ channels in rods and cones.
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PMID:[Intracellular calcium: physiology and physiopathology]. 1119 78

Channelopathy is a term used to describe clinical problems caused by disorders of membrane ion channels. Included in this disease category are certain types of periodic paralyses, ataxia, myotonia, migraine headache, epilepsy, nephrolithiasis, and long QT syndrome. This article briefly summarizes membrane ion channel structure and function and details several relatively common channelopathies. In hyperkalemic periodic paralysis, mutant skeletal muscle sodium channels fail to close completely after an action potential. This evokes two apparently opposite symptoms: myotonia (caused by a small depolarization and repetitive excitation) or paralysis (caused by larger depolarization and inexcitability). In hypokalemic periodic paralysis, mutation affects the closing of skeletal muscle calcium channels, causing transient paresis or paralysis. The task of the advanced practice nurse is to recognize these disorders, institute appropriate prophylactic measures and treatments, monitor symptom progression, and avoid complications. Understanding of channelopathies is advancing rapidly. On the horizon are therapies tailored to counter specific membrane ion channel defects.
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PMID:Channelopathies: potassium-related periodic paralyses and similar disorders. 1123 35

There are many diseases related to ion channels. Mutations in muscle voltage-gated sodium, potassium, calcium and chloride channels, and acetylcholine-gated channel may lead to such physiological disorders as hyper- and hypokalemic periodic paralysis, myotonias, long QT syndrome, Brugada syndrome, malignant hyperthermia and myasthenia. Neuronal disorders, e.g., epilepsy, episodic ataxia, familial hemiplegic migraine, Lambert-Eaton myasthenic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, hyperekplexia may result from dysfunction of voltage-gated sodium, potassium and calcium channels, or acetylcholine- and glycine-gated channels. Some kidney disorders, e.g., Bartter's syndrome, policystic kidney disease and Dent's disease, secretion disorders, e.g., hyperinsulinemic hypoglycemia of infancy and cystic fibrosis, vision disorders, e.g., congenital stationary night blindness and total colour-blindness may also be linked to mutations in ion channels.
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PMID:Ion channels-related diseases. 1131 Sep 70

Recently, a variety of ion channel defects have been identified as the biological basis of certain familial epilepsies, paroxysmal movement disorders, myopathies and some degenerative disorders of central nervous system. Ion channel defects were mainly caused by genetic and autoimmune mechanisms. Here, we reviewed several channelopathies including spinocerebellar ataxia type 6, familial hemiplegic migraine, episodic ataxia type 2, familial hypokalemic periodic paralysis, congenital myotonia, malignant hyperthermia, epilepsy, Gitelman syndrome and Lambert-Eaton syndrome.
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PMID:[Channelopathy]. 1223 44

Intracellular calcium ([Ca2+]i) is highly regulated in eukaryotic cells. The free [Ca2+]i is approximately four orders of magnitude less than that in the extracellular environment. It is, therefore, an electrochemical gradient favoring Ca2+ entry, and transient cellular activation increasing Ca2+ permeability will lead to a transient increase in [Ca2+]i. These transient rises of [Ca2+]i trigger or regulate diverse intracellular events, including metabolic processes, muscle contraction, secretion of hormones and neurotransmitters, cell differentiation, and gene expression. Hence, changes in [Ca2+]i act as a second messenger system coordinating modifications in the external environment with intracellular processes. Notably, information on the molecular genetics of the membrane channels responsible for the influx of Ca2+ ions has led to the discovery that mutations in these proteins are linked to human disease. Ca2+ channel dysfunction is now known to be the basis for several neurological and muscle disorders such as migraine, ataxia, and periodic paralysis. In contrast to other types of genetic diseases, Ca2+ channelopathies can be studied with precision by electrophysiological methods, and in some cases, the results have been highly rewarding with a biophysical phenotype that correlates with the ultimate clinical phenotype. This review outlines recent advances in genetic, molecular, and pathophysiological aspects of human Ca2+ channelopathies.
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PMID:Calcium channelopathies. 1677 82

Ion channelopathies are a diverse array of human disorders caused by mutations in ion channel genes. This review focuses on the pathogenic mechanisms of channelopathies affecting skeletal muscle and brain arising from mutations of voltage-gated ion channels and fast ligand-gated ion channels expressed at the surface membrane. Derangements in channel function alter the electrical excitability of the cell and thereby increase susceptibility to transient symptomatic attacks including myasthenia, periodic paralysis, myotonic stiffness, seizures, headache, dyskinesia, or episodic ataxia. Although these disorders are rare, they stand out as exemplary cases for which disease pathogenesis can be traced from a point mutation to altered protein function, to altered cellular activity, and to clinical phenotype. The study of these disorders has provided insights on channel structure-function relations, the physiological roles of ion channels, and rational approaches toward therapeutic intervention for many disorders of cellular excitability.
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PMID:Pathomechanisms in channelopathies of skeletal muscle and brain. 1677 91

Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia. Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Na(V)1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalaemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathology that are characteristic of hypokalaemic periodic paralysis. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies.
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PMID:Gating pore current in an inherited ion channelopathy. 1733 30

Neurologic channelopathies are rare, inherited paroxysmal disorders of muscle (e.g., the periodic paralyses and nondystrophic myotonias) and brain (e.g., episodic ataxias, idiopathic epilepsies, and familial hemiplegic migraine). Mutation is necessary but not sufficient for phenotypic expression and there are no simple phenotype-genotype relationships. Attacks may be spontaneous or triggered, with affected individuals often asymptomatic and neurologically normal between attacks. Performance of daily activities may be affected by the unpredictable nature; often late-onset degenerative changes cause permanent disability; for example, muscle atrophy and fixed weakness in periodic paralysis and cerebellar atrophy and progressive ataxia in the episodic ataxias. Currently, the natural history of these disorders is being defined. Clearly, the established methodologies for randomized controlled clinical trials are not feasible for rare diseases and innovative trial design is essential. There is a requirement for clinically relevant outcome measures for episodic disorders. Increasing our knowledge of the pathophysiology will help in targeting and designing rational therapeutic approaches. We will use the current understanding of the neurological channelopathies to illustrate some of the opportunities, challenges, and strategies in bringing safe and effective treatments to patients. There are reasons for optimism that new partnerships between clinical investigators, government, patient advocacy groups, and industry will prevent symptoms and progression of the neurological channelopathies.
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PMID:Challenges in the design and conduct of therapeutic trials in channel disorders. 1739 29


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