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Results for “Episodic ataxia”

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At least 19 recordsLinked to original sources

PubMed2005

A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia.

Episodic ataxias are ion channel disorders characterized by attacks of incoordination. The authors performed a genome-wide screen in a large pedigree segregating a novel episodic ataxia and found significant linkage on 1q42 with a multipoint lod score of 3.65. Haplotype analysis and fine mapping yielded a peak 2-point lod score of 4.14 and indicated a 4-cM region on 1q42 that is likely to harbor an episodic ataxia gene.

Adolescent↗

PubMed1997

A study of motor performance and motor learning in episodic ataxia.

Episodic ataxias are rare disorders in which periodic episodes of ataxia are separated by normal or near normal motor behaviour. They probably arise from dysfunctional membrane ion channels in the cerebellum. A patient with episodic ataxia EA-2 performed three motor tasks, before, during and after an ataxic episode. In all three tasks there were significant performance deficits during the ataxic episode. Two of the tasks also assessed motor adaptation (prism adaptation) or motor learning (ideogram drawing). In neither task was there significant disruption of motor adaptation or learning. These results suggest that the cerebellum may have separate roles in learning and in performance of visually guided movements, and that the dysfunction in this patient affected only his motor performance.

Ataxia↗

PubMed2005

New calcium channel mutations predict aberrant RNA splicing in episodic ataxia.

Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy characterized by paroxysmal cerebellar ataxia. Previous studies suggest that most EA2 cases are associated with mutations in the alpha1A subunit of the P/Q-type voltage-gated calcium channel gene CACNA1A. In a UK national study, the authors analyzed 15 index cases with typical EA2 and identified two unreported intronic mutations that predict aberrant splicing.

Adolescent↗

PubMed2001

Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia.

We have investigated the functional consequences of three P/Q-type Ca(2+) channel alpha1A (Ca(v)2.1alpha(1)) subunit mutations associated with different forms of ataxia (episodic ataxia type 2 (EA-2), R1279Stop, AY1593/1594D; progressive ataxia (PA), G293R). Mutations were introduced into human alpha1A cDNA and heterologously expressed in Xenopus oocytes or tsA-201 cells (with alpha(2)delta and beta1a) for electrophysiological and biochemical analysis. G293R reduced current density in both expression systems without changing single channel conductance. R1279Stop and AY1593/1594D protein were expressed in tsA-201 cells but failed to yield inward barium currents (I(Ba)). However, AY1593/1594D mediated I(Ba) when expressed in oocytes. G293R and AY1593/1594D shifted the current-voltage relationship to more positive potentials and enhanced inactivation during depolarizing pulses (3 s) and pulse trains (100 ms, 1 Hz). Mutation AY1593/1594D also slowed recovery from inactivation. Single channel recordings revealed a change in fast channel gating for G293R evident as a decrease in the mean open time. Our data support the hypothesis that a pronounced loss of P/Q-type Ca(2+) channel function underlies the pathophysiology of EA-2 and PA. In contrast to other EA-2 mutations, AY1593/1594D and G293R form at least partially functional channels.

Amino Acid Sequence↗

PubMed2025

Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.

Spinocerebellar ataxia 27 A (SCA27A) is a form of progressive cerebellar ataxia due to pathogenic variants in the Fibroblast Growth Factor 14 (FGF14) gene. The objective of this paper is to characterise the clinical spectrum of SCA27A microdeletions (> 50 bp, <2Mbp), and report two novel cases. Literature searches of PubMed, OMIM and ClinVar were carried out. We identified SCA27A microdeletions in 32 cases across 11 families. The phenotypic presentation is: 75% (24/32) nystagmus, 46% (15/32) ataxia, 21% (7/32) episodic ataxia, 21% (7/32) tremor, 15% (5/32) dysarthria, 34% (11/32) learning disability, 28% (8/32) neuropsychiatric disease. The presentation is variable within and between families. Episodic symptoms, nystagmus, learning disability and neuropsychiatric symptoms occur at an earlier age. Patient 1 represents the first case with a 58 kb FGF14 deletion who presented with a paroxysmal movement disorder. Patient 2 carries a 545 kb deletion and developed episodic ataxia and trigeminal neuralgia, a novel feature not previously described in this cohort. We report two cases of heterozygous FGF14 microdeletions: Patient 1 (58 kb) and Patient 2 (545 kb), expanding the phenotypic spectrum of FGF14 structural variants to 32 cases across 11 families. We review potential mechanism from pre-clinical studies relating FGF14 haploinsufficiency to cerebellar, cognitive, neuropsychiatric symptoms, as well as trigeminal neuralgia. We propose the hypothesis that the episodic symptoms in SCA27A align with the molecular pathology of a channelopathy and propose management strategies based on this insight.

Humans↗

PubMed2003

Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders.

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.

Alleles↗

PubMed2005

[Episodic ataxias].

