In vitro and in vivo effects of Ambroxol chaperone therapy in two Italian patients affected by neuronopathic Gaucher disease and epilepsy

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the acid β-glucosidase encoding gene (GBA1), resulting in the deficient activity of acid β-glucosidase (GCase). To date, there is no approved treatment for the neurological manifestations of the disease. The role of Ambroxol as a chaperone for mutant GCase has been extensively demonstrated in vitro. Furthermore, different authors have reported beneficial effects of high doses of Ambroxol on neurological manifestations in patients affected by GD. In this report, we describe the in vitro and in vivo effects of Ambroxol in two patients (P1 and P2) affected by the neurological form of GD and epilepsy, carrying mutations already reported as responsive to the chaperone. Indeed, P1 presented the N188S mutation in compound heterozygous with a null allele (IVS2 + 1G > A) and P2 was homozygous for the L444P mutation. As expected, a beneficial effect of Ambroxol was observed in cultured fibroblasts as well as in vivo, both on epilepsy and on biomarkers of GD, in P1. However, Ambroxol was completely undefective in P2, suggesting that other factors besides the GBA1 mutation itself would be involved in the response therapy which would be difficult to predict based on the patient genotype. The present report expands the experience of Ambroxol treatment in neurological GD patients and highlights the need to in vitro test the individual response to Ambroxol even in patients carrying mutations already classified as responsive to the chaperone