Episodische Ataxie Typ 2

Zusammenfassung

Die episodische Ataxie Typ 2 (EA2) ist eine seltene autosomal dominant vererbte Kanalopathie mit einem typischen Erstmanifestationsalter zwischen zwei und 20 Jahren. Die Hauptsymptome bestehen in rezidivierenden Attacken von Schwindel, Gang-und Standataxie, die durch körperliche Anstrengung und emotionalen Stress ausgelöst werden können. Im attackenfreien Intervall finden sich eine leichtgradige, im Verlauf meist langsam progrediente zerebelläre Ataxie und zentrale Okulomotorikstörung (mit Downbeat Nystagmus). Weiterhin leiden betroffene Patienten häufig unter Migränekopfschmerzen, selten unter myasthenen Symptomen und epileptischen Anfällen. Die wichtigste Differenzialdiagnose ist die vestibuläre Migräne. Bei ca. 60% der Fälle von EA2 finden sich missense-Mutationen des Kalziumkanalgens CACNA1A verbunden mit einem Funktionsverlust des hauptsächlich auf zerebellären Purkinjezellen lokalisierten spannungsabhängigen P/Q-Typ Kalziumkanals. Dadurch kommt es zur Reduktion der tonischen GABAergen zerebellären Efferenzen. Aufbauend auf diesem pathogenetischen Verständnis wurden zwei effektive pharmakologische Therapieansätze entwickelt: Acetazolamid und 4-Aminopyridin.

Summary

Episodic ataxia type 2 (EA2) is a rare channalopathy of autosomal dominant inheritance typically presenting at an age of two to 20 years. It manifests with recurrent disabling attacks of vertigo, imbalance and ataxia, which can be provoked by physical exertion and emotional stress. In the spell-free interval patients present with subtle – but regularly in the course of the disease progressive – cerebellar ataxia and central ocular motor dysfunction (e. g. downbeat nystagmus). Patients frequently suffer from migraine headache, rarely from myasthenia and seizures. The most important differential diagnosis is vestibular migraine. In 60% of EA2 cases a missense mutation of the calcium channal gene CACNA1A is found, which leads to dysfunction of the voltage-gated P/Q calcium channel (found mainly on cerebellar Purkinje cells). Thereby tonic GABAergic cerebellar output is reduced. On the basis of this putative pathogenesis two effective pharmacological therapeutic principles were introduced: Acetazolamide and 4-Aminopyridine.

Schlüsselwörter

Schwindel - Gleichgewichtsstörungen - Ataxie - Downbeat Nystagmus - Acetazolamid - 4-Aminopyridine

Keywords

Vertigo - balance - ataxia - downbeat nystagmus - acetacolamide - 4-aminopyridine

