The saccadic and neurological deficits in type 3 Gaucher disease

Abstract

Our objective was to characterize the saccadic eye movements in patients with type 3 Gaucher disease (chronic neuronopathic) in relationship to neurological and neurophysiological abnormalities. For approximately 4 years, we prospectively followed a cohort of 15 patients with Gaucher type 3, ages 8-28 years, by measuring saccadic eye movements using the scleral search coil method. We found that patients with type 3 Gaucher disease had a significantly higher regression slope of duration vs amplitude and peak duration vs amplitude compared to healthy controls for both horizontal and vertical saccades. Saccadic latency was significantly increased for horizontal saccades only. Downward saccades were more affected than upward saccades. Saccade abnormalities increased over time in some patients reflecting the slowly progressive nature of the disease. Phase plane plots showed individually characteristic patterns of abnormal saccade trajectories. Oculo-manual dexterity scores on the Purdue Pegboard test were low in virtually all patients, even in those with normal cognitive function. Vertical saccade peak duration vs amplitude slope significantly correlated with IQ and with the performance on the Purdue Pegboard but not with the brainstem and somatosensory evoked potentials. We conclude that, in patients with Gaucher disease type 3, saccadic eye movements and oculo-manual dexterity are representative neurological functions for longitudinal studies and can probably be used as endpoints for therapeutic clinical trials.

Trial registration: ClinicalTrials.gov NCT00001289.

Conflict of interest statement

Competing Interests: Research grants and honoraria from Genzyme Corporation, Shire HGT and Amicus Therapeutics.

Figures

Figure 1. CONSORT diagram for this study.

Figure 2. Saccadic eye movement parameters.

Figure 3. A. Slope of peak duration vs amplitude for vertical vs horizontal saccades.

The line is a least squares regression of the data points and has an R2 value of 0.3. This graph suggests there is a tendency for vertical and horizontal saccade performance to track together and the p value for that tendency is <0.005. B. Graph of regression slopes of saccade duration vs amplitude for vertical vs horizontal saccades. Again the least squares regression fit of the data points is shown and has an R2 value of 0.31. The test for relationship has a p<0.005. C. Graph of vertical vs horizontal latencies (data from the last visit). The regression line has an R2 of 0.68 and the test for relationship has p<0.00001.

Figure 4. Slope of peak duration vs amplitude for upward saccades over time.

Each point represents the results for a specific visit time.

Figure 5. Phase plane plots for saccadic velocity vs position.

These are phase plane plots of saccades made by 5 subjects on a specific date to differing target amplitudes. The origin of each saccade has been moved to zero and the velocity at each position along the saccade trajectory is shown. Since larger amplitude saccades typically generate faster velocities, this generates a family of curves where the saccade amplitude can be seen at the endpoint position. Here rightward curves are upward (A–F) or rightward (G–J) saccades and leftward saccades are downward (A–F) or leftward (G–J) saccades. A and B are plots of vertical saccades for 2 different normal controls. Horizontal saccades for normal controls were also similar to these plots and to each of the other normal controls. C and D show vertical saccades for Patient 3 at 2 different time points: D is 4 years later than C. E and F are similar vertical saccade plots for Patient 5, who had more difficulty making saccades. F is 4 years later than E. Note that for both patients downward saccades are slower than upward saccades. The plots in E and F also demonstrate the tendency for saccades to slow down and speed up during the course of the saccade. Although phase plane plots of normal controls' saccades looked similar to each other, each patient tended to have uniquely appearing phase plots that were reproducible over time as seen in these 2 patients. G through J are plots of horizontal saccadic velocity vs position. G and H are horizontal saccade phase plane plots for Patient 3, whose vertical saccades are plotted in C and D. Note that the horizontal saccades are slower here and tend to have more periods of slowing than for the same patient's vertical saccades. Again there is a 4-year time period between G and H. I and J are horizontal saccades for Patient 11 and there is a 4-year time period between J and I. These horizontal saccades are slower than in Patient 3 in A and B. In the later plot of both patients there is a tendency for the horizontal saccades to be slower over the 4-year period of observation.