Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

Rajakulendran, Sanjeev; Schorge, Stephanie; Kullmann, Dimitri M.; Hanna, Michael G.

doi:10.1016/j.nurt.2007.01.010

Cited by 93 publications

(97 citation statements)

References 72 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Neurology Episodic ataxia type 1 (EA1) is characterized by brief paroxysms of ataxia and interictal myokymia. 1 It is caused by heterozygous point mutations in the voltage-gated K V 1.1 potassium channel ␣-subunit, encoded by KCNA1. 2 Scrutiny of genetically confirmed kindreds reveals considerable phenotypic heterogeneity with respect to severity of ataxia and presence of additional features such as epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins

Graves¹,

Rajakulendran²,

Zuberi³

et al. 2010

Neurology

View full text Add to dashboard Cite

Objective: Episodic ataxia type 1 (EA1) is a monogenic channelopathy caused by mutations of the potassium channel gene KCNA1. Affected individuals carrying the same mutation can exhibit considerable variability in the severity of ataxia, neuromyotonia, and other associated features. We investigated the phenotypic heterogeneity of EA1 in 2 sets of identical twins to determine the contribution of environmental factors to disease severity. One of the mutations was also found in a distantly related family, providing evidence of the influence of genetic background on the EA1 phenotype. Methods:We evaluated 3 families with an EA1 phenotype, 2 of which included monozygotic twins. We sequenced the KCNA1 gene and studied the biophysical consequences of the mutations in HEK cells. Results:We identified a new KCNA1 mutation in each pair of twins. Both pairs reported striking differences in the clinical severity of symptoms. The F414S mutation identified in one set of twins also occurred in a distantly related family in which seizures complicated the EA1 phenotype. The other twins had an R307C mutation, the first EA1 mutation to affect an arginine residue in the voltage-sensor domain. Both mutants when expressed exerted a dominant-negative effect on wild-type channels. Conclusion:These results broaden the range of KCNA1 mutations and reveal an unexpectedly large contribution of nongenetic factors to phenotypic variability in EA1. The occurrence of epilepsy in 1 of 2 families with the F414S mutation suggests an interplay of KCNA1 with other genetic factors. Neurology Episodic ataxia type 1 (EA1) is characterized by brief paroxysms of ataxia and interictal myokymia.1 It is caused by heterozygous point mutations in the voltage-gated K V 1.1 potassium channel ␣-subunit, encoded by KCNA1.2 Scrutiny of genetically confirmed kindreds reveals considerable phenotypic heterogeneity with respect to severity of ataxia and presence of additional features such as epilepsy.1 Hitherto, attempts to account for phenotypic variability have concentrated on differences among distinct KCNA1 mutations with respect to their functional consequences when expressed in vitro. All EA1 mutations cause a loss of function, typically measured as a decrease in current density.1 Mutations associated with a severe phenotype have a dominant negative effect on wild-type channel function.3-5 A recent study in neurons has shown that KCNA1 mutations differentially affect action potential generation and neurotransmitter release.3 Despite attempts to correlate phenotypic severity with functional studies, even within affected kindreds there is *These authors contributed equally to this work.From the

show abstract

Section: Discussionmentioning

confidence: 99%

Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins

Graves¹,

Rajakulendran²,

Zuberi³

et al. 2010

Neurology

View full text Add to dashboard Cite

show abstract

“…Heterozygous mutations of KCNA1, which encodes the potassium channel subunit Kv1.1, cause episodic ataxia type 1 (EA1) (Browne et al, 1994), a dominantly inherited disorder that is characterized by paroxysmal cerebellar incoordination and interictal myokymia (Rajakulendran et al, 2007). Distinct mutations are associated with variable manifestations including cramps, contractures, titubation and seizures (Zuberi et al, 1999;Eunson et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release

Heeroma¹,

Henneberger²,

Rajakulendran³

et al. 2009

Disease Models &Amp; Mechanisms

Self Cite

View full text Add to dashboard Cite

SUMMARY Heterozygous mutations of KCNA1, the gene encoding potassium channel Kv1.1 subunits, cause episodic ataxia type 1 (EA1), which is characterized by paroxysmal cerebellar incoordination and interictal myokymia. Some mutations are also associated with epilepsy. Although Kv1.1-containing potassium channels play important roles in neuronal excitability and neurotransmitter release, it is not known how mutations associated with different clinical features affect the input-output relationships of individual neurons. We transduced rat hippocampal neurons, which were cultured on glial micro-islands, with lentiviruses expressing wild-type or mutant human KCNA1, and injected either depolarizing currents to evoke action potentials or depolarizing voltage commands to evoke autaptic currents. α-Dendrotoxin and tetraethylammonium allowed a pharmacological dissection of potassium currents underlying excitability and neurotransmission. Overexpression of wild-type Kv1.1 decreased both neuronal excitability and neurotransmitter release. By contrast, the C-terminus-truncated R417stop mutant, which is associated with severe drug-resistant EA1, had the opposite effect: increased excitability and release probability. Another mutant, T226R, which is associated with EA1 that is complicated by contractures and epilepsy, had no detectable effect on neuronal excitability; however, in common with R417stop, it markedly enhanced neurotransmitter release. The results provide direct evidence that EA1 mutations increase neurotransmitter release, and provide an insight into mechanisms underlying the phenotypic differences that are associated with different mutations.

show abstract

“…36 The spinocerebellar ataxia type 6 is also caused by a genetic alteration of the CACNA1A gene, with small, characteristic expansions of a CAG repeat within the last exon of this gene. 37 (For further details, see article by Rajakulendran et al 68 ) Despite the loss-of-function mutations in EA 2, one intact gene still expresses the normal ion-channel protein due to heterozygosity; however, the channel density and the calcium currents are reduced, 34 and thus neurotransmitters are released (namely, GABA in Purkinje cells and acetylcholine at the neuromuscular junction). 38,39 For this reason, it is assumed that ataxia is caused by impaired neurotransmission.…”

mentioning

confidence: 99%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

159

View full text Add to dashboard Cite

Summary: Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca V 2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

show abstract

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

Cited by 93 publications

References 72 publications

Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins

Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins

Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release

Episodic Ataxia Type 2

Contact Info

Product

Resources

About