Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Episodic ataxia type-1 syndrome (EA-1) is an autosomal dominant neurological disorder that manifests itself during infancy and results from point mutations in the voltage-gated potassium channel gene hKv1.1. The hallmark of the disease is continuous myokymia and episodic attacks of spastic contractions of the skeletal muscles, which cause permanent disability. Coexpression of hKv1.1 and hKv1.2 subunits produces heteromeric potassium channels with biophysical and pharmacological properties intermediate between the respective homomers. By using tandemly linked subunits, we demonstrate that hKv1.1 subunits bearing the EA-1 mutations V408A and E325D combine with hKv1.2 to produce channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence. Moreover, hKv1.1V408A single-channel analysis reveals a approximately threefold reduction of the mean open duration of the channel compared with the wild-type, and this mutation alters the open-state stability of both homomeric and heteromeric channels. The results demonstrate that human Kv1.2 and Kv1.1 subunits coassemble to form a novel channel with distinct gating properties that are altered profoundly by EA-1 mutations, thus uncovering novel physiopathogenetic mechanisms of episodic ataxia type-1 myokymia syndrome.
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PMID:Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function. 1042 58

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

Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 alpha-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (-/-, +/-, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 -/- animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/- mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1. 1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.
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PMID:Developmental seizure susceptibility of kv1.1 potassium channel knockout mice. 1057 55

Ciguatera is the most frequently observed form of tropical fish poisoning. It appears as a syndrome associating general signs, gastrointestinal, cardiac and neurological problems. Peripheral and central nervous system signs may be observed. We report a case of a 60-year-old man who developed Ciguatera poisoning with diarrhea, facial paresthesia, myalgia, cramps and weakness. Physical examination revealed a motor distal deficit of the four limbs, myokymia and ataxia. EMG testing was in favor of an axonal neuropathy. Neurologic symptoms persisted for two months. This case illustrates a new pathophysiological mechanism of neuropathy: "axonal channelopathy. Abnormalities of peripheral nerve sodium and potassium channels result in clinical and electrophysiological manifestations unrelated to axonal degeneration or demyelinization. The ciguatoxin mainly acts on sodium channels. Prolonged sodium channel activation results in repetitive axon firing. Recently ciguatoxin was recently demonstrated to have a novel action, blocking the sodium channel leading to slowed nerve conduction and decreased motor and sensory action potential amplitudes.
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PMID:[Ciguatera and peripheral neuropathy: a case report]. 1084 72

Autosomal-dominant cerebellar ataxias (ADCA) may present as progressive or paroxysmal disorders. While the progressive ataxias have been named spinocerebellar ataxias (SCA), the paroxysmal disorders are designated episodic ataxias (EA). Until now, three different mutational mechanisms resulting in distinctive pathogenesis have been identified. The first type of mutation present in SCA1, SCA2, SCA3, and SCA7 is an expanded CAG repeat in genes of unknown function that are translated into proteins with expanded polyglutamine tracts. A common ultrastructural feature of these disorders is the formation of neuronal intranuclear inclusions (NII) harboring the expanded disease proteins and a variety of other proteins. The pathogenic role of these inclusions has yet to be clarified. A second group of disorders is the result of mutations in genes that code for ion channels. In EA-1, a disorder characterized by episodes of ataxia provoked by movement and startle, missense mutations in a potassium channel gene, KCNA1, have been found. Patients with EA-2, another form of paroxysmal ataxia, carry nonsense mutations of the gene encoding the alpha1A voltage-dependent calcium channel subunit, CACNA1A, that are predicted to result in truncated channel proteins. In SCA6, a progressive ataxia, an expanded CAG repeat in the 3' translated region of the CACNA1A gene, has been found. The third type of mutation is an untranslated CTG expansion resembling the mutation found in myotonic dystrophy. It is associated with a progressive ataxia, SCA8.
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PMID:The molecular biology of the autosomal-dominant cerebellar ataxias. 1092 70

Clinicophysiological, haematological and biochemical effects of xylazine (0.05mgkg(-1)) and medetomidine (0.01mgkg(-1)) were studied in nine adult goats after lumbosacral subarachnoid administration. The onset of analgesia by xylazine and medetomidine was observed in 9.11+/-1.07 and 8.66+/-2.37min (mean+/-S.E.), respectively. Both alpha(2)-agonists produced moderate analgesia of hind quarter, perineum and flank, mild ataxia and sedation. The duration of analgesia after xylazine administration was 134.44+/-8.87min and that after medetomidine was 158.33+/-9.96min (mean+/-S.E.). Xylazine and medetomidine induced significant (p<0.05) decrease in heart rate, respiratory rate and hypothermia. Haemoglobin (Hb), packed cell volume (PCV) and total leukocyte count (TLC) decreased significantly. Changes in the physiological and haematological parameters were transient in nature. Xylazine and medetomidine produced a significant (p<0.05) increase in creatinine and glucose levels. However, these parameters fluctuated within normal range and started to recover within 120min. However, serum urea nitrogen (SUN), serum chloride, sodium and potassium did not show any significant change. The effects produced by xylazine and medetomidine were however, comparable at these dose levels. The study indicates that xylazine at 0.05mgkg(-1) and medetomidine at 0.01mgkg(-1) did not induce any serious alteration in the physiological, haematological and biochemical parameters and can be safely used in inducing hind quarter, flank and perineal analgesia in goats.
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PMID:Physiologic and biochemical effects of subarachnoidally administered xylazine and medetomidine in goats. 1102 38

