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)

This review addresses the molecular and cellular mechanisms of diseases caused by inherited mutations of ion channels in neurones. Among important recent advances is the elucidation of several dominantly inherited epilepsies caused by mutations of both voltage-gated and ligand-gated ion channels. The neuronal channelopathies show evidence of phenotypic convergence; notably, episodic ataxia can be caused by mutations of either calcium or potassium channels. The channelopathies also show evidence of phenotypic divergence; for instance, different mutations of the same calcium channel gene are associated with familial hemiplegic migraine, episodic or progressive ataxia, coma and epilepsy. Future developments are likely to include the discovery of other ion channel genes associated with inherited and sporadic CNS disorders. The full range of manifestations of inherited ion channel mutations remains to be established.
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PMID:The neuronal channelopathies. 1202 9

We analyzed the SCA8 CTA/CTG repeat in a large group of Japanese subjects. The frequency of large alleles (85-399 CTA/CTG repeats) was 1.9% in spinocerebellar ataxia (SCA), 0.4% in Parkinson disease, 0.3% in Alzheimer disease, and 0% in a healthy control group; the frequency was significantly higher in the group with SCA than in the control group. Homozygotes for large alleles were observed only in the group with SCA. In five patients with SCA from two families, a large SCA8 CTA/CTG repeat and a large SCA6 CAG repeat coexisted. Age at onset was correlated with SCA8 repeats rather than SCA6 repeats in these five patients. In one of these families, at least one patient showed only a large SCA8 CTA/CTG repeat allele, with no large SCA6 CAG repeat allele. We speculate that the presence of a large SCA8 CTA/CTG repeat allele influences the function of channels such as alpha(1A)-voltage-dependent calcium channel through changing or aberrant splicing, resulting in the development of cerebellar ataxia, especially in homozygous patients.
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PMID:SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6. 1450 11

Spinocerebellar ataxia type 6 (SCA6) is one of three allelic disorders caused by mutations of CACNA1A gene, coding for the pore-forming subunit of calcium channel type P/Q. SCA6 is associated with small expansions of a CAG repeat at the 3' end of the gene, while point mutations are responsible for its two allelic disorders (Episodic Ataxia type 2 and Familial Hemiplegic Migraine). Genetic, clinical, pathological and pathophysiological data of SCA6 patients are reviewed and compared to those of other SCAs with expanded CAG repeats as well as to those of its allelic channelopathies, with particular reference to Episodic Ataxia type 2. Overall SCA6 appears to share features with both types of disorders, and the question as to whether it belongs to polyglutamine disorders or to channelopathies remains unanswered at present.
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PMID:Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders. 1452 75

Episodic ataxia type 2 (EA-2) is an autosomal dominant neurological disorder, characterized by episodes of ataxia, vertigo, nausea, nystagmus, and fatigue, associated with acetazolamide responsiveness. The disease is caused by mutations in the P/Q-type calcium channel Ca(v)2.1 subunit gene, CACNA1A, located on chromosome 19p13.2. We analyzed a family with 13 affected individuals for linkage to this locus and reached a two-point maximum LOD score of 4.48. A novel CACNA1A mutation, IVS36-2A>G, at the 3' acceptor splice site of intron 36 was identified by sequencing. It is the first described CACNA1A acceptor splice site mutation and the most C-terminal EA-2-causing mutation reported to date.
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PMID:Novel splice site CACNA1A mutation causing episodic ataxia type 2. 1453 Sep 26

