Showing papers on "Episodic ataxia published in 2005"

Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures

Abstract: Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter. Methods: We examined our patient population with episodic ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3 , which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft. Results: A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect. Conclusion: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.

Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia—authors' response

Abstract: Sir, We thank Professor Strupp and colleagues for the pertinent points they raise in relation to our recent publication in Brain (Imbrici et al ., 2004). They highlight important issues in relation to treatment options in episodic ataxia type 2 (EA2) and absence epilepsy. Furthermore, their recent findings in combination with ours highlight the possible role of CaV2.1 dysfunction in human absence epilepsy (Jouvenceau et al ., 2001; Imbrici et al ., 2004; Strupp et al ., 2004). In our experience, most patients with uncomplicated ‘pure’ EA2 harbouring a mutation in the CACNA1A gene do respond well to acetazolamide therapy, although a proportion of such cases do not. This is also the experience in a series recently published by Jen et al . (2004). The precise mechanism underlying this acetazolamide response remains uncertain. Furthermore, the treatment of acetazolamide-resistant cases is problematic. The recent finding of Strupp et al . (2004) that episodes of ataxia in …

Diagnosis and management of acute movement disorders.

Abstract: Most movement disorders, reflecting degenerative disorders, develop in a slowly progressive fashion. Some movement disorders, however, manifest with an acute onset. We wish to give an overview of the management and therapy of those acute-onset movement disorders. Drug–induced movement disorders are mainly caused by dopamine–receptor blockers (DRB) as used as antipsychotics (neuroleptics) and antiemetics. Acute dystonic reactions usually occur within the first four days of treatment. Typically, cranial pharyngeal and cervical muscles are affected. Anticholinergics produce a prompt relief.Akathisia is characterized by an often exceedingly bothersome feeling of restlessness and the inability to remain still. It is a common side effect of DRB and occurs within few days after their initiation. It subsides when DRB are ceased.Neuroleptic Malignant Syndrome is a rare, but life–threatening adverse reaction to DRB which may occur at any time during DRB application. It is characterised by hyperthermia, rigidity, reduced consciousness and autonomic failure. Therapeutically immediate DRB withdrawal is crucial.Additional dantrolene or bromocriptine application together with symptomatic treatment may be necessary. Paroxysmal dyskinesias are childhood onset disorders characterised by dystonic postures, chorea, athetosis and ballism occurring at irregular intervals. In Paroxysmal Kinesigenic Dyskinesia they are triggered by rapid movements, startle reactions or hyperventilation. They last up to 5 minutes, occur up to 100 times per day and are highly sensitive to anticonvulsants. In Paroxysmal Non–Kinesiogenic Dyskinesia they cannot be triggered, occur less frequently and last longer.Other paroxysmal dyskinesias include hypnogenic paroxysmal dyskinesias, paroxysmal exertional dyskinesia, infantile paroxysmal dystonias, Sandifer's syndrome and symptomatic paroxysmal dyskinesias. In Hereditary Episodic Ataxia Type 1 attacks of ataxia last for up to two minutes, may be accompanied by dysarthria and dystonia and usually respond to phenytoin. In Type 2 they can last for several hours, may be accompanied by vertigo, headache and malaise and usually respond to acetazolamide. Symptomatic episodic ataxias can occur in a number of metabolic disorders, but also in multiple sclerosis and Behcet's disease.

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

Abstract: 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.

Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A

Abstract: Episodic ataxia type 2 (EA2) is caused by calcium channel (CACNA1A) mutations and typically begins before age 20 years. The molecular basis of late-onset EA2 is unclear. The authors describe a case of late-onset EA2 associated with the first multiple-base pair insertion in CACNA1A. Molecular expression revealed evidence of impaired calcium channel function, suggesting that genetically induced reduction in calcium channel function may associate with cases of late-onset EA2.

New calcium channel mutations predict aberrant RNA splicing in episodic ataxia

Abstract: 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 α 1A 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.

Nonconsensus intronic mutations cause episodic ataxia.

Abstract: We discovered intronic mutations in two episodic ataxia type 2 (EA2) families: a four-nucleotide GAGT deletion at IVS41+(3-6) and a single nucleotide insertion (insT) at IVS24+3. We expressed minigenes harboring the mutations in cell lines to demonstrate exon skipping from the deletion mutation and the activation of a cryptic splice donor site from the insertion mutation. The identification of these disease-causing mutations expands the spectrum of EA2 mutations and emphasizes the importance of intronic sequences in regulating gene expression.

