Niemann-Pick disease type A (NPD-A) is a rare, autosomal-recessive lysosomal storage disorder caused by pathogenic variants in the SMPD1 gene. These variants lead to a deficiency of acid sphingomyelinase. This report describes an NPD-A case diagnosed in early infancy following the deaths of two siblings. A novel SMPD1 variant was identified in this case.

A two-month-old female infant was referred to our institution with a preliminary diagnosis of NPD-A, prompted by a family history of sibling deaths. Physical examination revealed a flat nasal bridge and hepatosplenomegaly; otherwise, systemic findings were normal. The neurological examination was normal. Biochemical analysis revealed significantly reduced acid sphingomyelinase activity (2.1 nmol MU/mg protein/17 hours), which warranted further molecular investigation. Sequencing revealed a previously unreported homozygous frameshift variant in the SMPD1 gene (c.368del; p.N123Ifs*3) that was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Follow-up at four months showed progression of hepatosplenomegaly. The patient had achieved some developmental milestones. However, at ten months of age, she presented with acute respiratory distress and severe cyanosis. Despite receiving intensive care and ventilatory support, she died from her illness at 10.5 months of age.

This case highlights the identification of a likely pathogenic variant in the SMPD1 gene associated with the severe infantile phenotype of NPD-A. The patient’s clinical presentation and disease course were consistent with the classic form of the disorder. These findings contribute to the expanding mutational spectrum of SMPD1 and emphasize the importance of early diagnosis in at-risk populations.