BACKGROUND: Episodic ataxias (EAs) exist in sporadic and familial forms. They have considerable genetic and clinical heterogeneity. Better understanding of the disorders will hopefully improve management. MATERIAL AND METHODS: This review is based on personal experience and recent literature. RESULTS: EAs are rare autosomal dominant paroxysmic disorders. At present, five forms have been identified. EA 1 is caused by mutations in the potassium channel gene KCNA1 on chromosome 12p13, EA 2 by mutations in the calcium channel gene CACNA1A gene on chromosome 19p13, and EA 5 by mutations in the calcium channel gene CACNB4&beta on chromosome 2q22-q23. Neither gene nor linkage has been identified for EA 3 and 4. As the name indicates, EAs are characterized by paroxystic ataxia. Patients with EA 1 also have interictal myokymia. EAs are characterized by both locus and allelic heterogeneity, since different genes can cause an almost similar phenotype and different mutations in a gene can cause different disorders. Beside EA, mutations in the KCNA1 gene can cause partial epilepsy and myokymia alone, mutations in the CACNA1A gene can cause familial hemiplegic migraine 1 and spinocerebellar ataxia 6, while mutations in the CACNB4&beta4 gene can cause generalized epilepsy and juvenile myoclonic epilepsy. EA can often be efficiently treated with acetazolamide. INTERPRETATION: EAs are rare autosomal dominant disorders caused by mutations in ion-channel genes. The disorders are not life threatening but disabling without treatment or when medical treatment is ineffective or not tolerated.

Adolescent↗

PubMed2001

Spinocerebellar ataxia type 6 and episodic ataxia type 2 in a Korean family.

Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM) have been known as allelic disorders, which are caused by the alteration of the alpha1A voltage-dependent calcium channel subunit. Expansions of the CAG repeat in the CACNA1A gene on the short arm of the chromosome 19 induce SCA6, and point mutations in the same gene are responsible for EA2 and FHM. In recent studies, both SCA6 and EA2 have been concurrently found in families with 26 CAG repeats without previously reported point mutations either in coding sequences or in intron-exon junctions. We describe a Korean family with CAG26 repeats in the CACNA1A gene. Some of the affected family members had progressive ataxia typical of SCA6 whereas others had episodic vertigo responsive to acetazolamide typical of EA2. Our family support that SCA6 and EA2 are allelic disorders with a high phenotypic variability.

Adolescent↗

PubMed2003

Novel splice site CACNA1A mutation causing episodic ataxia type 2.

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.

Adolescent↗

PubMed1998

Three novel KCNA1 mutations in episodic ataxia type I families.

Hereditary paroxysmal ataxia, or episodic ataxia (EA), is a rare, genetically heterogeneous neurological disorder characterized by attacks of generalized ataxia. By direct sequence analysis, a different missense mutation of the potassium channel gene (KCNA1) has been identified in three families with EA.

Amino Acid Substitution↗

PubMed2003

A mouse model of episodic ataxia type-1.

Episodic ataxia type-1 (EA1) is a dominant human neurological disorder characterized by stress-induced attacks of ataxia. EA1 is caused by mutations in the voltage-gated potassium channel Kv1.1, and affected individuals are heterozygous. Here we introduced the V408A EA1 mutation into mice using homologous recombination. In contrast to Kv1.1 null mice, homozygous V408A/V408A mice died after embryonic day 3 (E3). V408A/+ mice showed stress-induced loss of motor coordination that was ameliorated by acetazolamide, a carbonic anhydrase inhibitor that minimizes EA1 symptoms in human patients. We made electrophysiological recordings from cerebellar Purkinje cells in both V408A/+ mice and their wild-type littermates. V408A/+ mice showed a greater frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) than did wild type; however, the amplitude or frequency of miniature IPSCs and the basket cell firing frequency did not differ between groups. The stress-induced motor dysfunction in V408A mice is similar to that of family members harboring the EA1 allele, and our findings suggest that these behavioral changes are linked to changes in GABA release.

Acetazolamide↗

PubMed2005

Dominant-negative effects of human P/Q-type Ca2+ channel mutations associated with episodic ataxia type 2.

Episodic ataxia type 2 (EA2) is an inherited autosomal dominant disorder related to cerebellar dysfunction and is associated with mutations in the pore-forming alpha(1A)-subunits of human P/Q-type Ca(2+) channels (Cav2.1 channels). The majority of EA2 mutations result in significant loss-of-function phenotypes. Whether EA2 mutants may display dominant-negative effects in human, however, remains controversial. To address this issue, five EA2 mutants in the long isoform of human alpha(1A)-subunits were expressed in Xenopus oocytes to explore their potential dominant-negative effects. Upon coexpressing the cRNA of alpha(1A)-WT with each alpha(1A)-mutant in molar ratios ranging from 1:1 to 1:10, the amplitude of Ba(2+) currents through wild-type (WT)-Cav2.1 channels decreased significantly as the relative molar ratio of alpha(1A)-mutants increased, suggesting the presence of an alpha(1A)-mutant-specific suppression effect. When we coexpressed alpha(1A)-WT with proteins not known to interact with Cav2.1 channels, we observed no significant suppression effects. Furthermore, increasing the amount of auxiliary subunits resulted in partial reversal of the suppression effects in nonsense but not missense EA2 mutants. On the other hand, when we repeated the same coinjection experiments of alpha(1A)-WT and mutant using a splice variant of alpha(1A)-subunit that contained a considerably shorter COOH terminus (i.e., the short isoform), no significant dominant-negative effects were noted until we enhanced the relative molar ratio to 1:10. Altogether, these results indicate that for human WT-Cav2.1 channels comprising the long-alpha(1A)-subunit isoform, both missense and nonsense EA2 mutants indeed display prominent dominant-negative effects.