Protective and susceptibility effects of hSKCa3 allelic variants on juvenile myoclonic epilepsy

Abstract: Juvenile myoclonic epilepsy (JME; OMIM 606904) is a subtype of common idiopathic generalised epilepsy (IGE) and affects up to 26% of all individuals with IGE.1–3 JME is characterised by the onset in adolescence of bilateral myoclonic jerks usually affecting the upper limbs.1,4 Patients also have generalised tonic-clonic seizures and about one third experience absence seizures. Genetic factors are known to play an important role in the etiology of JME.3,4 While identification of genes underlying predisposition to JME has been relatively slow due to clinical and genetic heterogeneity,5,6 progress made so far in the isolation and characterisation of genes associated with other monogenic subtypes of IGE, provides evidence that most idiopathic epilepsy syndromes are caused by mutations in genes encoding ion channels.7 The implications of these findings in monogenic subtypes of the disorder for the complex polygenic subset are now being increasingly appreciated.8 Two types of voltage gated potassium channels have been associated with seizure disorders, the KCNQ channels and the Kv channels. Loss of function mutations for the potassium channels KCNQ2 and KCNQ3 have been identified in families with a rare autosomal dominant subtype of IGE called benign familial neonatal convulsions (BFNC).9,10 Allelic association of JME with KCNQ3 has been suggested in a South Indian cohort of JME patients.11 Mutation in human KCN1A predisposes to episodic ataxia and partial epilepsy.12 These findings emphasise the importance of potassium channels in controlling neuronal excitability and thus make potassium channel genes potentially interesting candidates for idiopathic epilepsy syndromes. The calcium activated potassium channels are an interesting class of potassium channels that regulate neuronal excitability.13,14 These are gated by intracellular calcium ions and their activity is responsible in part for the afterpolarisation that follows a single action …

Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia—a comment

Abstract: Sir, We read with great interest the article by Imbrici et al . (2004) recently published in your journal. The authors report on a family in which absence epilepsy segregated in an autosomal dominant fashion through three generations, and five of its members exhibited a combination of absence epilepsy and episodic ataxia type 2 (EA2). DNA sequence analysis identified a novel point mutation that resulted in a radical amino acid substitution (E147K) in the main pore-forming α1A subunit of the brain calcium channel CaV2.1. In a detailed description of two of the patients (case II:6 and case III:3), the authors point out that the patients exhibited marked cerebellar ataxia or a …

Episodic Ataxia Type 2 with Downbeating Nystagmus Caused by Mutation in the CACNA1A: A Case Report

Abstract: Episodic ataxia type 2 (EA 2) is a rare disorder characterized by intermittent episodes of ataxia with interictal nystagmus. The authors report a patient with EA 2, who presented with recurrent episodes of vertigo, gait ataxia and interictal downbeat nystagmus, which had developed about 16 years before. The chromosomal analysis revealed a translocation between chromosome 7 and chromosome 19 (t(7;19)). The break point in chromosome 19 was the P13 locus of the CACNA1A gene.

Ion Channels and Human Disorders

Abstract: The human channelopathies are a rapidly expanding group of primarily genetic conditions. They are characterised by dysfunction of membrane-bound glycoproteins (ion channels). Several neurological and general medical disorders have been shown to be due to underlying ion channel dysfunction and genetic analysis is now often routine clinical practice. These disorders exhibit extensive phenotypic and genetic heterogeneity with many distinct diseases caused by dysfunction of the same channel by differing mechanisms. Our understanding of the mechanisms behind these diseases continues to extend as more mutations are identified and functional analysis is performed. In the future this will lead to the identification of better targeted treatments for these diseases. Key Concepts: Ion channels are transmembrane glycoproteins important in intra- and intercellular processes. Channelopathies are commonly due to mutations in functionally important regions of either pore-forming or auxillary channel subunits. Mutations often cause disease by altering channel gating, voltage dependence and channel assembly. Channelopathies may manifest with intermittent symptoms which may completely recover or have a secondary progression. Channleopathies, like myotonia congenita, have extensive phenotypic variability even within a single pedigree. Genetic heterogeneity occurs in many channelopathies like the episodic ataxias and periodic paralyses. In the calcium channel, CACNA1A, different mutations cause distinct central nervous diseases. Mutations in a number of channel genes can increase the predisposition to epilepsy. Keywords: channelopathy; myotonia; migraine; epilepsy; episodic ataxia; spinocerebellar ataxia