Saccades velocity is strongly influenced by polyglutamine size in spinocerebellar ataxia type 2

Background: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant inherited disorder which is clinically characterized by progressive cerebellar ataxia, dysarthria, neuropathy and early slowing of horizontal saccadic eye movements. The underlying mutation is an unstable expansion of a polyglutamine domain within the protein ataxin-2. The prevalence of SCA2 is particulary high in Holguín province, Cuba.

Methods: We measured the horizontal saccade velocity of 82 Cuban SCA2 patients with genetically tested polyglutamine repeat size ranging from 34 to 50 (mean 40, SD 3) and disease duration from 1 to 42 years (mean 13.3, SD 7.9). The clinical assessment (ataxia score) was carried out using the International Cooperative Ataxia Rating Scale. 80 healthy non-paid volunteers served as control group.

Horizontal saccades with amplitudes of 10°, 20°, 30° and 60° were recorded binocularly with silver-silver electrodes and a 2-channel Otoscreen AC electronystagmograph (Jaeger-Toennies, Höchberg, Germany) and analysed by MATLAB software and statistical tests.

Results: Maximum saccadic velocity (MSV) showed significant differences at 10°, 20°, 30° and 60° (p<0.0001) between SCA2 patients and controls. Abnormal MSV was found already in patients with manifest ataxia for only 1 to 5 years. Stepwise linear regression analysis showed that 60° MSV was strongly influenced by polyglutamine size, and to a lesser degree by disease duration.

In contrast to MSV the strongest influence on ataxia score was through disease duration and less through polyglutamine expansion size.

Conclusion: Saccade velocity is a sensitive, specific and objective surrogate disease marker useful to search for modulation of polyglutamine toxicity by modifier genes.