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

Using in situ hybridization and immunochemical methods, we have observed an increase in the expression of SNS/PN3 sodium channel mRNA and protein in cerebellar Purkinje cells of the taiep rat. These changes are present in taiep rats at 12 months of age, following loss of myelin, but not at one month, prior to loss of myelin. Increased SNS/PN3 expression is not associated with aging per se, because it was not observed in control rats at 12 months of age. These results suggest that altered sodium channel expression in Purkinje cells may contribute to the ataxia that occurs in taiep rats.
 ...
PMID:Abnormal expression of SNS/PN3 sodium channel in cerebellar Purkinje cells following loss of myelin in the taiep rat. 1032 59

A mutation of alanine to threonine in the III S4-S5 linker of the mouse Scn8a sodium channel has previously been identified as causing the ataxia in med(jo) mice. The electrophysiological effects of this mutation in Scn8a sodium channels were characterized in Xenopus oocytes. The med(jo) mutation caused a 10 mV positive shift in the voltage dependence of activation, without any significant changes in the kinetics of either inactivation or recovery from inactivation. The shift in the voltage dependence of activation observed for the mutant channel would reduce the spontaneous activity of Purkinje cells and lead to a decrease in output from the cerebellum, which is consistent with the phenotype of cerebellar ataxia observed in med(jo) mice.
 ...
PMID:A mutation that causes ataxia shifts the voltage-dependence of the Scn8a sodium channel. 1054 17

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.
 ...
PMID:[Ciguatera and peripheral neuropathy: a case report]. 1084 72

Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.
 ...
PMID:Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. 1102 57

The human genome contains 10 voltage-gated sodium channel genes, 7 of which are expressed in neurons of the CNS and PNS. The availability of human genome sequences and high-throughput mutation screening methods make it likely that many human disease mutations will be identified in these genes in the near future. Mutations of Scn8a in the mouse demonstrate the broad spectrum of neurological disease that can result from different alleles of the same sodium channel gene. Null mutations of Scn8a produce motor neuron failure, loss of neuromuscular transmission, and lethal paralysis. Less severe mutations result in ataxia, tremor, muscle weakness, and dystonia. The effects of Scn8a mutations on channel properties have been studied in the Xenopus oocyte expression system and in neurons isolated from the mutant mice. The Scn8a mutations provide insight into the mode of inheritance, effect on neuronal sodium currents, and role of modifier genes in sodium channel disease, highlighting the ways in which mouse models of human mutations can be used in the future to understand the pathophysiology of human disease.
 ...
PMID:Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. 1149 24

Sodium channels are expressed at high density in myelinated axons and play an obligatory role in conducting action potentials along axons within the mammalian brain and spinal cord. It is not surprising, therefore, that they are involved in several aspects of the pathophysiology of multiple sclerosis (MS). First, the deployment of additional sodium channels to demyelinated parts of the axon (which had expressed low densities of sodium channels when covered by the myelin) provides a molecular substrate for the restoration of action potential conduction, a process that contributes to remissions in patients with MS. Second, there is evidence for changes in the expression pattern of sodium channels within Purkinje cells, both in animal models of MS and in human MS. It has been hypothesized that dysregulated sodium channel expression may contribute to symptom production in MS. If this hypothesis is correct, subtype-specific channel blockade may be therapeutically effective as a symptomatic treatment for ataxia and other cerebellar symptoms in MS. Finally, a noninactivating sodium conductance can trigger calcium-mediated axonal injury via reverse sodium-calcium exchange. Identifying the underlying channel may permit the development of therapeutic strategies that will prevent or retard axonal degeneration in MS.
 ...
PMID:Sodium channels as molecular targets in multiple sclerosis. 1205 67

Scn8a encodes an abundant, widely distributed voltage-gated sodium channel found throughout the central and peripheral nervous systems. Mice with different mutant alleles of Scn8a provide models of the movement disorders ataxia, dystonia, tremor and progressive paralysis. We previously reported that the phenotype of the hypomorphic allele of Scn8a, medJ, is dependent upon an unlinked modifier locus, Scnm1. Strain C57BL/6J carries a sensitive allele of the modifier locus that results in juvenile lethality. We now provide evidence that the modifier acts on the splicing efficiency of the mutant splice donor site. Mutant mice display either 90% or 95% reduction in the proportion of correctly spliced mRNA, depending on modifier genotype. The abundance of the channel protein, Na(v)1.6, is also reduced by an order of magnitude in medJ mice, resulting in delayed maturation of nodes of Ranvier, slowed nerve conduction velocity, reduced muscle mass and reduction of brain metabolic activity. medJ mice provide a model for the physiological effects of sodium channel deficiency and the molecular mechanism of bigenic disease.
 ...
PMID:Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). 1237 66

The sodium channel gene Scn8a encodes the channel NaV1.6, which is widely distributed in the central and peripheral nervous system. NaV1.6 is the major channel at the nodes of Ranvier in myelinated axons. Mutant alleles of mouse Scn8a result in neurological disorders including ataxia, tremor, paralysis, and dystonia. We generated a floxed allele of Scn8a by inserting loxP sites around the first coding exon. The initial targeted allele containing the neo-cassette was a severe hypomorph. In vivo deletion of the neo-cassette by Flp recombinase produced a floxed allele that generates normal expression of NaV1.6 protein. Ubiquitous deletion of the floxed exon by Cre recombinase in ZP3-Cre transgenic mice produced the Scn8a(del) allele. The null phenotype of Scn8a(del) homozygotes confirms the in vivo inactivation of Scn8a. Conditional inactivation of the floxed allele will make it possible to circumvent the lethality that results from complete loss of Scn8a in order to investigate the physiologic role of NaV1.6 in subpopulations of neurons.
 ...
PMID:Floxed allele for conditional inactivation of the voltage-gated sodium channel Scn8a (NaV1.6). 1528 95

Allelic mutations of Scn8a in the mouse have revealed the range of neurological disorders that can result from alternations of one neuronal sodium channel. Null mutations produce the most severe phenotype, with motor neuron failure leading to paralysis and juvenile lethality. Two less severe mutations cause ataxia, tremor, muscle weakness, and dystonia. The electrophysiological effects have been studied at the cellular level by recording from neurons from the mutant mice. The data demonstrate that Scn8a is required for the complex spiking of cerebellar Purkinje cells and for persistent sodium current in several classes of neurons, including some with pacemaker roles. The mouse mutations of Scn8a have also provided insight into the mode of inheritance of channelopathies, and led to the identification of a modifier gene that affects transcript splicing. These mutations demonstrate the value of mouse models to elucidate the pathophysiology of human disease.
 ...
PMID:Allelic mutations of the sodium channel SCN8A reveal multiple cellular and physiological functions. 1561 59

Since the first mutations of the neuronal sodium channel SCN1A were identified 5 years ago, more than 150 mutations have been described in patients with epilepsy. Many are sporadic mutations and cause loss of function, which demonstrates haploinsufficiency of SCN1A. Mutations resulting in persistent sodium current are also common. Coding variants of SCN2A, SCN8A, and SCN9A have also been identified in patients with seizures, ataxia, and sensitivity to pain, respectively. The rapid pace of discoveries suggests that sodium channel mutations are significant factors in the etiology of neurological disease and may contribute to psychiatric disorders as well.
 ...
PMID:Sodium channel mutations in epilepsy and other neurological disorders. 1607 41


<< Previous 1 2 3 4 Next >>