Episodic ataxia type 2

Neurotherapeutics, Apr 2007

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 Cav2.1 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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Episodic ataxia type 2

Michael Strupp Michael.Strupp@med 0 1 2 Andreas Zwergal 0 1 2 Thomas Brandt 0 1 2 0 M.D. , Department of Neurology, University of Munich , Marchionin- istrasse 15, 81377 Munich, Germany 1 Department of Neurology, University of Munich , Munich, Germany 2 Neurotherapeutics, Vol. 4, No. 2, 2007 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 CaV2.1 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: acetazolVol. 4, 267-273, April 2007 The American Society for Experimental NeuroTherapeutics, Inc. - The first purpose of this review on episodic ataxia type 2 (EA 2) is to describe its clinical features, genetics, and the correlation between mutations and clinical findings, as well as the current treatment options. Special emphasis is placed on the pharmacological effects of the two agents currently used for treatment: acetazolamide (ACTZ) and 4-aminopyridine (4-AP). The second purpose is to address open questions in EA 2, namely the pathophysiology of the induction of the attacks, the mechanisms of action of ACTZ and 4-AP, and the absence of randomized, controlled trials. The current classification of different types of episodic ataxia (EA) is based on genetics and clinical presentation. To date, there are six genetically defined types of EA, all of them autosomal dominant. Some other diseases that characteristically have the same clinical presentation as EA have not yet been genotyped. Given the variety of their clinical presentations, it seems logical to amide (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. Key Words: Episodic ataxia type 2, downbeat nystagmus, PQ-calcium channel, acetazolamide, aminopyridine. classify the EAs on a predominantly genetic basis. More detailed information about the coherence of genotype and phenotype will lead to modifications and expansion in the future. Episodic ataxia type 1 (EA 1) is characterized by brief attacks of ataxia, lasting for minutes, that are provoked by abrupt postural changes, emotional stress, and vestibular stimulation. Between spells, the patients have neuromyotonia: that is, an ongoing spontaneous highfrequency muscle fiber activity due to axonal hyperactivity.1 EA 1 is caused by missense point mutations of the voltage-gated potassium channel KCNA1 protein (chromosome band 12p13), which forms the Kv1.1 channels and is expressed in the peripheral and central nervous systems (OMIM #160120). These mutations lead to an altered neuronal excitability by affecting the temporal integration and action potential firing rates.2 First-choice treatment options are phenytoin and carbamazepine.3 (For details, see the article by Kordasiewicz and Hanna.67) Patients with EA 2, the focus of this review, present with attacks of imbalance, vertigo, and ataxia. EA 2 is the most frequent subtype of episodic ataxia. EA 3, a very rare disorder, has so far been described in only one family (chromosome 1q 24, OMIM %606554). It is characterized by recurrent attacks (lasting minutes to hours) with vestibular ataxia, vertigo, tinnitus, and headache and (in half of the patients) with interictal myokymia.4 Patients respond to ACTZ. In EA 4, patients have recurrent episodes of vertigo, ataxia, and diplopia, slowly progressive ataxia, and impaired smooth-pursuit eye movements.5 These patients do not have myokymia and do not respond to ACTZ. No genetic locus has been identified (OMIM %606552). EA 5 is caused by mutations of the calcium channel CACNB4 4 protein (chromosome region 2q22 q23; OMIM 601949), which lead to attacks of vertigo, ataxia, and sei (...truncated)


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Michael Strupp, Andreas Zwergal, Thomas Brandt. Episodic ataxia type 2, Neurotherapeutics, 2007, pp. 267-273, Volume 4, Issue 2, DOI: 10.1016/j.nurt.2007.01.014