Our purpose was to study the preventive effect of the calcium channel blocker flunarizine on headache, postural ataxia, and memory deficits occurring during decompression to high altitude in a randomized, placebo-controlled, double-blind study. After 7-day pretreatment with the study drugs, 20 healthy men were investigated at 490 m and 0.5, 2, 4, and 6 h later at a simulated altitude of 4559 m. Headache severity was evaluated on a 4-point scale. Sway path and anteroposterior and lateral sway were recorded with open and closed eyes by static posturography. Short- and long-term memory was studied by testing the recall of verbal and figural material immediately and 2 h after presentation, respectively. Blood pressure (BP) and arterial oxygen saturation (Sa(O2)) were also assessed. Headache scores showed a trend to be lower in the flunarizine group that was significant after 4 and 6 h. Headache scores expressed as difference from baseline values showed a nonsignificant trend to be lower at 4 and 6 h in subjects treated with flunarizine. Postural stance, memory, BP, and Sa(O2) were similar in both treatment groups. Although the low number of investigated subjects may have prevented the detection of a significant therapeutic effect of flunarizine, the present data do not show that flunarizine is effective for prevention of headache, postural ataxia, and neurocognitive deficits occurring at simulated high altitude.
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PMID:Flunarizine in prevention of headache, ataxia, and memory deficits during decompression to 4559 m. 1456 Dec 38

An abnormally expanded CAG repeats (25, normal; 4-20) was identified in the alpha 1A voltage-dependent calcium channel (CACNA1A) gene of a 50-year-old Japanese man with 25 years history of schizophrenia. At age 45, he first noted unsteadiness of standing and gait, which gradually worsened subsequently. In addition to the psychiatric symptoms of schizophrenia, neurological examination revealed marked truncal ataxia and mild limb ataxia. Brain magnetic resonance imaging showed atrophy of the cerebellar vermis. Gene analysis confirmed the diagnosis of spinocerebellar ataxia type 6 (SCA 6). No family members showed similar neuropsychiatric symptoms except that the patient's father had been suffering from an unknown dementing disease. Occurrence of both schizophrenia and SCA 6 in the identical patient may be coincidental. However, growing evidence has shown that various mutations in the CACNA1A gene are associated with phenotypic variability, such as progressive ataxia, episodic ataxia, migraine, coma, epilepsy and mental retardation. Therefore, the schizophrenic symptoms, association of which with SCA 6 has previously reported in a few cases, may represent rare clinical features of the channelopathy associated with the mutation in the CACNA1A gene.
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PMID:[A case of spinocerebellar ataxia 6 accompanied with schizophrenia]. 1502 29

Expression of the calcium channel Ca(V)2.2 is markedly suppressed by coexpression with truncated constructs of Ca(V)2.2. Furthermore, a two-domain construct of Ca(V)2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca(V)2.1 currents. We have now determined the specificity of this effect, identified a potential mechanism, and have shown that such constructs also inhibit endogenous calcium currents when transfected into neuronal cell lines. Suppression of calcium channel expression requires interaction between truncated and full-length channels, because there is inter-subfamily specificity. Although there is marked cross-suppression within the Ca(V)2 calcium channel family, there is no cross-suppression between Ca(V)2 and Ca(V)3 channels. The mechanism involves activation of a component of the unfolded protein response, the endoplasmic reticulum resident RNA-dependent kinase (PERK), because it is inhibited by expression of dominant-negative constructs of this kinase. Activation of PERK has been shown previously to cause translational arrest, which has the potential to result in a generalized effect on protein synthesis. In agreement with this, coexpression of the truncated domain I of Ca(V)2.2, together with full-length Ca(V)2.2, reduced the level not only of Ca(V)2.2 protein but also the coexpressed alpha2delta-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed Ca(V)2.2 currents and also reduced the expression level of both Ca(V)2.2 and alpha2delta-2 protein. We propose that voltage-gated calcium channels represent a class of difficult-to-fold transmembrane proteins, in this case misfolding is induced by interaction with a truncated cognate Ca(V) channel. This may represent a mechanism of pathology in episodic ataxia-2.
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PMID:Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response. 1519 Jan 13

