Episodic ataxia type 2
Michael Strupp
Michael.Strupp@med
0
1
2
Andreas Zwergal
0
1
2
Thomas Brandt
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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.
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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)