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)

Familial hemiplegic migraine (FHM) has been related to mutations in a brain calcium channel gene among Chr19p linked FHM families. Subsequent genetic Studies in different FHM families showed that additional causative genes must reside in other regions of the genome, including the long arm of Chromosome 1. Parallel discoveries in mouse mutants involving ion channel genes have also accelerated our understanding of the spectrum and functional significance of the CNS-related ion channel disorders. These studies have clear implications for migraine, epilepsy, and ataxia. An association study was suggested that other 'susceptibility' genes like the dopamine DRD2 receptor will be important in characterizing the genetic components of the larger, heterogeneous group of migraine disorders.
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PMID:Current status of genetic discoveries in migraine: familial hemiplegic migraine and beyond. 964 38

The leaner (tgla) mutation in mice results in severe ataxia and an overt neurodegeneration of the cerebellum. Positional cloning has revealed that the tgla mutation occurs in a gene encoding the voltage-activated calcium channel alpha1A subunit. The alpha1A subunit is highly expressed in the cerebellum and is thought to be the pore-forming subunit of P- and Q-type calcium channels. In this study we used both whole-cell and single-channel patch-clamp recordings to examine the functional consequences of the tgla mutation on P-type calcium currents. High-voltage-activated (HVA) calcium currents were recorded from acutely dissociated cerebellar Purkinje cells of homozygous leaner (tgla/tgla) and age-matched wild-type (+/+) mice. In whole cell recordings, we observed a marked reduction of peak current density in tgla/tgla Purkinje cells (-35.0 +/- 1.8 pA/pF) relative to that in +/+ (-103.1 +/- 5.9 pA/pF). The reduced whole-cell current in tgla/tgla cells was accompanied by little to no alteration in the voltage dependence of channel gating. In both genotypes, HVA currents were predominantly of the omega-agatoxin-IVA-sensitive P-type. Cell-attached patch-clamp recordings revealed no differences in single-channel conductance between the two genotypes and confirmed the presence of three distinct conductance levels (9, 13-14, and 17-18 pS) in cerebellar Purkinje cells. Analysis of patch open-probability (NPo) revealed a threefold reduction in the open-probability of channels in tgla/tgla patches (0.04 +/- 0.01) relative to that in +/+ (0.13 +/- 0.02), which may account for the reduced whole-cell current in tgla/tgla Purkinje cells. These results suggest that the tgla mutation can alter native P-type calcium channels at the single-channel level and that these alterations may contribute to the neuropathology of the leaner phenotype.
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PMID:Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. 974 39

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

The SCA6 mutation, a small expansion of a CAG repeat in a calcium channel gene CACNA1A, was identified in three pedigrees. Point mutations in other parts of the gene CACNA1A were excluded and new clinical features of SCA6 reported--namely, central positional nystagmus and episodic ataxia responsive to acetazolamide. The three allelic disorders, episodic ataxia type 2, familial hemiplegic migraine, and SCA6, have overlapping clinical features.
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PMID:Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia. 977 87

A 39-year-old man with episodic ataxia with nystagmus (EA-2) was reported. He showed intermittent cerebellar dysfunction, i.e., ataxia, nystagmus, dysarthria and vertigo, since he was 10 years old. Although this attack lasted for several hours, he was normal with exception of interictal nystagmus. His parents and sister showed no episodic ataxia. We ruled out the diseases, which may cause episodic ataxia, such as multiple sclerosis, vascular disorders, metabolic disorders and congenital anomalies. He was released from the attack by treatment with acetazolamide. EA-2 has been associated with mutations in the alpha 1A-voltage dependent calcium channel gene (CACNL1A4), which is also affected in familial hemiplegic migraine (FMH) and spinocerebellar ataxia type 6 (SCA6). In EA-2, frame-shift mutation leading to premature stop and splice-site mutation leading to truncated, non-functional channel protein have been reported. However, our patient did not have the mutations in the CACNL1A4 gene that were previously reported. In addition, our patient did not have an expanded CAG allele in the CACNL1A4 gene which is responsible for SCA6. Further examination is required to address whether a new mutation exists in the CACNL1A4 gene in our patient.
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PMID:[A sporadic case of episodic ataxia with nystagmus (EA-2)]. 980 92

Tottering mice inherit a recessive mutation of the calcium channel alpha1A subunit that causes ataxia, polyspike discharges, and intermittent dystonic episodes. The calcium channel alpha1A subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the tottering mouse phenotype, calcium channel blockers were tested for their ability to block the motor episodes. Pharmacologic agents that specifically block L-type voltage-dependent calcium channels, but not P/Q-type calcium channels, prevented the inducible dystonia of tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented restraint-induced tottering mouse motor episodes. Conversely, the L-type calcium channel agonist Bay K8644 induced stereotypic tottering mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated that L-type calcium channel alpha1C subunit mRNA expression was up-regulated in the Purkinje cells of tottering mice. Radioligand binding with [3H]nitrendipine also revealed a significant increase in the density of L-type calcium channels in tottering mouse cerebellum. These data suggest that although a P/Q-type calcium channel mutation is the primary defect in tottering mice, L-type calcium channels may contribute to the generation of the intermittent dystonia observed in these mice. The susceptibility of L-type calcium channels to voltage-dependent facilitation may promote this abnormal motor phenotype.
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PMID:L-type calcium channels contribute to the tottering mouse dystonic episodes. 988 94

