Submission Details

The relationship between SMPD1 and acid sphingomyelinase deficiency (ASMD), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of May 18, 2022. SMPD1 encodes acid sphingomyelinase (ASM), an enzyme found in lysosomes and in the extracellular space where it catalyzes the conversion of sphingomyelin, a major component of membranes, into ceramide and phosphocholine (Gorelik et al, 2016, PMID: 27435900).

Historically, biallelic variants in SMPD1 have been associated with Niemann-Pick disease types A and B. Niemann-Pick disease type A, the neurovisceral form, is characterized by hepatosplenomegaly with rapid neurological deterioration leading to death in the first few years of life. Niemann-Pick disease type B, a later-onset, chronic visceral form, is characterized by progressive visceral organ symptoms including hepatosplenomegaly and pulmonary insufficiency, and survival into adulthood. Some patients present with an intermediate phenotype, Niemann-Pick disease type A/B. Based on this clinical continuum of disease, these conditions are now described as “acid sphingomyelinase deficiency” (ASMD) (Wasserstein and Schuchman, 2021, PMID: 20301544). Indeed, per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern for Niemann-Pick disease types A and B. Therefore, these disease entities have been lumped under one disease entity, acid sphingomyelinase deficiency, for this curation. Of note, variants in SMPD1 have also been reported as risk factors for Parkinson disease (Ysselstein et al, 2019, PMID 30726573; Paciotti et al, 2020, PMID: 32098196). The relationship between SMPD1 and Parkinson disease was not assessed here but may be curated at a later date.

Biallelic variants in SMPD1 were first reported in patients with ASMD in 1991 (Levran et al, PMID: 2023926; Felinz et al, PMID: 1718266). Since then, over 180 disease-associated variants have been reported (Zampieri et al, 2016, PMID: 26499107). In this curation, data on 10 unique variants (5 missense, 2 nonsense, 2 frameshift, 1 inframe deletion) from 8 probands from 5 publications were collected (Levran et al, 1991, PMID: 2023926; Takahashi et al, 1992, PMID: 1618760; Pittis et al, 2004, PMID: 15241805; Desnick et al, 2010, PMID: 20386867; Ordieres-Ortega et al, 2020, PMID: 32375665). The MANE reference sequence, NM_000543.4, was used. This leads to a shift of +2 amino acids for some published variants, particularly for variants in older literature, due to an leucine-alanine dipeptide within the polymorphic signal peptide (Zampieri et al, 2016, PMID: 26499107). ASMD is a pan-ethnic condition, but is more common in individuals of Ashkenazi Jewish descent, associated with the founder variants c.996delC, p.Leu304Pro and p.Arg498Leu. The most frequently reported mutation worldwide is p.Arg610del, associated with a milder phenotype (Zampieri et al, 2016, PMID: 26499107; see Table 6 in Wasserstein and Schuchman, 2021, PMID: 20301544) ). The disease mechanism is loss of function. Further genetic evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached.

Experimental evidence supporting this gene-disease relationship includes the biochemical function of the gene product of SMPD1 (acid sphingomyelinase), which is consistent with the biochemical and clinical findings in patients (Schuchman et al, 1991, PMID: 1840600; Jenkins et al, 2009, PMID: 19385042), the features of a knock out mouse model and a cat with ASM deficiency (Horinouchi et al, 1995, PMID: 7670466; Takaichi et al, 2020, PMID: 32347185), improvement in the clinical, biochemical and histological features in mice treated with AAV9-hASM gene therapy (Samaranch et al, 2019, PMID: 31434754), and adults with ASM deficiency treated with enzyme replacement therapy (Wasserstein et al, 2022, PMID: 35471153). Additional experimental evidence is available in the literature but the maximum points for experimental evidence (6 points) has been reached.

In summary, SMPD1 is definitively associated with acid sphingomyelinase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the Lysosomal Diseases GCEP on July 8, 2022 (SOP Version 9).

Data provided by the ClinGen Prenatal GCEP on February 19, 2025: Review of the prenatal presentation of this gene has shown no clear evidence of a prenatal phenotype in patients with biallelic pathogenic variants in SMPD1. There are two reports (PMID: 15305357; 27928775) of this condition presenting with non-immune hydrops fetalis using biochemical testing but no genetic testing was performed.