4-Aminopyridine in Episodic Ataxia Type 2

This study aims to determine whether 4-aminopyridine (4AP) can reduce attacks of ataxia in
patients with episodic ataxia type 2 (EA2), a rare but often debilitating condition.
Episodic ataxia (EA) is a group of inherited disorders characterized by recurrent, discrete
episodes of vertigo and ataxia variably associated with progressive ataxia. EA2, the most
common and the best characterized of all the EA syndromes, is caused by heterozygous
mutations in CACNA1A, which encodes the main subunit of a neuronal voltage-gated calcium
channel, Cav2.1.

Although observational data suggest symptomatic resolution with acetazolamide in many EA2
patients, the investigators found in our patient databases that at least a third of the EA2
patients continue to suffer debilitating ataxia attacks, either because of incomplete
control while on acetazolamide or because of intolerability or hypersensitivity to
acetazolamide. For these patients there is no alternative intervention. 4-Aminopyridine
(4AP) has been found to be helpful in a handful of patients with EA2. Recently,
dalfampridine, an extended release formulation of 4AP (AMPYRA) by Acorda Therapeutics,
received FDA approval to improve gait in multiple sclerosis.

In collaboration with Acorda, the investigators plan to recruit 20 subjects with genetically
defined EA2 who suffer frequent ataxia episodes (at least 3 episodes a month) to conduct a
randomized trial of 4AP to examine its efficacy and tolerability in EA2. Study subjects will
be recruited at UCLA and the University of Rochester to participate in a randomized,
double-blind, double-crossover trial of 4AP.Each treatment period is 2-months with a 1-week
wash-out period in between each treatment period. Participating subjects will undergo
standardized history and physical examination at the time of enrollment. Participants will
log their ataxia attacks daily by interactive voice response (IVR) system and will be
interviewed monthly for events and side effects/toxicity. Study visits will occur at the
beginning and the end of the study.

Inclusion Criteria:

Patients will be included if they:

- Have EA2 genetically confirmed to harbor mutations in CACNA1A

- Are ≥ 18 years of age

- Are not taking acetazolamide (because of intolerance, poor response, or allergy)

- Are able to maintain a daily log of ataxia episode(s) and report daily by using an
Interactive Voice Recording System (IVR) throughout the study

- Experience ≥ 3 ataxia episodes per month during the two-month screening period to
qualify for randomization

Exclusion Criteria:

Patients will be excluded if they:

- Have seizures or a history of seizures

- Have first-degree relatives with EA2 and seizures

- Have renal disease with impaired function (Creatinine clearance CrCl≤50ml/min)

- Are pregnant or breast feeding (women of childbearing age will be tested for
pregnancy and must be using birth control)

- Are unable to comply with the study requirement