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EPISODIC ATAXIA TYPE-2 What is episodic ataxia type 2? 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.

INTRODUCTION: 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.

CLINICAL FEATURES OF EPISODIC ATAXIA TYPE-2: Episodic ataxia type 2 usually begins in early childhood, most often before the age of 20. Symptoms may manifest in patient older than 50. However, such late onset may be related to certain mutations, such as multiple base pair insertions in CACNA1A.

CHARECTERISTICS: • Recurrent attacks of ataxia lasting for several hours to days. It may be provoked by physical exertion, emotional stress or alcohol. • Several patients have myasthenic symptoms due to impaired neuromuscular transmission. • Attacks may occur daily or over longer intervals • Migraine headache occurs in more than half.

SYMPTOMS: • central ocular motor disturbances such as gaze-holding deficits • saccadic smooth pursuit • impaired visual suppression of the vestibulo-ocular reflex • downbeat nystagmus • Mental retardation has also been reported • rarely bilateral internuclear ophthalmoplegia. • weakness • dystonia

GENETICS: The autosomal dominant hereditary disorder EA 2 is commonly (see below) caused by mutations of the calcium channel gene CACNA1A on chromosome 19p13. This gene encodes the CaV2.1 subunit of the P/Q-type calcium channel (2261 amino acids), which acts as the voltage sensor and ion-conducting pore. More than 30 mutations distributed throughout the gene have been described. Most of them are nonsense or frameshift mutations that lead to a disruption of the reading frame, or intronic mutations that predict aberrant splicing. There have also been reports of missense mutations (T4747C transition in the highly conserved transmembrane segment S6; AY1593/1594D), which result in a loss of function of the xpressed CACNA1A protein.33,34 At least two families with CAG-repeat expansions of the CACNA1A gene (defining the SCA 6 genotype) have been reported whose clinical presentation was indistinguishable from EA 2.

Notably, no mutation of the CACNA1A gene can be detected in approximately 30% to 50% of all patients presenting with typical clinical features of EA 2. Mutations lead to changes not only in ion currents and the release of neurotransmitters, but also in pH and metabolism, which may be related to the induction of the attacks and neurodegeneration. Localized phosphorus (31P) and proton (1H) magnetic resonance spectroscopy were performed in the cerebellum and the occipital lobe of six patients with EA 2. The 31P magnetic resonance spectroscopy showed decreased high-energy phosphate ratios in the cerebrum and increased pH in the cerebellum and cerebrum in untreated patients. The 1H magnetic resonance spectroscopy revealed high lactate peaks in three of the six patients. These metabolic alterations were probably induced by the calcium channelopathy and may characterize EA 2.

ANIMAL MODELS USED FOR EPISODIC ATAXIA TYPE 2:

There are several animal models of mutations in the CACNA1A gene (e.g., the tottering mouse, leaner mouse, rolling mouse Nagoya). The tottering mouse mutant contains a homozygous spontaneous C-to-T change at position 1802, which leads to a nonconservative prolineto- leucine amino acid substitution near the conserved P domain of the CACNA1A proteins. This mutation alters the pore function of the P/Q calcium channel and thereby reduces calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. Like patients with EA 2, the tottering mouse suffers from episodic attacks of ataxia induced by emotional and chemical stress. This animal model is most suitable for systematically analyzing the mechanism underlying attack precipitation.

The leaner mouse mutant also harbors a homozygous spontaneous mutation in the gene encoding the voltage gated Ca2 channel 1A subunit, the pore-forming subunit of P/Q-type Ca2_ channels. On the basis of this mutation, an out-of-frame splicing event in the carboxy terminus occurs which results in dramatic reductions in P-type Ca2channel function in cerebellar Purkinje neurons. These mice show degeneration of differentiated granule, Golgi, and Purkinje cells within the cerebellum. Leaner mice show features similar to those of tottering mice but have more severe ataxia.

TREATMENT:

Based on the pathophysiological understanding of EA 2, two established pharmacologic approaches focus on modulating the pH level and membrane ion conductance: ACTZ and 4-AP.

ACETAZOLAMIDE: ACTZ is the drug of first choice for preventive treatment of EA, with dosages of 250 to 1000 mg per day, although its efficacy has never been proven in a randomized controlled trial. ACTZ is a carbonic anhydrase inhibitor, which was initially shown to decrease the number of attacks in hypokalemic periodic paralysis patients.

The mechanism by which ACTZ prevents attacks—most likely via changes in pH—may be a key to understanding the disease pathomechanism, especially how the attacks are triggered. Changes in extracellular and intracellular pH cause alterations of the transmembrane conductance: for instance, a decrease in intracellular pH reduces potassium conductance, an increase in pH raises it. Thus, one hypothesis is that attacks are secondary to abnormally high intracellular pH values and that it is by reducing this pH level that ACTZ may prevent attacks.

4-AMINOPYRIDINE: It was recently shown that aminopyridines (such as potassium channel blockers) improve downbeat nystagmus, most likely by increasing the inhibitory influence of the Purkinje cells, a hypothesis that findings in animal experiments have supported. The loss-of-function mutations lead to the reduction of calcium-dependent neurotransmitter release, especially of the Purkinje cells. It is; therefore, assumed that ataxia in EA 2 is due to a dysfunction of the Purkinje cells, which leads to a reduced release of the inhibitory transmitter GABA. Thus, 4-AP may prevent attacks in EA 2 and improve downbeat nystagmus by increasing the release of GABA in the Purkinje cells. The following mechanisms also appear to be involved: 1) Animal experiments have shown that 4-AP increases the excitability of Purkinje cells; 1 to 10 micromolar concentrations of 4-AP markedly shortened the latency of calcium spike firing after the onset of depolarizing pulses. 2) 4-AP prolongs the duration of action potentials and increases the release of neurotransmitters by blocking several potassium currents: for example, the A-current and the delayed-rectifier current.

These effects of 4-AP were further evaluated in animal models of EA 2. It is remarkable that 4-AP was observed to completely prevent attacks of ataxia in the tottering mouse, but it did not affect the severity of breakthrough attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack.