Favorable clinical response to olipudase alfa in a patient with two variants of uncertain significance in SMPD1: a case report

Abstract Background Acid sphingomyelinase deficiency (ASMD), also known as Niemann–Pick disease, is a rare lysosomal storage disorder caused by biallelic pathogenic variants in the Sphingomyelin phosphodiesterase 1 (SMPD1) gene, leading to the deficient activity of acid sphingomyelinase (ASM) enzyme. Case presentation We report a pediatric case of ASMD with non-neurological involvement in a 13-year-old patient. Although ASM activity was significantly reduced, initial genetic testing identified two SMPD1 variants classified as variants of uncertain significance (VUS). The patient initiated enzyme replacement therapy (ERT) with olipudase alfa at age 11, following its approval for ASMD with non-neurological manifestations. After 18 months of treatment, the patient experienced substantial clinical improvement without adverse effects. Conclusion This case underscores the therapeutic benefit of olipudase alfa in ASMD, even in the setting of initially inconclusive genetic findings, and highlights the importance of context-specific interpretation and reassessment of VUS in clinical decision-making.