SMPD1 – Niemann-Pick disease type A

Niemann-Pick disease type A (NPA; MONDO:0009756) is a rare, autosomal recessive neurovisceral lysosomal storage disorder caused by biallelic loss-of-function variants in SMPD1 (HGNC:11120), encoding acid sphingomyelinase (ASM). Affected infants present with failure to thrive, hepatosplenomegaly, profound neurodegeneration and death in early childhood (HP:0001433, HP:0001263, HP:0001522). Early diagnosis relies on detecting deficient ASM activity and confirming SMPD1 variants.

Multiple unrelated NPA families (>20 probands across at least 12 kindreds) have been reported with homozygous or compound heterozygous SMPD1 pathogenic variants, including frameshift and missense changes (e.g., NM_000543.5:c.398G>A (p.Cys133Tyr)) supporting autosomal recessive inheritance (AR)[PMID:31941852][PMID:10694919]. A founder 677delT frameshift allele underlies clustering of NPA in 12 Israeli Arab families (premature stop) segregating with disease (PMID:10694919).

The variant spectrum in NPA includes: 2-bp deletions (c.1785_1786del (p.Ala597fs)) and single-base substitutions disrupting the ASM saposin domain (c.398G>A (p.Cys133Tyr))[PMID:26913189][PMID:31941852]. Recurrent alleles such as c.573del (p.Ser192fs) occur in consanguineous pedigrees, while Ashkenazi Jewish founder mutations (c.905T>C (p.Leu302Pro)) have been functionally modelled in iPSC lines to recapitulate ASM deficiency (HP:0001263)[PMID:31132580].

Segregation analyses in multiplex families, including consanguineous kindreds, confirm that affected sib pairs and cousins inherit biallelic SMPD1 variants with complete penetrance and no heterozygote manifestation[PMID:10694919]. No conflicting evidence has been reported for NPA.

Functional studies demonstrate that NPA-associated SMPD1 missense (p.Cys133Tyr) and frameshift alleles yield undetectable ASM activity in patient fibroblasts and heterologous COS-7 or HeLa cell models, without impairing lysosomal targeting but abolishing catalysis (haploinsufficiency via loss of catalytic function)[PMID:31941852][PMID:37628828]. Patient-derived liver organoids further show sphingomyelin accumulation and lysosomal stress gene signatures mirroring human disease[PMID:37628828].

Integration of genetic and experimental data supports a definitive gene-disease relationship: SMPD1 biallelic loss-of-function causes early-onset NPA via profound ASM deficiency. SMPD1 sequencing and enzymatic assays are essential for diagnosis, carrier screening and guiding future enzyme-based therapies. Key take-home: Biallelic pathogenic SMPD1 variants definitively underlie Niemann-Pick disease type A, enabling precise molecular diagnosis and therapeutic development.

References

• F1000Research • 2015 • Case Report: Genetic analysis and anesthetic management of a child with Niemann-Pick disease Type A. PMID:26913189
• The Tohoku journal of experimental medicine • 2020 • An Early-Onset Neuronopathic Form of Acid Sphingomyelinase Deficiency: A SMPD1 p.C133Y Mutation in the Saposin Domain of Acid Sphingomyelinase. PMID:31941852
• Human mutation • 1998 • Niemann Pick Disease type A in Israeli Arabs: 677delT, a common novel single mutation. PMID:10694919
• Stem cell research • 2019 • An induced pluripotent stem cell line (TRNDi009-C) from a Niemann-Pick disease type A patient carrying a heterozygous p.L302P (c.905 T>C) mutation in the SMPD1 gene. PMID:31132580
• International journal of molecular sciences • 2023 • Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis. PMID:37628828

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