Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation

Abstract

Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15-65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0-40) was an average of 3.15 for all participants (range 0-14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean=50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed episodic ataxia type 1 and episodic ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed episodic ataxia type 1 (21%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.

Keywords: KCNA1; episodic ataxia type 1 (EA1); quality of life.

Figures

Figure 1

Ability of genetically proven EA1 participants to walk during an attack (n = 33). Participants were asked to rate how difficult it would be for them to walk during an average attack and were given the following options: unaided, with one stick, with a frame, with the aid of one person, with the aid of two people or not at all.

Figure 2

SF-36 domain scores in genetically proven EA1 participants, with and without persistent cerebellar ataxia. *P < 0.05. We compared scores on the SF-36 between those with genetically confirmed EA1 with attacks only (n = 26) and those with attacks and persistent cerebellar ataxia (n = 7). We hypothesized that persistent rather than intermittent symptoms would lead to a worse quality of life.

Figure 3

Comparison between SF-36 scores in those with genetically proven EA1 and those with EA1-like disease.