Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A 34-year-old man was admitted with his unsteady gait, difficulty in speech and a paroxysmal severe headache accompanied with sensori-motor disturbance of the right extremities and aphasic symptom. His family history was unremarkable. His unsteadiness has progressed very slowly from childhood. He noted to be inarticulate at the age of 18 years. At the age of 33 years, he suddenly had an attack of severe throbbing headache, which was mainly left parietal, with nausea and photophobia. During the headache, his right extremities were paralyzed and he became aphasic. He had lost a partial memory of the event All these symptoms had gone within 24 hours. Thereafter, the same headache occurred about once a month. Neurological examination revealed a mild truncal ataxia and ataxic dysarthria. Electroencephalography (EEG) showed intermittent delta waves restricted over the left fronto-temporal region. Brain MRI showed a moderate atrophy of superior cerebellar vermis and anterior cerebellar lobe. The diagnosis of sporadic hemiplegic migraine (SHM) with cerebellar ataxia was made. Our case was very similar to familial hemiplegic migraine (FHM) 1, of which some families are accompanied with transient amnesia, cerebellar ataxia and EEG abnormality. Although we did not detect any mutations in CACNA1A gene previously reported in FHM1, our case might share same pathogenesis with FHM1.
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PMID:[Case of sporadic hemiplegic migraine with cerebellar ataxia]. 1959 4

An association between hemiplegic migraine (HM) and episodic ataxia type 2 (EA2) has been described; both disorders are linked to mutations in the CACNA1A gene. Although confusion occurs in 21% of patients with HM, we found only one case in the literature of confusional episodes associated with ataxia without hemiplegia. These findings raise the possibility of confusional episodes being part of both the HM and EA2 phenotype. However, a patient with episodic ataxia, confusional spells and CACNA1A gene mutations has not been identified. We describe four individuals, spanning three generations of a family, with episodic ataxia without hemiplegia and confusion, in association with a CACNA1A mutation. We follow with a description of the relationship between the CACNA1A mutations and the three syndromes, suggesting a potential need for a new classification in which the conditions can be subsumed.
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PMID:Link between confusional migraine, hemiplegic migraine and episodic ataxia type 2: hypothesis, family genealogy, gene typing and classification. 1962 85

Familial episodic ataxias are inherited channelopathies that manifest as episodes of vertigo and ataxia triggered by emotional stress and physical exertion. Mutations in two neuronal ion-channel genes KCNA1 and CACNA1A abundantly expressed in the cerebellum account for the majority of the identified cases of episodic ataxia. Overlapping features between episodic ataxia and the more common recurrent vertigo and ataxia syndromes, particularly those associated with migraine, suggest shared underlying mechanisms. Altered neuronal excitability in the brain and inner ear could contribute to the central and peripheral features of migrainous vertigo. Given the familial aggregation of migraine and migrainous vertigo, our objective was to identify predisposing genetic factors. Preliminary findings demonstrate that migrainous vertigo is genetically heterogeneous and complex. Efforts are ongoing to perform genomewide association studies to identify risk alleles for migrainous vertigo, which may also be relevant to migraine in general.
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PMID:Familial episodic ataxia: a model for migrainous vertigo. 1964 8

Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific antibody against the disease protein of SCA6 (i.e., pathologically altered alpha-1A subunit of the P/Q type voltage-dependent calcium channel, CACNA1A) have not been confirmed so far, the occurrence and central nervous system distribution of neuronal protein aggregates in SCA6 is still a matter of debate. Owing to the fact that the antibody against the pathologically altered CACNA1A is not commercially available, we decided to apply a recently generated p62 antibody on brain tissue from two clinically diagnosed and genetically confirmed SCA6 patients. Application of this p62 antibody revealed numerous cytoplasmic neuronal inclusions in the degenerated cerebellar dentate nucleus and inferior olive of both SCA6 patients studied, whereby a subset of these aggregates were also ubiquitin-immunopositive. In view of the known role of p62 in protein degradation as well as aggresome/sequestosome formation, the p62 aggregate formation observed in the present study suggests that SCA6 not only is associated with an impairment of the calcium channel function and an elongated polyglutamine stretch in CACNA1A, but also with a defective protein handling by the protein quality control system.
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PMID:The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia type 6. 1978 49

The CACNA1A gene encodes the poreforming, voltage-sensitive subunit of the voltage-dependent Ca(v)2.1 calcium channel. Mutations in this gene have been linked to several human disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6. In mice, mutations of the homolog Cacna1a cause recessively inherited phenotypes in tottering, rolling Nagoya, rocker, and leaner mice. Here we describe two knockdown mice with 28.4+/-3.4% and 13.8+/-3.3% of the wild-type Ca(v)2.1 quantity. 28.4+/-3.4% level mutants displayed ataxia, absence-like seizures and progressive cerebellar atrophy, although they had a normal life span. Mutants with 13.8+/-3.3% level exhibited ataxia severer than the 28.4+/-3.4% level mutants, absence-like seizures and additionally paroxysmal dyskinesia, and died premature around 3 weeks of age. These results indicate that knock down of Ca(v)2.1 quantity to 13.8+/-3.3% of the wild-type level are sufficient to induce the all neurological disorders observed in natural occurring Cacna1a mutants. These knockdown animals with Ca(v)2.1 calcium channels intact can contribute to functional studies of the molecule in the disease.
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PMID:Knockdown of Cav2.1 calcium channels is sufficient to induce neurological disorders observed in natural occurring Cacna1a mutants in mice. 1985 54

