Exploring the long-term use of ambroxol in Gaucher disease type 2: insights from two pediatric cases.

Gaucher disease 2 (GD2) is a rare and rapidly progressive neuropathic lysosomal storage disorder with an average survival of 11-19 months. To date, no approved therapy is available, but the variant-dependent pharmacological chaperone ambroxol (ABX) has emerged as a promising off-label therapy. This long-term observational study encompasses 2 GD2 patients treated with high-dose ABX from the age of 4 and 1 months, respectively, in addition to enzyme replacement therapy (ERT). Previously published data of patient 1 demonstrated a significant increase in β-glucocerebrosidase activity in ABX-treated patient fibroblasts alongside nearly age-appropriate neurocognitive and motor development after 3 years of ABX therapy. Follow-up assessments at the present age of 6.5 years continued to show normal neurocognitive development. Glucosylsphingosine (Lyso-GL1) levels in cerebrospinal fluid (CSF) remained significantly decreased compared to pre-treatment levels. In patient 2, ABX-treated fibroblasts exhibited a slight increase in β-glucocerebrosidase activity. Nevertheless, Lyso-GL1 levels in CSF showed a notable decrease compared to baseline. Neurocognitive and motor function assessments at 40 months of age indicated a moderate to severe developmental delay, yet continuous developmental progress. These interim findings contribute to the mounting evidence supporting ABX as a variant-dependent treatment for GD2 patients.