P-type and Q-type calcium channels mediate neurotransmitter release at many synapses in the mammalian nervous system. The alpha 1A calcium channel has been implicated in the etiologies of conditions such as episodic ataxia, epilepsy and familial migraine, and shares several properties with native P- and Q-type channels. However, the exact relationship between alpha 1A and P- and Q-type channels is unknown. Here we report that alternative splicing of the alpha 1A subunit gene results in channels with distinct kinetic, pharmacological and modulatory properties. Overall, the results indicate that alternative splicing of the alpha 1A gene generates P-type and Q-type channels as well as multiple phenotypic variants.
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PMID:Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. 1032 Dec 43

Rolling mouse Nagoya (rolling: tg(rol)) is a neurologic mutant mouse exhibiting severe ataxia. Two alleles of the rolling mutation, tottering (tg) and leaner(tg(la)), have been identified as mutations in the voltage-dependent calcium channel alpha1A subunit. No specific light and electron microscopic findings have been reported for the rolling mouse cerebellum except a decreased number of granule cells, while altered Purkinje cell/parallel fiber synapses have been observed in tottering and leaner cerebella. Rolling mouse cerebella were analyzed using anti-calbindin-D immunohistochemistry and transmission electron microscopy to investigate Purkinje cell morphology and synaptic contacts between Purkinje cell dendritic spines and parallel fiber varicosities. Multiple Purkinje cell dendritic spines synapsing with single parallel fiber varicosities were frequently observed in rolling cerebella. The correlation between the presence of altered Purkinje cell synapses and ataxia in rolling mice warrants further investigation.
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PMID:Morphologic investigation of rolling mouse Nagoya (tg(rol)/tg(rol)) cerebellar Purkinje cells: an ataxic mutant, revisited. 1033 81

We herein report the findings of an autopsy case of spinocerebellar ataxia type 6 (SCA6) which revealed a mild CAG-repeat expansion in the alpha1A voltage-dependent calcium channel (CACNL1A4) gene on chromosome 19p13. A 39-year-old man who showed slowly progressive mental disorders and gait ataxia was clinically diagnosed to have cortical cerebellar atrophy (CCA) and schizophrenia. None of his relatives revealed any symptoms such as spinocerebellar disease, however, his younger brother had shown some mental disorders. The patient eventually died at 52 years of age, and an autopsy was thus performed. The main histopathological findings included a severe neuronal cell loss of Purkinje cells and inferior olivary nuclei. The number of Purkinje cells in our case had decreased severely in comparison to that in either OPCA or age-matched control cases, and the Purkinje cells in the cerebellar hemisphere were more affected than those in the cerebellar vermis. The neurons of the dentate nucleus and pontine nuclei were well-preserved, and no pathological changes were seen in cerebral cortices or basal ganglia. The clinicopathological findings were similar to those of late cortical cerebellar atrophy (LCCA), Holmes' cortical cerebellar atrophy (Holmes type) or SCA6 cases reported previously. Using genomic DNA extracted from archival paraffin-embedded sections in the frontal lobe, cerebral basal ganglia and cerebellum, the identical mild CAG-repeat expansions in the CACNL1A4/SCA6 gene were revealed in all samples examined. These findings suggest that in cases with LCCA or Holmes type atrophy, we should thus examine the CAG-repeat expansions in the SCA6 gene, and the genomic DNA extracted from paraffin-embedded sections was thus found to be useful in diagnosing SCA6 retrospectively.
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PMID:An autopsy case of spinocerebellar ataxia type 6 with mental symptoms of schizophrenia and dementia. 1044 62

To investigate the clinical range of spinocerebellar ataxia type 6 (SCA6), we screened CAG repeat expansion in the voltage-dependent alpha 1A calcium channel gene (CACNL1A4) in 71 ataxic patients in 60 families; 54 patients in 43 families with hereditary ataxia and 17 sporadic patients. Thirteen patients with SCA6 were detected to have elongated CAG in CACNL1A4. Of these, 7 patients had been diagnosed as having hereditary cerebellar cortical atrophy, and 6 patients had been found to have sporadic occurrence. One patient showed distinct pontine atrophy with prominent horizontal or oblique gaze nystagmus which is an unusual feature in sporadic olivopontocerebellar atrophy. For the efficient screening of SCA6, we would propose testing CAG repeat expansion in CACNL1A4, in patients with one of two markers: (1) horizontal or oblique gaze nystagmus without other eye movement disorders, (2) pure cerebellar atrophy, even if occurrence is sporadic. We should note that the pontine atrophy could also be caused by CAG repeat expansion in CACNL1A4.
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PMID:Pontine atrophy in spinocerebellar ataxia type 6. 1060 3


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