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)

Synaptotagmins are abundant synaptic proteins that represent the best candidate for the calcium sensor at the nerve terminal. The pore-forming, voltage-sensing transmembrane alpha-1 subunit of the P/Q voltage-gated calcium channel (or Ca(v)2.1) encoded by the CACNA1A gene is another major component of the process of action potential-evoked exocytosis at the adult mammalian neuromuscular junction. Defects of these proteins, in nonhuman species, result in severe disruption of rapid synaptic transmission. This paper investigates the molecular bases of inherited presynaptic deficits of neuromuscular transmission in humans. Patients with congenital presynaptic failure, including two patients with episodic ataxia type 2 (EA-2) due to CACNA1A mutations, were studied with muscle biopsy, microelectrode studies, electron microscopy, DNA amplification, and sequencing. All patients, including EA-2 patients, showed selective failure of the action potential-dependent release without reduction of the spontaneous release of neurotransmitter. In addition, patients with EA-2 showed partial blockade of neuromuscular transmission with the N-type blocker omega-conotoxin not seen in controls. The EM showed a varied degree of increased complexity of postsynaptic folds. Mutational analysis in candidate genes, including human synaptotagmin II, syntaxin 1A, synaptobrevin I, SNAP 25, CACNA1A, CACNB2, and Rab3A, was unrevealing. Although no mutations in candidate genes were found in patients with inborn presynaptic failure, functional and structural similarities between this group and patients with EA-2 due to CACNA1A mutations suggest a common pathogenic mechanism.
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PMID:Effect of inherited abnormalities of calcium regulation on human neuromuscular transmission. 1459 59

Episodic ataxia type 2 (EA2) is a dominantly inherited disorder, characterized by spells of ataxia, dysarthria, vertigo, and migraines, associated with mutations in the neuronal calcium-channel gene CACNA1A. Ataxic spells lasting minutes to hours are provoked by stress, exercise, or alcohol. Some patients exhibit nystagmus between spells and some develop progressive ataxia later in life. At least 21 distinct CACNA1A mutations have been identified in EA2. The clinical and genetic complexities of EA2 have offered few insights into the underlying pathogenic mechanisms for this disorder. We identified a novel EA2 kindred in which members had ataxic spells induced by fevers or high environmental temperature. We identified a novel CACNA1A mutation (nucleotides 1253+1 G-->A) that was present in all subjects with febrile spells or ataxia. Moreover, we found that, regardless of age or interictal clinical status, all affected subjects had objective evidence of abnormal saccades, ocular fixation, and postural stability. These findings suggest that early cerebellar dysfunction in EA2 results from the intrinsically abnormal properties of the CACNA1A channel rather than a degenerative process.
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PMID:Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. 1468 82

The authors searched for mutations in CACNA1A in patients with episodic ataxia and describe the clinical spectrum in genetically defined patients. Eighteen families and nine sporadic cases of episodic ataxia were evaluated for mutations in CACNA1A. The families were first genotyped to check for linkage to the chromosome 19p locus of CACNA1A. In families consistent with linkage and in the sporadic cases, the authors screened for polymorphisms in CACNA1A using single-strand conformational polymorphism and denaturing high performance liquid chromatography followed by direct sequencing to identify specific nucleotide changes. Of the 18 families, 11 were linked to 19p and mutations were found in 9. Mutations were detected in four of the nine sporadic cases. Overall, five nonsense mutations, four missense mutations, two deletions, one insertion, and one donor splice mutation were identified. All but two of the 64 genetically defined patients reported episodes of ataxia (two members of one family only had progressive ataxia). All but one had onset before age 20 and all but four had interictal nystagmus. Migraine headaches occurred in more than half, and about two thirds reported a good response to treatment with acetazolamide. Vertigo and weakness accompanied the ataxia in more than half of the genetically defined patients. One family had multiple members with epilepsy. A wide range of mutations in CACNA1A were associated with episodic ataxia. Four of 13 were missense mutations; the remainder predicted truncated proteins. The mutations were scattered throughout the gene, and only 2 of the 13 mutations identified in our laboratory have been reported by other laboratories, so it will not be possible to screen a few "hot spots" in CACNA1A. Overall, the type of mutation, missense versus nonsense, or the location of altered or truncated amino acid residues did not predict the clinical phenotype.
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PMID:Clinical spectrum of episodic ataxia type 2. 1471 90

