The patient from non-consanguineous Albanian parents presented at four months with isolated splenomegaly. Oculomotor apraxia and hepatomegaly progressively appared during the second half of the first year. Hematological values showed intermittent bicytopenia (hemoglobin 103-113 g/L [reference >100], neutrophils 1.25-1.80 G/L [>1.50] and thrombocytes 71-116 G/L [>150]). Chitotriosidase was 27.5 mU/ml (reference <1.03). Decreased beta-glucosidase activity in lymphocytes confirmed the diagnosis of Morbus Gaucher (residual activity 10%). The double homozygous mutations c.882 T>G and c.1342 G>C detected in the GBA gene of our patient (AMC Amsterdam) have been described earlier in Gaucher type II patients. At one year, tip-toe-posture and slight extension reaction of the upper limbs were the only additional neurologic abnormalities in an otherwise well developing girl, suggesting an intermediary rather than type II Gaucher, and prompted us to introduce combined enzyme-replacing (ERT) and substrate-reduction (SRT) therapies. Since treatment initiation (follow-up 9 months), both ERT and SRT are well tolerated, hepatosplenomegaly and blood cell counts have normalized almost completely. Moreover, psychomotor development is near to normal and neurological signs stable. Notwithstanding the necessarily cautious interpretation of the short follow-up, these findings suggest that early initiation of combined ER-and SR-therapies might improve outcome in Gaucher disease. Background: In GD1, deficient acid β-glucosidase activity causes glucosylceramide accumulation. Eliglustat, a potent and specific glucosylceramide synthase inhibitor, is under development as an oral substrate reduction therapy for GD1. Objective: Report long-term efficacy and safety results. Methods: Efficacy outcomes included changes in hemoglobin and platelet levels, spleen and liver volumes, and bone mineral density (BMD). Achievement of therapeutic goals was measured. Results: Of 26 enrolled patients, 19 completed 3 years. After 3 years, mean hemoglobin level and platelet count increased by 2.6 g/dL and 91%, respectively; mean spleen and liver volumes decreased by 61% and 29%, respectively (all P<.0001). The majority of patients met long-term therapeutic goals for these parameters; all met ≥3 long-term therapeutic goals. Mean lumbar spine BMD increased by 0.6 Z-Score; femur dark marrow was reduced or stable. There were no bone crises; new lytic lesions or bone infarcts; or worsening of pre-existing lytic lesions or bone infarcts. Eliglustat was welltolerated. Most adverse events (AEs) were mild and unrelated to treatment. Eight drug-related AEs, all mild, occurred in 6 patients. Conclusions: Eliglustat has shown promising efficacy and safety, with clinically meaningful improvements in hematologic, visceral, and bone parameters. Three Phase 3 trials are enrolling patients. Conflict of Interest declared.