Familial hemiplegic migraine (FHM) is a clinically and genetically heterogeneous disease most commonly linked to CACNA1A gene mutation. Epilepsy rarely occurs in FHM and is seen predominantly with specific CACNA1A gene mutations. Here we report a sporadic case of FHM1 linked to S218L CACNA1A gene mutation with the triad of prolonged hemiplegic migraine, cerebellar symptoms, and epileptic seizures. Epilepsy in this syndrome follows the pattern of isolated unprovoked seizures occurring only during childhood and hemiplegic migraine-provoked seizures occurring during adulthood. Clinical and electrographic status epilepticus can occur during prolonged migraine attacks. We suggest that patients with seizures, ataxia, and hemiplegic migraine be genetically tested for FHM. Patients with prolonged hemiplegic migraine attacks and confusion should be tested with continuous EEG recording to ascertain whether electrographic status is occurring, as intensive antiepileptic treatment not only resolves status but immediately stops hemiplegic migraine and improves associated neurological deficits.
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PMID:Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation. 2007 Dec 44

Episodic ataxia type 2 is a rare autosomal dominant disease characterized by recurrent attacks of vertigo and cerebellar ataxia. The disease was caused by mutations in the CACNA1A gene, on chromosome 19p. We perform a mutational screening in a group of 43 unrelated patients. Forty-two patients presented episodes of disequilibrium and ataxia, and one child was studied because of the occurrence of episodic torticollis. The genetic analysis showed 15 mutated patients (35%). In 13 cases we found novel CACNA1A gene mutations, including missense, protein truncating, and aberrant splicing mutations. Two truncating mutations lead to the uppermost premature stop so far reported, challenging recent hypotheses on dominant negative effect. In patients without CACNA1A mutations, molecular testing for CACNB4 gene mutations excluded this genetic subtype. Clinical features of mutated subjects mostly confirmed previous sign and symptoms associated with EA2, including paroxysmal torticollis and mental retardation. CACNA1A mutated patients have an earlier age at onset, interictal nystagmus, and abnormalities of ocular movements. A review of all CACNA1A mutations so far reported showed that they are mainly located downstream exon 18. Our data substantially increase the number of the described CACNA1A mutations, and propose clinical and molecular criteria for a more focused genetic screening.
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PMID:Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. 2012 25

Mutations in CACNA1A, which encodes the principal subunit of the P/Q calcium channel, underlie episodic ataxia type 2 (EA2). In addition, some patients with episodic ataxia complicated by epilepsy have been shown to harbour CACNA1A mutations, raising the possibility that P/Q channel dysfunction may be linked to human epilepsy. We undertook a review of all published CACNA1A EA2 cases and this showed that 7% have epilepsy--representing a sevenfold increased epilepsy risk compared to the background population risk (P<0.001). We also studied a series of 17 individuals with episodic ataxia accompanied by epilepsy and/or clearly epileptiform electroencephalograms (EEGs). We screened the entire coding region of CACNA1A for point mutations and rearrangements to determine if genetic variation in the gene is associated with the epilepsy phenotype, and measured the functional impact of all missense variations on heterologously expressed P/Q channels. We identified two large scale deletions and two new missense mutations in CACNA1A. When expressed, L621R had little detectable effect on P/Q channel function, while the other missense change, G540R, caused an approximately 30% reduction in current density. In nine patients we also identified the previously reported non-synonymous coding variants (E921D and E993V) which also resulted in impairment of P/Q channel function. Taken together, 12 of the 17 patients have genetic changes which decrease P/Q channel function. We conclude that variants in the coding region of CACNA1A that confer a loss of P/Q-type channel function are associated with episodic ataxia and epilepsy. Our data suggest that functional stratification of all variants, including common polymorphisms, rare variants and novel mutations, may provide new insights into the mechanisms of channelopathies.
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PMID:Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. 2015 48

Mutations in the CACNA1A gene that encodes the pore-forming alpha1 subunit of human voltage-gated CaV2.1 (P/Q-type) Ca2+ channels cause several autosomal-dominant neurologic disorders, including familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). For each channelopathy, the review describes the disease phenotype as well as the functional consequences of the disease-causing mutations on recombinant human CaV2.1 channels and, in the case of FHM1 and SCA6, on neuronal CaV2.1 channels expressed at the endogenous physiological level in knockin mouse models. The effects of FHM1 mutations on cortical spreading depression, the phenomenon underlying migraine aura, and on cortical excitatory and inhibitory synaptic transmission in FHM1 knockin mice are also described, and their implications for the disease mechanism discussed. Moreover, the review describes different ataxic spontaneous cacna1a mouse mutants and the important insights into the cerebellar mechanisms underlying motor dysfunction caused by mutant CaV2.1 channels that were obtained from their functional characterization.
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PMID:CaV2.1 channelopathies. 2020 99

Episodic ataxia type 2 (EA-2) is an inherited disorder that is characterized by intermittent vertigo, ataxia, and interictal gaze-evoked nystagmus. Although abnormalities associated with this disorder have been found in the CACNA1A gene encoding the alpha1A (Cav2.1) subunit of the P/Q-type calcium channel, there are few reports of genetically confirmed EA-2 in Korea. In 1998, a Korean family with acetazolamide-responsive hereditary paroxysmal ataxia was reported, but the genetic background was not defined at that time. In the present study we performed direct sequencing of the entire exons and their flanking intronic sequences of the CACNA1A gene and found a deletion mutation (c.2042_2043delAG).
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PMID:Episodic Ataxia Type 2 due to a Deletion Mutation in the CACNA1A Gene in a Korean Family. 2039 31


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