SMPD1 encodes sphingomyelin phosphodiesterase 1 (acid sphingomyelinase), a lysosomal enzyme catalyzing sphingomyelin hydrolysis to ceramide and phosphocholine 1. Loss-of-function SMPD1 mutations cause acid sphingomyelinase deficiency (ASMD), presenting as Niemann-Pick disease types A and B—autosomal recessive lysosomal storage disorders with distinct severity profiles 2. Type A manifests neuronopathic features with visceral involvement and premature death, while type B presents primarily visceral manifestations including hepatosplenomegaly and pulmonary disease 3. Biochemically, ASMD patients show decreased peripheral leukocyte acid sphingomyelinase activity and elevated plasma 7-ketocholesterol levels correlating with disease severity 3. Genotype-phenotype correlations identify specific variants associated with disease onset and progression; for example, p.Arg602His and p.Asn522Ser homozygotes exhibit late-onset type B, while p.His284SerfsX18 and related variants correlate with neuronopathic type A 3. Beyond inherited disease, SMPD1 inhibition shows therapeutic potential in glioblastoma and hepatocellular carcinoma through ceramide pathway modulation and lysosomal dysfunction induction 41. Additionally, SMPD1 variants contribute to Parkinson's disease genetic burden, implicating lysosomal dysfunction in neurodegeneration 5. Enzyme replacement therapy with olipudase α represents the first approved disease-modifying treatment for ASMD patients 2.