SMPD1 – Niemann-Pick Disease

Sphingomyelin phosphodiesterase-1 (SMPD1; HGNC:11120) encodes acid sphingomyelinase (ASM), whose deficiency underlies Niemann-Pick disease (MONDO:0001982). This autosomal recessive lysosomal storage disorder manifests with hepatosplenomegaly, pulmonary involvement, and in type A pronounced neurodegeneration and cherry-red macula (HP:0001433).

Genetic evidence for SMPD1 in Niemann-Pick disease is definitive. Over 185 distinct pathogenic SMPD1 alleles have been identified in more than 500 unrelated cases across diverse populations ([PMID:26499107]). Inheritance follows an autosomal recessive pattern, with compound heterozygosity or homozygosity for loss-of-function variants in SMPD1 consistently observed in probands.

Segregation analyses in multiple pedigrees further support pathogenicity. In a Serbian family, a T1177→G transition (c.1177T>G; p.Trp393Gly) cosegregated with disease in five affected individuals and two obligate carriers ([PMID:7762557]). In Ashkenazi Jewish cohorts, the p.Arg496Leu founder allele was homozygous in 10 of 31 alleles in type A patients and absent in 180 controls ([PMID:2023926]).

The variant spectrum includes missense (∼65%), frameshift (∼19%), splice-site, and in-frame deletions. Recurrent founder variants include p.Arg496Leu in Ashkenazi Jews (32% of type A alleles; [PMID:2023926]) and ΔR608 in type B patients ([PMID:1885770]). A representative severe allele, c.1735G>A (p.Gly579Ser), abolishes ASM activity in COS-1 cells and was first described in a type A patient ([PMID:1718266]).

Functional studies demonstrate loss-of-function mechanism. Expression of L302P and R496L ASM cDNAs in COS-1 cells yields <1% residual activity, consistent with type A phenotype ([PMID:1391960]). Imprinting at SMPD1 further modulates phenotype via maternal allele predominance; treatment with 5-aza-2′-deoxycytidine reactivates the paternal allele and increases ASM levels ([PMID:16642440]). Animal models expressing R496L and ΔR608 recapitulate visceral and neurological features and inform enzyme replacement strategies.

Collectively, genetic and experimental data establish a definitive association between SMPD1 and Niemann-Pick disease. Diagnostic confirmation relies on enzyme assay and SMPD1 sequencing, enabling carrier screening in high-risk populations and guiding emerging therapies. Key Take-home: SMPD1 genetic testing and ASM activity assay are essential for accurate diagnosis and management of Niemann-Pick disease.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients PMID:2023926
• American Journal of Human Genetics • 1995 • Molecular analysis of the acid sphingomyelinase deficiency in a family with an intermediate form of Niemann-Pick disease PMID:7762557
• Biochemical and Biophysical Research Communications • 1991 • Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A PMID:1718266
• Blood • 1992 • Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients PMID:1391960
• American Journal of Human Genetics • 2006 • Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease PMID:16642440
• Human Mutation • 2016 • SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants PMID:26499107

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