Animals↗

PubMed2001

[Episodic ataxia type 2].

Episodic ataxia type 2 is an autosomal dominant paroxysmal cerebellar ataxia characterized by acetazolamide-responsive recurrent attacks with interictal nystagmus. This disease is caused by mutations (mainly truncating mutation) within the alpha1(A) subunit of P/Q type voltage-dependent calcium channel gene, CACNA1A. Further researches would establish the genotype/phenotype correlation and clarify the mechanism of this disorder.

English Abstract↗

PubMed1998

Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia.

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.

Acetazolamide↗

PubMed2000

Familial Episodic Ataxias and Related Ion Channel Disorders.

Familial episodic ataxias are unusual hereditary disorders of early onset characterized by recurrent episodes of ataxia. Most patients recover fully between attacks, but some may develop progressive ataxia with cerebellar atrophy. There are two subtypes of episodic ataxia: type 1 (EA1), with interictal myokymia, and type 2 (EA2), with interictal nystagmus. Stress and fatigue can trigger ataxic spells, which can be responsive to acetazolamide. These clinical features are reminiscent of other channelopathies or paroxysmal neurologic disorders with progressive features caused by ion channel mutations. Familial episodic ataxias indeed are channelopathies. EA1 is caused by mutations in a potassium channel-encoding gene, whereas EA2 is caused by mutations in a calcium channel-encoding gene, which is also the disease-causing gene in spinocerebellar ataxia type 6 and several kindreds with familial hemiplegic migraine. Treatment with acetazolamide can be effective in decreasing the frequency of attacks and is generally well tolerated. Understanding the mechanism of action of acetazolamide and the functional consequences of these mutations will help one to develop a rational pharmacologic treatment for these disorders, which may share similar mechanisms with benign recurrent vertigo and more common forms of migraine.

Journal Article↗

PubMedDate not supplied

Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo).

Episodic ataxia (EA) is a rare, disabling condition of autosomal dominant inheritance, but it is not a distinct clinical entity. Synonyms are familial periodic ataxia or hereditary paroxysmal cerebellar ataxia. Family members have a similar clinical syndrome; however, the syndrome varies considerably from family to family. At least two groups of disorders have been separated clinically: (1) episodic ataxia type 1 (EA-1), which manifests without vertigo and is associated with 'interictal' myokymia, and (2) episodic ataxia type 2 (EA-2), which often manifests with vertigo and is associated with 'interictal' nystagmus. EA-1 and EA-2 have been identified as channelopathies. EA-1 is due to different heterozygous missense point mutations in a voltage-gated (delayed rectifier) potassium channel gene (KCNA1/Kv1.1) on chromosome 12p13, whereas EA-2 is caused by mutations of the cerebral P/Q-type calcium channel alpha 1 subunit gene CACNL1A4 localized on chromosome 19p, which is highly expressed in the cerebellum. The diagnosis of EA-1 and EA-2 is important, since they can be easily treated and are often mislabeled. As effective as acetazolamide is in preventing attacks, prospective studies still have to prove whether it can prevent progressive ataxia in EA-2 or even improve chronic cerebellar deficits.

Acetazolamide↗

PubMed2001

An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus.

The authors report an autosomal dominant episodic ataxia that is clinically distinct from the other episodic ataxias. Vestibular ataxia, vertigo, tinnitus, and interictal myokymia are prominent; attacks are diminished by acetazolamide. Linkage analyses of markers flanking the EA1 and EA2 loci demonstrate genetic exclusion from the other autosomal dominant episodic ataxias. The authors suggest EA3 for periodic vestibulocerebellar ataxia and EA4 for the disorder described here.

Adolescent↗

PubMed1986

Autosomal dominant episodic ataxia: a heterogeneous syndrome.

We describe six kindreds with autosomal dominant episodic ataxia, apparently representing three distinct syndromes. Four kindreds were characterized by episodic ataxia and response to acetazolamide, and in three, interictal nystagmus. One kindred was characterized by paroxysmal ataxia and in one member, paroxysmal choreoathetosis. The last kindred had brief attacks of ataxia and interictal neuromyotonia. The age of onset and severity of the disorder varied within each kindred. These kindreds illustrate the heterogeneity of episodic ataxia as well as the variable expressivity within each kindred.

Adult↗