Time to rethink Gaucher disease types, study says

New research has found that Gaucher disease may be more phenotypically diverse than previously thought, underscoring the need to revisit the existing disease classifications.

“The greatest interest in oculomotor function in Gaucher disease is the pursuit of quantifiable outcome measures for therapeutic trials for neuronopathic disease. Given the variability in clinical features and rate of disease progression, a good biomarker is required to demonstrate efficacy of novel drugs,” the researchers said. “To date, no robust biochemical or clinical measure has been identified.”

In a sample of 39 patients with type 1 (non-neurological) and 21 with type 3 (neurological) Gaucher disease, the researchers sought to evaluate the utility of eye movement as a biomarker, using the EyeSeeCam device to record and quantify saccades and eye reaction times. Thirty-five healthy controls were also included, from whom reference ranges were computed.

Saccade performance was significantly impaired in both Gaucher disease types relative to controls. For instance, saccades were significantly longer in all directions in type 3 Gaucher disease patients, while those with type 1 disease had similarly prolonged saccades relative to controls, but only along the horizontal. [Orphanet J Rare Dis 2020;15:349]

Between type 1 and type 3 patients, the latter also showed significantly longer saccade durations along the horizontal.

Eye response times in all directions were likewise greater in patients with type 3 Gaucher disease than in healthy controls, while among type 1 patients, leftward and upward eye response times were significantly prolonged. No such difference was reported between the two disease types.

The researchers also reported a significant, but expected, difference between type 3 patients and controls in terms of saccade velocity.

Notably, there was a similar discrepancy in peak saccade velocity between type 1 Gaucher disease patients and controls (p<0.017), with the exception of downward peak velocity. Since type 1 disease is known to be non-neuronopathic, this was an unexpected finding, they said.

Looking at each patient individually revealed slower eye movements, with 19 (56 percent) of the type 1 patients logging peak saccade velocities below the reference range; 14 of them shared saccade abnormalities in at least three measures.

“The most striking finding in this study was a cohort of patients who had been phenotypically categorized as having type 1 Gaucher disease but who have significantly slower saccadic eye movements than healthy controls…” the researchers said. “Some such patients also had subtle additional neurological features which hadn’t previously been explained.”

To explore this phenomenon deeper, they looked at the genotype of these 14 patients and found that 12 of them had the R463C variant of the GBA1 gene.

When the R463C patients were taken as their own distinct Gaucher subgroup, repeating the statistical analyses for saccade performance across four groups (type 1, type 3, R463C, and controls) revealed distinct and clear differences for most parameters in the left, right, up, and down directions.

“This study showed that a subgroup of patients with type 1 Gaucher disease and a shared GBA1 mutation all had significantly slowed saccades suggestive of a greater phenotypic spectrum of Gaucher disease than previously described,” the researchers said.

“[T]hese observations raise the question of the utility of current phenotypic categorization of Gaucher disease for patients where the disease descriptions are becoming increasingly heterogeneous,” they added.