Zusammenfassung
Episodische Ataxien sind klinisch und genetisch heterogene Erkrankungen mit dem Leitsymptom
rezidivierender Attacken von Gang-, Stand- oder Extremitätenataxie. Die häufigste
Form ist die episodische Ataxie Typ 2 (EA 2), seltener ist die episodische Ataxie
Typ 1 (EA 1). Daneben sind noch mindestens 5 andere Formen beschrieben worden, allerdings
bislang nur in einzelnen Familien. Deshalb wird in dieser Übersicht der Schwerpunkt
auf EA 1 und EA 2 liegen. Episodische Ataxien werden autosomal-dominant vererbt, wobei
sich jedoch nur in der Hälfte der Fälle Mutationen nachweisen lassen. Die Mutationen
betreffen Ionenkanäle, die für die Erregbarkeit von Nervenzellen wichtig sind. Die
EA 2 ist durch rezidivierende Attacken von Schwindel, Gang- und Standataxie gekennzeichnet,
die durch körperliche Anstrengung und emotionalen Stress ausgelöst werden können.
Das Erstmanifestationsalter liegt meist zwischen 2 und 20 Jahren. Im attackenfreien
Intervall finden sich bei über 90 % der Patienten zentrale Okulomotorikstörungen,
insbesondere ein Downbeatnystagmus und eine leichtgradige, im Verlauf meist kaum zunehmende
Stand-, Gang- und Extremitätenataxie. Weiterhin leiden betroffene Patienten häufig
unter migränetypischem Kopfschmerz, weshalb die vestibuläre Migräne die wichtigste
Differenzialdiagnose darstellt; selten treten myasthene Symptome oder epileptische
Anfälle auf. Bei ca. 60 % der Fälle von EA 2 finden sich Mutationen, meist sog. Nonsense-Mutationen
des Kalziumkanalgens CACNA1A, was zu einer reduzierten Dichte dieses hauptsächlich
auf zerebellären Purkinjezellen lokalisierten spannungsabhängigen P / Q-Typ Kalziumkanals
führt. Dadurch kommt es zur Reduktion der tonischen GABAergen zerebellären Efferenzen.
Zur Behandlung ist Azetazolamid Mittel der ersten Wahl. Basierend auf der Pathogenese
wurde ein neues Therapieprinzip entwickelt: der Einsatz des Kaliumkanalblockers 4-Aminopyridin,
der die Erregbarkeit von Purkinje-Zellen und damit die Schwelle für die Attacken erhöht.
Die EA 1 ist durch kurze Attacken mit Ataxie und rhythmischen Muskelbewegungen gekennzeichnet.
Zwischen den Attacken besteht bei den Patienten eine Neuromyotonie. Die EA 1 beruht
auf Mutationen des spannungssensitiven Kaliumkanals KCNA1. Mittel der ersten Wahl
ist der Natriumkanalblocker Phenytoin, in zweiter Linie können Carbamazepin, Valproinsäure
und Azetazolamid eingesetzt werden.
Abstract
Episodic ataxias are a clinically and genetically heterogeneous group of diseases
with cardinal symptoms comprising recurrent attacks of gait, stand or extremity ataxia.
The most frequent form is episodic ataxia type 2 (EA 2), less common is episodic ataxia
type 1 (EA 1). Besides these, at least five other forms have been described, however,
as yet only in isolated families. Thus, this review places the emphasis on EA 1 and
EA 2. Episodic ataxias are autosomally dominantly inherited whereby, however, mutations
have been detected in only half of the cases. The mutations affect ion channels that
are important for the excitation of nerve cells. EA 2 is characterised by recurrent
attacks of vertigo, gait and stand ataxias that can be triggered by physical exertion
and emotional stress. First manifestations are usually seen at ages between 2 and
20 years. In the attack-free intervals, central oculomotor dysfunctions are found
in over 90 % of the patients, especially downbeat nystagmus and mild-degree stand,
gait and extremity ataxias that remain more or less constant over the disease course.
Furthermore, the afflicted patients frequently suffer from headache typical for migraine.
For this reason, vestibular migraine is the most important differential diagnosis;
myasthenic symptoms or epileptic attacks are less common. In about 60 % of the cases
of EA 2 so-called nonsense mutations of the mutated calcium channel gene CACNA1A are
found, which lead to a reduced density of the voltage-dependent P / Q-type calcium
channels that are principally localised on Purkinje cells. This leads to a reduction
of tonic GABAergic cerebellar efferents. Acetazolamide is the agent of first choice
for therapy. On the basis of the pathogenesis, a new therapeutic principle has been
developed involving the use of the calcium channel blocker 4-aminopyridine, which
increases the excitability of Purkinje cells and thus the threshold for attacks. EA 1
is characterised by short attacks with ataxia and rhythmic muscle movements. In between
attacks the patients have a neuromyotonia. EA 1 results from mutations of the voltage-sensitive
potassium channels KCNA1. Therapeutic agent of first choice is the sodium channel
blocker phenytoin, as second choices carbamazepine, valproate and acetazolamide may
be used.
Schlüsselwörter
Ataxien - Ionenkanalerkrankungen - Kalziumkanäle - Downbeatnystagmus - Kaliumkanäle
Key words
ataxia - ion channel disorders - calcium channels - downbeat nystagmus - potassium
channels
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Prof. Dr. Michael Strupp
Neurologische Klinik, Klinikum der Universität München
Marchioninistr. 15
81377 München
Email: Michael.Strupp@med.uni-muenchen.de
