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Acid sphingomyelinase deficiency (ASMD), encompassing Niemann-Pick disease types A and B, is an autosomal recessive lysosomal storage disorder caused by biallelic loss-of-function variants in SMPD1 (SMPD1) leading to sphingomyelin accumulation in multiple organs (Acid sphingomyelinase deficiency). Clinical validity is Definitive based on over 150 unrelated probands, consanguineous and non-consanguineous pedigrees, robust segregation data and concordant functional studies.
ASMD is inherited in an autosomal recessive manner. More than 25 families with ≥2 affected sib pairs and >100 sporadic cases have been reported worldwide, with multi-family segregation demonstrating complete penetrance in homozygotes and compound heterozygotes ([PMID:22367733], [PMID:30795770]).
Genetic evidence is Strong: over 200 distinct SMPD1 pathogenic alleles have been identified, including missense, nonsense, splice site, frameshift and small indels. Recurrent variants such as c.1829_1831del (p.Arg610del) and c.1076C>A (p.Ala359Asp) show founder effects in Mediterranean and Chilean populations, respectively. Segregation analyses report at least 19 affected relatives across pedigrees sharing biallelic SMPD1 variants.
Variant spectrum spans 65% missense and 19% frameshift mutations, with additional splice and deep-intronic changes documented in multi-ethnic cohorts ([PMID:26499107]). A representative coding change is c.340G>A (p.Val114Met), shown to abolish enzyme function in patient fibroblasts and heterologous systems.
Functional evidence is Strong: missense and frameshift SMPD1 alleles consistently yield <5% residual acid sphingomyelinase activity in patient cells and COS-1/COS-7 expression assays ([PMID:1718266], [PMID:1391960]). Mouse models carrying common NP-A/B mutations (e.g., p.R496L, ΔR608) recapitulate visceral lipid storage and neurological phenotypes, while patient-derived liver organoids exhibit sphingomyelin and cholesterol ester accumulation with lysosomal stress signatures ([PMID:18815062], [PMID:37628828]).
Therapeutic interventions with olipudase alfa, a recombinant enzyme replacement therapy, demonstrate significant reductions in hepatosplenomegaly, normalization of liver enzymes and stabilization of lipid biomarkers in infant and pediatric patients over 2 years of follow-up ([PMID:39834487], [PMID:40236726]). Early initiation correlates with better growth and pulmonary outcomes.
No credible conflicting evidence has been reported; sequence variants classified as benign maintain normal enzyme activity. Key take-home: genetic screening for SMPD1 variants and biochemical enzyme assays enable definitive ASMD diagnosis, inform carrier counseling, and guide timely enzyme replacement therapy.
Gene–Disease AssociationDefinitiveOver 150 unrelated probands across multiple families with consistent segregation and functional concordance Genetic EvidenceStrong
Functional EvidenceStrongEnzyme assays in patient cells, COS-cell expression, organoids and mouse models demonstrating loss-of-function |