Glucosylsphingosine (Lyso-Gb1) Dynamics in Untreated States in Gaucher Disease

Glucosylsphingosine (lyso-Gb1) serves as a biomarker for evaluating disease activity in Gaucher disease (GD). While treatment-related changes are documented, the dynamics of lyso-Gb1 during untreated states remain poorly understood. This retrospective, longitudinal cohort study utilized a large GD database comprising 701 patients and over 6200 visits with lyso-Gb1 measurements. Patients with at least two untreated visits were included in the analysis (n = 272). A significant change was defined as ≥50 ng/mL for lyso-Gb1, ≥1 g/dL for hemoglobin, and ≥50 × 109/L for platelet count. Multivariable logistic regression analyses identified clinical factors associated with lyso-Gb1 decline or an increase. During untreated states, 35 patients (12.9%; 95% CI 9.4–17.5%) exhibited a decline in lyso-Gb1, with a median decrease of 96.3 ng/mL. This decline was more common in females (OR 3.50, p = 0.032) and associated with higher initial lyso-Gb1 levels (p < 0.001) and baseline hemoglobin (p = 0.032). An increase in lyso-Gb1 was observed in 98 patients (36.0%; 95% CI 30.5–41.9%), with a median rise of 135.1 ng/mL. This increase correlated with lower baseline platelet counts (p = 0.003), lower baseline hemoglobin (p = 0.002), and longer follow-up duration (p = 0.001). In many cases, lyso-Gb1 increases were observed without a preceding change in hemoglobin or platelet count. In summary, declines in lyso-Gb1 in untreated states are rare but possible. The association with female sex may reflect inflammatory effects. Although increases in lyso-Gb1 were expected without treatment, they occurred mainly in patients with higher disease severity markers. Nevertheless, most patients in the untreated states remained stable within ±50 ng/mL. These findings demonstrate a heterogeneous trajectory of lyso-Gb1 across untreated states and highlight the importance of interpreting lyso-Gb1 changes within the clinical context when making treatment decisions.