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

Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary movements that last up to several hours and occur at rest both spontaneously and following caffeine or alcohol consumption. We analyzed a Polish-American kindred with autosomal dominant PDC and identified tight linkage between the disorder and microsatellite markers on chromosome 2q (maximum two-point LOD score 4.77; recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant PDC on distal chromosome 2q. The fact that three other paroxysmal neurological disorders (periodic ataxia with myokymia and hypo- and hyperkalemic periodic paralysis) are due to mutation in ion-channel genes raises the possibility that PDC is also due to an ion-channel gene mutation. It is noteworthy that a cluster of sodium-channel genes is located on distal chromosome 2q, near the PDC locus. Identifying the PDC locus on chromosome 2q will facilitate discovery of the PDC gene and enable investigators to determine whether PDC is genetically homogeneous and whether other paroxysmal movement disorders are also genetically linked to the PDC locus.
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PMID:Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q. 865 18

Recent advances in the field of molecular myology have provided significant insight into the pathological mechanisms underlying a variety of neuromuscular disorders. Genetic abnormalities can now be linked to primary and secondary pathophysiological changes in muscle fibres which compromise structural, metabolic, regulatory or contractile mechanisms. Ion channel myopathies such as paramyotonia congenita, hyper- and hypokalaemic periodic paralysis, myotonia congenita, episodic ataxia and malignant hyperthermia were established as linked to mutations in genes encoding the sodium channel, dihydropyridine receptor, chloride channel, potassium channel and the ryanodine receptor calcium release channel, respectively. Metabolic disorders affecting skeletal muscle were found to be due to deficiencies in a variety of enzymes. Identification of defects in components belonging to the gigantic dystrophin-glycoprotein complex led to the discovery of the molecular pathogenesis of Duchenne muscular dystrophy and related disorders. Based on these molecular findings, it is now feasible to design and evaluate new techniques such as gene and myoblast transfer therapy in order to replace defective components in diseased muscle fibres.
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PMID:[Molecular pathogenesis of muscular diseases]. 903 37

Some of the most common diseases in humans occur intermittently in people who are otherwise healthy and active. Such disorders include migraine headache, epilepsy, and cardiac arrhythmias. Because electrical signals are critical to the function of neurons, muscle cells, and heart cells, proteins that regulate electrical signaling in these cells are logical sites where abnormalities might lead to disease. All of these diseases have prominent genetic components. Difficulty in understanding these diseases arises from the complexity of the clinical phenotypes as well as from the genetic heterogeneity that is almost certain to exist. Therefore, early work in may laboratory was aimed at understanding the pathogenesis of rare disorders that are similar in their episodic nature. These disorders of muscle (the periodic paralyses), lead to attacks of weakness that occur intermittently in otherwise normal people. We, and others, have shown that hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) result from mutations in a gene encoding a skeletal muscle sodium channel. We have also shown that hypokalemic periodic paralysis (hypoKPP) is caused by mutations in a gene encoding a voltage-gated calcium channel. The characterization of these diseases as channelopathies has served as a paradigm for other episodic disorders. One example is periodic ataxia, which results from mutations in voltage-gated potassium calcium channels. Long QT syndrome, an episodic cardiac dysrhythmia syndrome, is known to result from mutations in either voltage-gated sodium or potassium channels. We have recently mapped genes that cause a familial paroxysmal dyskinesia (non-kinesiogenic paroxysmal dystonia/choreoathetosis) in humans and a reflex epilepsy in mice. The similarities among all these disorders, including their episodic nature, precipitating factors, and therapeutic responses, are striking. Understanding gained from work in these rare monogenic episodic disorders is not only allowing characterization of the molecular and physiologic basis of these diseases, but may ultimately shed light on our understanding of the pathophysiology of more common and genetically complex disorders of the central nervous system.
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PMID:Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. 919 7

Channels involved in the influx and intracellular mobilization of calcium have been implicated as targets of diverse genetic and immune-mediated neurological diseases. These include the L-type voltage-gated calcium channel of skeletal muscle (hypokalemic periodic paralysis), the neuronal P/Q-type voltage-gated calcium channel (familial hemiplegic migraine, episodic ataxia type 2, spinocerebellar ataxia 6, and Lambert-Eaton myasthenic syndrome), and the skeletal muscle ryanodine receptor (malignant hyperthermia and central core disease). The discovery of these and other calcium channelopathies should help to clarify how different mutations affect channel function and how altered channel function produces disease, and may lead to new treatments for these conditions.
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PMID:Calcium channels in neurological disease. 930 47

Since 1990, many mutations, in genes encoding ion channels have been discovered to cause disorders characterized by hyper- or hypoexcitability of skeletal muscle or the central nervous system (CNS): i) mutations in the muscle chloride channel gene lead to a loss or change of function of the channels and cause an abnormally low total chloride conductance resulting in hyperexcitability of the muscle fiber membrane in the dominant and recessive form of myotonia congenita; ii) numerous dominant point mutations in the gene encoding the muscle sodium channel alpha-subunit cause incomplete sodium channel inactivation. Dependent on the inactivation parameter altered and the degree of the gain of function induced by a given mutation, the muscle episodically becomes hyper- or hypoexcitable (i.e. stiff or weak), particularly in response to elevated serum potassium (potassium-aggravated myotonia, hyperkalemic periodic paralysis) or cold environment (paramyotonia congenita); iii) dominant point mutations in the gene coding for the muscle L-type calcium channel alpha(1)-subunit can cause episodes of muscle inexcitability (i.e. weakness), particularly in response to lowered serum potassium (hypokalemic periodic paralysis); despite the recently discovered etiology of the disease, the pathogenesis of the weakness is still unknown; iv) dominant mutations in a voltage-gated potassium channel expressed in the CNS cause episodic ataxia type 1 presumably by antagonizing repolarization of the cell membrane; v) dominant mutations in a neuronal calcium channel alpha-subunit may cause either episodic ataxia type II or familial hemiplegic migraine by a so far unknown pathomechanism; vi) the first mutation in an ion channel associated with an inherited form of epilepsy, nocturnal frontal lobe epilepsy, was found in the alpha(4)-subunit of a neuronal nicotinic acetylcholine receptor.
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PMID:[Ion channel diseases in neurology]. 948 Feb 90