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

The highest prevalence rate of spinocerebellar ataxia type 6 (SCA6) in the worldwide population is in the Chugoku and Kansai areas of Western Japan, but the reason of this geographic characteristics is unclear. We investigated the predisposing haplotypes and their geographic distribution. Genotyping of five microsatellite markers and three single nucleotide polymorphisms linked to the CACNA1A gene in 150 Japanese SCA6 patients from unrelated 118 families revealed three major haplotypes, carrying a pool of one common haplotype core. A founder chromosome was thought to have historically diverged into at least three types. One of the major haplotypes newly identified showed a strong geographical cluster around the Seto Inland Sea in the Chugoku and Kansai areas of Western Japan, whereas the others were widely distributed throughout Japan. The distribution of predisposing haplotypes contributes to the geographical differences in prevalence of SCA6.
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PMID:A novel haplotype of spinocerebellar ataxia type 6 contributes to the highest prevalence in western Japan. 1502 60

We performed a population-based clinical and molecular genetic study of spinocerebellar ataxia type 6 (SCA6) in the northeast of England. The minimum point prevalence of SCA6 was 1.59 in 100,000 (95% confidence interval [CI], 1.04-2.14), and the number of individuals who either had SCA6 or are at risk of developing SCA6 was at least 5.21 in 100,000 (95% CI, 4.31-6.10), or 1 in 19,210. Microsatellite analysis of the CACNA1A gene indicated a founder effect for SCA6 within this region.
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PMID:Molecular epidemiology of spinocerebellar ataxia type 6. 1512 20

Patients with episodic ataxia type 2 (EA2) can often be successfully treated with acetazolamide. The authors report three patients with EA2 (two with proven mutations in the CACNA1A gene) whose attacks were prevented with the potassium channel blocker 4-aminopyridine (4-AP; 5 mg tid). Attacks recurred after treatment was stopped; subsequent treatment alleviated the symptoms (mean follow-up time 6 months). These effects might be due to an improvement of the impaired functioning of Purkinje cells.
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PMID:Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. 1513 97

Episodic ataxia type 2 (EA2) is an autosomal dominant condition characterized by paroxysmal attacks of ataxia, vertigo, and nausea, typically lasting minutes to days in duration. These symptoms can be prevented or significantly attenuated by the oral administration of acetazolamide; however, the mechanism by which acetazolamide ameliorates EA2 symptoms is unknown. EA2 typically results from nonsense mutations in the CACNA1A gene that encodes the alpha1A (Cav2.1) subunit of the P/Q-type calcium (Ca2+) channel. We have identified a novel H1736L missense mutation in the CACNA1A gene associated with the EA2 phenotype. This mutation is localized near the pore-forming region of the P/Q-type Ca2+ channel. Functional analysis of P/Q-type channels containing the mutation show that the H1736L alteration affects several channel properties, including reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values. Although these findings are consistent with an overall loss of P/Q-type channel function, the mutation also caused some biophysical changes consistent with a gain of function. We also tested the direct effect of acetazolamide on both wild-type and H1736L mutated P/Q-type channels and did not observe any direct action on channel properties of this pharmacological agent used to treat EA2 patients.
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PMID:Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. 1529 73

A case of hereditary acetazolamide-responsive paroxysmal ataxia with mild mental retardation in an autopsied Japanese man is described. His ataxic attacks had occurred for approximately 65 years since the age of 6. One of his daughters had severe mental retardation and epilepsy, and the other had paroxysmal ataxic attacks and mild mental retardation. Analysis of the subject's CACNA1A gene and that in his daughter revealed neither mutations nor CAG expansion. Neuropathologically, cortical degeneration consisting of the marked loss of Purkinje and granule cells was found exclusively in the cerebellar vermis. This was consistent with findings at autopsy for cases reported as spinocerebellar ataxia 6. In addition, there were minor anomalies, such as hypoplastic cerebellum and brainstem, heterotopic Purkinje cells, and cortical microdysgenesis of the temporal lobe. It is considered that the cerebellar cortical degeneration and the minor malformations found in the brain are closely related to one another, rather than having occurred independently.
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PMID:Hereditary paroxysmal ataxia with mental retardation: a clinicopathological study in relation to episodic ataxia type 2. 1530 Apr 51

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with hemiparesis during the aura. In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus. Recently, mutations in ATP1A2 on chromosome 1q23 encoding a Na+/K+ -ATPase subunit were identified in four families (FHM2). We now describe an FHM2 pedigree with a fifth ATP1A2 mutation coding for a G301R substitution. The phenotype was particularly severe and included hemiplegic migraine, seizure, prolonged coma, elevated temperature, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria. A mild crossed cerebellar diaschisis during an attack further supported the clinical evidence of a cerebellar deficit. This is the first report suggesting cerebellar involvement in FHM2. A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus. The study of this family suggests that the absence of cerebellar signs may not be a reliable indicator to clinically differentiate FHM2 from FHM1.
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PMID:A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. 1545 25


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