Fampridine and Acetazolamide in EA2 and Related Familial EA: A Prospective Randomized Placebo-controlled Trial

ObjectiveWe determine the efficacy and safety of the treatment with prolonged-release 4-aminopyridine (fampridine) and acetazolamide for patients with episodic ataxia type 2 (EA2). Therefore, 30 patients with EA2 were treated with a random sequence of fampridine, acetazolamide, and placebo in a three-period crossover trial.MethodsA total of 30 patients with EA2 (eight female; aged 20-71 years; 18 genetically confirmed, four with a positive family history, eight with the clinical diagnosis) were enrolled in this phase III, randomised, double-blind, placebo-controlled, three-period crossover trial. Each period lasted 12 weeks with a four-week washout-period. Each patient received a random sequence of 20 mg/d fampridine, 750 mg/d acetazolamide, and placebo. The primary endpoint was the number of attacks during the last 30 days within the 12-week treatment-period. Participants, caregivers, and those assessing the outcomes were blinded to the intervention.ResultsCompared to placebo, fampridine reduced the number of attacks to 63% (95% CI 54% - 74%) and acetazolamide to 52% (95% CI 46% - 60%). A total of 39 (26.5%) adverse events were observed under treatment with fampridine (mostly tingling paraesthesia, and fatigue), 66 (44.9%) happened under acetazolamide (mostly taste disturbance, gastrointestinal complaints), and 42 (28.6%) under placebo (mostly gastrointestinal complaints).ConclusionBoth fampridine and acetazolamide significantly reduce the number of attacks in patients with EA2 and related EA in comparison to placebo. Fampridine 10 mg twice daily had fewer side effects than acetazolamide 250 mg three times daily.

Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2

Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of P/Q-type voltage-gated Ca2+ channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients. CACNA1A is heavily spliced and some of the identified EA2 mutations are predicted to disrupt selective isoforms of this gene. Modulating splicing of CACNA1A may therefore represent a promising new strategy to develop improved EA2 therapies. Because RNA splicing is dysregulated in many other genetic diseases, several tools, such as antisense oligonucleotides, trans-splicing, and CRISPR-based strategies, have been developed for medical purposes. Here, we review splicing-based strategies used for genetic disorders, including those for Duchenne muscular dystrophy, spinal muscular dystrophy, and frontotemporal dementia with Parkinsonism linked to chromosome 17, and discuss their potential applicability to EA2.