Hereditary paroxysmal ataxia

Griggs, Robert C.; Moxley, Richard T.; Lafrance, Richard A.; McQuillen, James

doi:10.1212/wnl.28.12.1259

Cited by 203 publications

(85 citation statements)

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“…50 -52 ACTZ is a carbonic anhydrase inhibitor, which was initially shown to decrease the number of attacks in hypokalemic periodic paralysis patients. [53][54][55][56] Its efficacy, discovered accidentally in a patient with EA 2 misdiagnosed as having periodic paralysis, 51 was later confirmed by others. 57,58 ACTZ effectively prevents or attenuates the attacks in approximately 50% to 75% of all patients.…”

Section: Acetazolamidementioning

confidence: 97%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

160

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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.

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Section: Acetazolamidementioning

confidence: 97%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

160

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“…The LFOs in tg/tg mice provide a possible mechanism for transient cerebral cortical dysfunction and the reduction of LFOs by ACTZ and 4-AP argues for a connection between the oscillations in tg/tg mice and the human P/Q-type Ca 2ϩ channelopathies. In EA2 patients, ACTZ reduces the frequency and severity of ataxic bouts (Griggs et al, 1978) and ameliorates noncerebellar features, including migraine attacks and abnormal EEG activity (Zasorin et al, 1983;Neufeld et al, 1996). Similar to ACTZ, 4-AP effectively decreases attack frequency and severity, interictal ataxia, and migraine occurrence in EA2 patients (Strupp et al, 2004;Löhle et al, 2008;Jung et al, 2010).…”

Section: Role For Lfos In Episodic Cortical Dysfunctionmentioning

confidence: 99%

Abnormal Excitability and Episodic Low-Frequency Oscillations in the Cerebral Cortex of thetotteringMouse

et al. 2015

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The Ca 2ϩ channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Ca v 2.1 (P/Q-type) voltage-gated Ca 2ϩ channel include episodic ataxia type 2 (EA2). Although, in EA2 the emphasis has been on cerebellar dysfunction, patients also exhibit episodic, nonmotoric abnormalities involving the cerebral cortex. This study demonstrates episodic, low-frequency oscillations (LFOs) throughout the cerebral cortex of tottering (tg/tg) mice, a widely used model of EA2. Ranging between 0.035 and 0.11 Hz, the LFOs in tg/tg mice can spontaneously develop very high power, referred to as a high-power state. The LFOs in tg/tg mice are mediated in part by neuronal activity as tetrodotoxin decreases the oscillations and cortical neuron discharge contain the same low frequencies. The high-power state involves compensatory mechanisms because acutely decreasing P/Q-type Ca 2ϩ channel function in either wild-type (WT) or tg/tg mice does not induce the high-power state. In contrast, blocking L-type Ca 2ϩ channels, known to be upregulated in tg/tg mice, reduces the high-power state. Intriguingly, basal excitatory glutamatergic neurotransmission constrains the high-power state because blocking ionotropic or metabotropic glutamate receptors results in high-power LFOs in tg/tg but not WT mice. The high-power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, suggesting disease relevance. Together, these results demonstrate that the high-power LFOs in the tg/tg cerebral cortex represent a highly abnormal excitability state that may underlie noncerebellar symptoms that characterize CACNA1A mutations.

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“…The efficacy of drugs such as acetazolamide is also more marked in EA-2 patients. 7 With the discovery of novel mutations in EA-1, the phenotypic spectrum of the disorder has widened. In addition to the classical description, phenotypic variants include EA-1 with partial epilepsy, 14,17 EA-1 without myokymia, 37 and even isolated severe neuromyotonia.…”

Section: Clinical Featuresmentioning

confidence: 99%

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

et al. 2007

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Summary: Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A, the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.

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Hereditary paroxysmal ataxia

Cited by 203 publications

References 0 publications

Episodic Ataxia Type 2

Episodic Ataxia Type 2

Abnormal Excitability and Episodic Low-Frequency Oscillations in the Cerebral Cortex of thetotteringMouse

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

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