Molecular genetics of Iranian patients with acid sphingomyelinase deficiency and Niemann-Pick disease type C: A comparative case series

Background Acid sphingomyelinase deficiency (ASMD), historically termed Niemann-Pick disease types A and B, and Niemann-Pick disease type C (NPC) represent distinct lysosomal storage disorders with different molecular etiologies. ASMD results from SMPD1 mutations causing sphingomyelinase deficiency, whereas NPC arises from NPC1 or NPC2 mutations disrupting intracellular cholesterol trafficking. Despite their historical grouping under “Niemann-Pick disease,” these conditions are genetically, biochemically, and clinically distinct. Methods This study investigated 11 unrelated Iranian individuals referred for genetic testing with suspected NPD (Niemann-Pick disease). Whole exome sequencing (WES) was performed, and variants were classified according to ACMG guidelines. Results Pathogenic or likely pathogenic variants were identified in 10 of 11 cases. SMPD1 variants (ASMD) were detected in six cases, with truncating variants associated with severe neuronopathic presentations (type A) and missense variants associated with predominantly visceral involvement (type B). NPC1 variants were identified in three cases, and NPC2 variants in two cases. Homozygosity was observed in 10 of 11 cases, consistent with autosomal recessive inheritance and the high rate of consanguinity (63.6%) in this cohort. Conclusion This study provides a comparative genetic analysis of ASMD and NPC in the Iranian population, highlighting the variant spectrum and genotype-phenotype correlations within each distinct disorder. The findings underscore the importance of molecular diagnosis for accurate classification and genetic counseling, particularly in populations with high consanguinity.