Two young females with severe morbid obesity presented with Wernicke's syndrome after Roux-en-Y gastro-jejunum bypass had been performed. The first patient had recurrent vomiting and dyplopia two months post-surgery. Physical examination indicated bilateral ophthalmoparesia with conserved convergence and ataxia. The second patient had frequent vomiting episodes over the previous three months together with lower limb hypotonia, myoclonia and generalised tonicoclonic seizures on two occasions within one year of surgery. In both cases routine blood test, ion levels (sodium, potassium, calcium, phosphates), electroencephalogram and CT scan were normal. Thiamine therapy was instigated on the basis of clinical intuition and the first patient achieved complete remission within 24 hours while the second improved gradually in that two years later only mild lower limb hypotonia and a slight cognitive deficit remains. Erythrocyte transketolase activity determinations were abnormal on two separate occasions for this second patient. Vitamin B1 determinations were not available for the first patient. In conclusion, the restriction in energy intake and the persistent vomiting together with malabsorption induced by the surgical intervention could explain the vitamin deficiency causing Wernicke's encephalopathy. This indicates a need for close monitoring and systematic vitamin supplementation in those patients who undergo bariatric surgery.
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PMID:Wernicke's syndrome after bariatric surgery. 1103 Oct 78

An 11-year-old female crossbred dog showed signs of polyuria, polydipsia, vomiting, posterior weakness and ataxia. Clinical and laboratory findings suggested the diagnosis of polycythaemia vera. The haematological values shown over a six-month period are presented. In four samples some aspects of erythrocyte function (glucose-6-phosphate dehydrogenase [G6PD] and pyruvate kinase [PK] activities, 2,3 diphosphoglycerate [2,3 DPG] concentration, osmotic fragility and intracellular sodium and potassium concentrations) were studied. Variable activities of G6PD and PK, probably related to different reticulocyte number, were detected together with normal osmotic fragility and intracellular sodium and potassium concentrations. 2,3 DPG concentration was higher than normal in all four samples. This could be interpreted as a response to a low tissue perfusion rather than a higher content of 2,3 DPG in red blood cells from the polycythaemic dog.
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PMID:Some aspects of erythrocyte metabolism in a dog with polycythaemia vera. 1105 23

Malfunction in ion channels, due to mutations in genes encoding channel proteins or the presence of autoantibodies, are increasing being implicated in causing disease conditions, termed channelopathies. Dysfunction of potassium (K(+)) channels has been associated with the pathophysiology of a number of neurological, as well as peripheral, disorders (e.g., episodic ataxia, epilepsy, neuromyotonia, Parkinson's disease, congenital deafness, long QT syndrome). K(+) channels, which demonstrate a high degree of diversity and ubiquity, are fundamental in the control of membrane depolarisation and cell excitability. A common feature of K(+) channelopathies is a reduction or loss of membrane potential repolarisation. The identification of K(+) channel subtype specific openers will allow the recovery of the mechanism(s) responsible for counteraction of uncontrolled cellular depolarisation. Synthetic agents that demonstrate K(+) channel opening properties are available for a variety of K(+) channel subtypes (e.g., K(ATP), BK(Ca), GIRK and M-channel). This study reviews the realistic therapeutic potential that may be gained in a broad spectrum of clinical conditions by K(+) channel openers. K(+) channel openers would therefore identify dysfunctional K(+) channel as therapeutic targets for clinical benefit, in addition being able to modulate normally functioning K(+) channels to gain clinical management of pathophysiological events irrespective of the cause.
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PMID:Is there a role for potassium channel openers in neuronal ion channel disorders? 1106 Aug 6

Familial episodic ataxias are unusual hereditary disorders of early onset characterized by recurrent episodes of ataxia. Most patients recover fully between attacks, but some may develop progressive ataxia with cerebellar atrophy. There are two subtypes of episodic ataxia: type 1 (EA1), with interictal myokymia, and type 2 (EA2), with interictal nystagmus. Stress and fatigue can trigger ataxic spells, which can be responsive to acetazolamide. These clinical features are reminiscent of other channelopathies or paroxysmal neurologic disorders with progressive features caused by ion channel mutations. Familial episodic ataxias indeed are channelopathies. EA1 is caused by mutations in a potassium channel-encoding gene, whereas EA2 is caused by mutations in a calcium channel-encoding gene, which is also the disease-causing gene in spinocerebellar ataxia type 6 and several kindreds with familial hemiplegic migraine. Treatment with acetazolamide can be effective in decreasing the frequency of attacks and is generally well tolerated. Understanding the mechanism of action of acetazolamide and the functional consequences of these mutations will help one to develop a rational pharmacologic treatment for these disorders, which may share similar mechanisms with benign recurrent vertigo and more common forms of migraine.
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PMID:Familial Episodic Ataxias and Related Ion Channel Disorders. 1109 68


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