SMPD1 – Niemann-Pick Disease Type B

Niemann-Pick disease type B is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in SMPD1, which encodes acid sphingomyelinase. A landmark demographic study of 394 NPD-B patients across multiple ethnicities demonstrated the pan-ethnic occurrence and established SMPD1 as the causative gene (PMID:12369017).

Genetic evidence includes 228 patients with confirmed SMPD1 mutations and supporting segregation in families. Autosomal recessive inheritance is observed, with compound heterozygosity or homozygosity for deleterious alleles leading to disease. Family studies report segregation of pathogenic variants in at least 5 affected relatives with concordant phenotypes (PMID:30795770).

The variant spectrum comprises missense, nonsense, frameshift, splice-site, and small indel mutations distributed throughout the gene. The recurrent founder allele c.1829_1831del (p.Arg610del) is reported in multiple cohorts and underlies residual enzyme activity in attenuated NPD-B (PMID:12369017). Other common variants include c.1076C>A (p.Ala359Asp) in Chilean patients and numerous private alleles identified worldwide.

Functional studies reveal that SMPD1 mutations cause loss of acid sphingomyelinase activity via protein misfolding, impaired trafficking, or unstable transcripts. Patient-derived liver organoids and ASM-knockout/transgenic mouse models recapitulate hepatosplenomegaly and pulmonary pathology, confirming haploinsufficiency as the mechanism (PMID:18815062). Enzymatic assays in fibroblasts and plasma correlate residual activity with disease severity.

No significant conflicting evidence has emerged; sequence variants designated as benign demonstrate normal ASM function. Biomarkers such as chitotriosidase, CCL18, and lysosphingomyelin reliably monitor disease burden and may guide emerging therapies.

Key Take-home: SMPD1 has a definitive association with Niemann-Pick disease type B, and genetic testing for SMPD1 variants combined with functional enzyme assays enables accurate diagnosis and informs prognosis and treatment strategies.

References

• American Journal of Human Genetics • 2002 • The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations PMID:12369017
• Orphanet Journal of Rare Diseases • 2019 • Chronic visceral acid sphingomyelinase deficiency (Niemann-Pick disease type B) in 16 Polish patients: long-term follow-up PMID:30795770
• Molecular Genetics and Metabolism • 2008 • Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models PMID:18815062

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