• Literatur

• 1 Bain PG. et al. Familial periodic cerebellar-ataxia – A problem of cerebellar intracellular ph homeostasis. Annals of Neurology 1992; 31: 147-154.
• 2 Bawa B, Abbott L. Analysis of calcium ion homeostasis and mitochondrial function in cerebellar granule cells of adult Ca-V 2.1 calcium ion channel mutant mice. Neurotoxicity Research 2008; 13: 1-18.
• 3 Bense S. et al. F-18-fluorodeoxyglucose hypometabolism in cerebellar tonsil and flocculus in downbeat nystagmus. Neuroreport 2006; 17: 599-603.
• 4 Brandt T. A chameleon among the episodic vertigo syndromes: ‘migrainous vertigo’ or ‘vestibular migraine’. Cephalalgia 2004; 24: 81-82.
• 5 Cader MZ. et al. A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia. Neurology 2005; 61: 156-158.
• 6 Etzion Y, Grossman Y. Highly 4-aminopyridine sensitive delayed rectifier current modulates the excitability of guinea pig cerebellar Purkinje cells. Experimental Brain Research 2001; 139: 419-425.
• 7 Griggs RC, Nutt J. Episodic ataxias As channelopathies. Annals of Neurology 1995; 37: 285-287.
• 8 Guida S. et al. Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. American Journal of Human Genetics 2001; 68: 759-764.
• 9 Hawkes CH. Familial paroxysmal ataxia – report of a family. Journal of Neurology Neurosurgery and Psychiatry 1992; 55: 212-213.
• 10 Hille B. Ionic Channels – molecular pores of excitable-membranes. Harvey Lectures 1988; 82: 47-69.
• 11 Hirose H. et al. A family of episodic ataxia type 2: No evidence of genetic linkage to the CACNA1A gene. International Journal of Molecular Medicine 2003; 11: 187-189.
• 12 Imbrici P. et al. Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A. Neurology 2005; 65: 944-946.
• 13 Imbrici P. et al. Dysfunction of the brain calcium channel Ca(V)2.1 in absence epilepsy and episodic ataxia. Brain 2004; 127: 2682-2692.
• 14 Jn JC, Baloh R. Genetics of episodic ataxia. Myoclonus and paroxysmal dyskinesias 2002; 89: 459-461.
• 15 Jen JC. et al. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 2007; 130: 2484-2493.
• 16 Jen JC, Kim, Baloh R. Clinical spectrum and genotype/phenotype correlation in episodic ataxia type 2. Neurology 2002; 58: A508.
• 17 Jodice C. et al. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Human Molecular Genetics 1997; 06: 1973-1978.
• 18 Kalla R. et al. 4-aminopyridine restores vertical and horizontal neural integrator function in downbeat nystagmus. Brain 2007; 130: 2441-2451.
• 19 Kalla R. et al. 4-aminopyridine improves downbeat nystagmus, smooth pursuit, and VOR gain. Neurology 2004; 62: 1228-1229.
• 20 Krishnan AV. et al. Axonal function in a family with episodic ataxia type 2 due to a novel mutation. Journal of Neurology 2008; 255: 750-755.
• 21 Lafrance R. et al. Hereditary paroxysmal ataxia responsive to Acetazolamide. Neurology 1977; 27: 370.
• 22 Mantuano E. et al. Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders. Cytogenetic and Genome Research 2003; 100: 147-153.
• 23 Maselli RA. et al. Presynaptic failure of neuromuscular transmission and synaptic remodeling in EA2. Neurology 2003; 61: 1743-1748.
• 24 Mochizuki Y. et al. Hereditary paroxysmal ataxia with mental retardation: a clinicopathological study in relation to episodic ataxia type 2. Acta Neuropathologica 2004; 108: 345-349.
• 25 Otis TS, Jen JC. Blessed are the pacemakers. Nat Neurosci 2006; 09: 297-298.
• 26 Sappey-Marinier D. et al. Phosphorus and proton magnetic resonance spectroscopy in episodic ataxia type 2. Annals of Neurology 1999; 46: 256-259.
• 27 Sasaki O. et al. Neurotological findings in a family with episodic ataxia. Journal of Neurology 2003; 250: 373-375.
• 28 Scoggan KA, Friedman JH, Bulman DE. CACNA1A mutation in a EA-2 patient responsive to acetazolamide and valproic acid. Canadian Journal of Neurological Sciences 2006; 33: 68-72.
• 29 Spacey SD. et al. Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia. Archives of Neurology 2005; 62: 314-316.
• 30 Strupp M. et al. Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. Neurology 2004; 62: 1623-1625.
• 31 Strupp M, Zwergal A, Brandt T. Episodic ataxia type 2. Neurotherapeutics 2007; 04: 267-273.
• 32 Tottene A. et al. Familial hemiplegic migraine mutations increase Ca²⁺ influx through single human Ca(V)2.1 channels and decrease maximal Ca(V)2.1 current density in neurons. Proceedings of the National Academy of Sciences of the United States of America 2002; 99: 13284-89.
• 33 Vahedi K. et al. A Gene for Hereditary Paroxysmal Cerebellar-Ataxia Maps to Chromosome 19P. Annals of Neurology 1995; 37: 289-293.
• 34 VanBogaert P, Szliwowski HB. EEG findings in acetazolamide-responsive hereditary paroxysmal ataxia. Neurophysiologie Clinique-Clinical Neurophysiology 1996; 26: 335-340.
• 35 Veneziano L. et al. Episodic Ataxia 2, Spinocerebellar ataxia 6 and CACNA1A gene mutations. European Journal of Human Genetics 2002; 10: 270.
• 36 Vighetto A. et al. Magnetic-resonance imaging in familial paroxysmal Aataxia. Archives of Neurology 1988; 45: 547-549.
• 37 Vonbrederlow B. et al. Mapping the gene for acetazolamide responsive hereditary paryoxysmal Cerebellar-ataxia to chromosome 19P. Human Molecular Genetics 1995; 04: 279-284.
• 38 Wan J. et al. CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology 2005; 64: 2090-2097.
• 39 Wappl E. et al. Functional consequences of P/Q-type Ca2+ channel Ca(v)2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. Journal of Biological Chemistry 2002; 277: 6960-6966.
• 40 Weisz CJC. et al. Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering. Journal of Neuroscience 2005; 25: 4141-4145.
• 41 Yue Q. et al. De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia. American Journal of Medical Genetics 1998; 77: 298-301.
• 42 Zasorin NL, Baloh RW, Myers LB. Acetazolamide-Responsive Episodic Ataxia Syndrome. Neurology 1983; 33: 1212-1214.