Since a few years, many mutations in genes encoding voltage-dependent ion channels have been identified. The related disorders are quoted as "channelopathies". These mutations are responsible for several skeletal muscle, brain, heart or kidney diseases. Abnormal calcium channels genes are responsible for hypokaleamic periodic paralysis (CACNA1S) as well as some forms of ataxia, cerebellar degeneration and migraine (CACNA1A). The preliminary studies of the recently discovered calcium channelopathies are undergoing. Both in vitro and in vivo studies of the diseased genes should help to the understanding of the related pathologies as well as to extend our knowledge of calcium channel function. In addition, autoantibodies against calcium channels are retrieved in some autoimmune diseases, such as Lambert-Eaton myasthenic syndrome (LEMS). Complementary studies are necessary to identify the precise implication of calcium channels in these auto-immune channelopathies.
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PMID:[Physiopathology of calcium channels: identification of calcium channelopathies]. 975 59

What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are "paroxysmal disorders" whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.
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PMID:Ion channel genes and human neurological disease: recent progress, prospects, and challenges. 1022 Mar 66

By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular. Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease. A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify. It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies. Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized. Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes.
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PMID:Voltage-gated ion channels and hereditary disease. 1050 36

The pathogenesis of chronic fatigue syndrome (CFS) is unknown but one of the most characteristic features of the illness is fluctuation in symptoms which can be induced by physical and/or mental stress. Other conditions in which fluctuating fatigue occurs are caused by abnormal ion channels in the cell membrane. These include genetically determined channelopathies, e.g. hypokalemic periodic paralysis, episodic ataxia type 2 and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis and inflammatory demyelinating polyneuropathies. Our hypothesis is that abnormal ion channel function underlies the symptoms of CFS and this is supported also by the finding of abnormal cardiac-thallium201 SPECT scans in CFS, similar to that found in syndrome X, another disorder of ion channels. CFS and syndrome X can have identical clinical symptoms. CFS may begin after exposure to specific toxins which are known to produce abnormal sodium ion channels. Finally, in CFS, increased resting energy expenditure (REE) occurs, a state influenced by transmembrane ion transport. The hypothesis that ion channels are abnormal in CFS may help to explain the fluctuating fatigue and other symptoms.
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PMID:The symptoms of chronic fatigue syndrome are related to abnormal ion channel function. 1109 Mar 4

A whole range of cell functions are regulated by the free cytosolic Ca(2+)concentration. Activator Ca(2+)from the extracellular space enters the cell through various types of Ca(2+)channels and sometimes the Na(+)/Ca(2+)-exchanger, and is actively extruded from the cell by Ca(2+)pumps and Na(+)/Ca(2+)-exchangers. Activator Ca(2+)can also be released from internal Ca(2+)stores through inositol trisphosphate or ryanodine receptors and is taken up into these organelles by means of Ca(2+)pumps. The resulting Ca(2+)signal is highly organized in space, frequency and amplitude because the localization and the integrated free cytosolic Ca(2+)concentration over time contain specific information. Mutations or functional abnormalities in the various Ca(2+)transporters, which in vitro seem to induce trivial functional alterations, therefore, often lead to a plethora of diseases. Skeletal-muscle pathology can be caused by mutations in ryanodine receptors (malignant hyperthermia, porcine stress syndrome, central-core disease), dihydropyridine receptors (familial hypokalemic periodic paralysis, malignant hyperthermia, muscular dysgenesis) or Ca(2+)pumps (Brody disease). Ca(2+)-pump mutations in cutaneous epidermal keratinocytes and cochlear hair cells lead to, skin diseases (Darier and Hailey-Hailey) and hearing/vestibular problems respectively. Mutated Ca(2+)channels in the photoreceptor plasma membrane cause vision problems. Hemiplegic migraine, spinocerebellar ataxia type-6, one form of episodic ataxia and some forms of epilepsy can be due to mutations in plasma-membrane Ca(2+)channels, while antibodies against these channels play a pathogenic role in all patients with the Lambert-Eaton myasthenic syndrome and may be of significance in sporadic amyotrophic lateral sclerosis. Brain inositol trisphosphate receptors have been hypothesized to contribute to the pathology in opisthotonos mice, manic-depressive illness and perhaps Alzheimer's disease. Various abnormalities in Ca(2+)-handling proteins have been described in heart during aging, hypertrophy, heart failure and during treatment with immunosuppressive drugs and in diabetes mellitus. In some instances, disease-causing mutations or abnormalities provide us with new insights into the cell biology of the various Ca(2+)transporters.
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PMID:Abnormal intracellular ca(2+)homeostasis and disease. 1094


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