The molecular basis of idiopathic generalized epilepsy remains poorly understood. Absence epilepsy with 3 Hz spike-wave EEG is one of the most common human epilepsies, and is associated with significant morbidity. Several spontaneously occurring genetic mouse models of absence epilepsy are caused by dysfunction of the P/Q-type voltage-gated calcium channel CaV2.1. Such mice exhibit a primary generalized spike-wave EEG, with frequencies in the range of 5-7 Hz, often associated with ataxia, evidence of cerebellar degeneration and abnormal posturing. Previously, we identified a single case of severe primary generalized epilepsy with ataxia associated with CaV2.1 dysfunction, suggesting a possible link between this channel and human absence epilepsy. We now report a family in which absence epilepsy segregates in an autosomal dominant fashion through three generations. Five members exhibit a combination of absence epilepsy (with 3 Hz spike-wave) and cerebellar ataxia. In patients with the absence epilepsy/ataxia phenotype, genetic marker analysis was consistent with linkage to the CACNA1A gene on chromosome 19, which encodes the main pore-forming alpha1A subunit of CaV2.1 channels (CaV2.1alpha1). DNA sequence analysis identified a novel point mutation resulting in a radical amino acid substitution (E147K) in CaV2.1alpha1, which segregated with the epilepsy/ataxia phenotype. Functional expression studies using human CACNA1A cDNA demonstrated that the E147K mutation results in impairment of calcium channel function. Impaired function of the brain calcium channel CaV2.1 may have a central role in the pathogenesis of certain cases of primary generalized epilepsy, particularly when associated with ataxia, which may be wrongly ascribed to anticonvulsant medication.
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PMID:Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. 1614 13

Mutations in P/Q-type calcium channels generate common phenotypes in mice and humans, which are characterized by ataxia, paroxysmal dyskinesia, and absence seizures. Subsequent functional changes of T-type calcium channels in thalamus are observed in P/Q-type calcium channel mutant mice and these changes play important roles in generation of absence seizures. However, the changes in T-type calcium channel function and/or expression in the cerebellum, which may be related to movement disorders, are still unknown. The leaner mouse exhibits severe ataxia, paroxysmal dyskinesia, and absence epilepsy due to a P/Q-type calcium channel mutation. We investigated changes in T-type calcium channel expression in the leaner mouse thalamus and cerebellum using quantitative real-time polymerase chain reaction (qRT-PCR) and quantitative in situ hybridization histochemistry (ISHH). qRT-PCR analysis showed no change in T-type calcium channel alpha 1G subunit (Cav3.1) expression in the leaner thalamus, but a significant decrease in alpha 1G expression in the whole leaner mouse cerebellum. Interestingly, quantitative ISHH revealed differential changes in alpha 1G expression in the leaner cerebellum, where the granule cell layer showed decreased alpha 1G expression while Purkinje cells showed increased alpha 1G expression. To confirm these observations, the granule cell layer and the Purkinje cell layer were laser capture microdissected separately, then analyzed with qRT-PCR. Similar to the observation obtained by ISHH, the leaner granule cell layer showed decreased alpha 1G expression and the leaner Purkinje cell layer showed increased alpha 1G expression. These results suggest that differential expression of T-type calcium channels in the leaner cerebellum may be involved in the observed movement disorders.
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PMID:Differential expression of T-type calcium channels in P/Q-type calcium channel mutant mice with ataxia and absence epilepsy. 1551 88

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative, monogenic, and autosomic dominant disease which is characterized by a global cerebellar atrophy. Typically the onset is at mature age and undergoes a moderate evolution. This illness has been associated with a mutation in the gene CACNA1A, that encodes for subunit alpha1A of P/Q type voltage/dependent calcium channel. The mutation results in the expansion of a CAG triplet repeat located in the last exon of the gene, which is translated into a polyglutamine chain in the carboxyl tail of the calcium channel subunit. Several studies have been made to clarify the mechanism for the toxicity of polyglutamines in cerebellar neurons; SCA6 could be considered a polyglutamine proteinopathy linked to caspases mediated death pathway. However, SCA6 is also considered a channelopathy, like paroxysmal diseases as hemiplegic familiar migraine and episodic ataxia type 2. The goal of this review is to analyze the intracellular mechanism triggering neuronal death in cerebellum, and the subsequent neurodegeneration.
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PMID:[Molecular physiopathology of the spinocerebellar ataxia type 6 (SCA6)]. 1561 20


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