Alpha-mannosidosis (AM) is a rare lysosomal storage disease with heterogeneous disease manifestations and a continuous spectrum of severity. The only specific treatment for AM is enzyme replacement therapy with velmanase alfa (VA). The focus of this analysis was to assess changes in physician-reported clinical manifestations of AM following VA treatment, using data from Étoile Alpha, a multicenter, non-interventional registry of AM patients treated with VA in France. The cohort included 16 patients (7 females [43.7%]) and 9 males [56.3%]), with a median (range) age at VA initiation and duration of VA treatment of 15.7 (6.1–49.4) and 3.3 (1.1–9.2) years, respectively. Clinical outcomes, including 3-minute stair climb test, 6-minute walk test, forced expiratory volume in 1 second and forced vital capacity, showed numerical improvements from baseline to the last assessment. VA treatment was associated with significant ( p < 0.0001) improvements in overall physician-assessed health assessment scores, encompassing motor, quality of life and psychological domains. Across all individual clinical manifestations, VA led to either improvement or stability, with no deteriorations reported. Lower patient age at inclusion, diagnosis and at VA initiation were significantly ( p < 0.05) associated with improvement of clinical manifestations. To complement these clinical data, physician-reported narratives recorded before and after VA treatment were evaluated using natural language processing. Sentiment analysis revealed that all pre-treatment narratives were negative, with shifting to positive sentiment in 81.3% of cases following treatment. This analysis highlights the varied clinical manifestations associated with AM and underscores the potential benefits of early intervention with enzyme replacement therapy.