Acid sphingomyelinase deficiency

Summary

Acid sphingomyelinase deficiency (MONDO:0100464) is a disease with 1 cohort gene and 10 clinical trials. Top therapeutic interventions include olipudase alfa.

At a glance

• Cohort genes: 1
• ClinVar variants: 10
• Clinical trials: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acid sphingomyelinase deficiency
Mondo ID	MONDO:0100464
UMLS	C5243927
MedGen	1800807
GARD	0026231
Is cancer (heuristic)	no

Data availability: 10 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › lymphoid system disorder › lymphatic system disorder › histiocytosis › non-Langerhans cell histiocytosis › Niemann-Pick disease › acid sphingomyelinase deficiency

Related subtypes (3): Niemann-Pick disease type C, Niemann-Pick disease type E, chronic neurovisceral acid sphingomyelinase deficiency

Subtypes (2): Niemann-Pick disease type A, Niemann-Pick disease type B

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

10 retrieved; paginated sample, class counts are floors:

6 pathogenic, 2 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1427800	NM_000543.5(SMPD1):c.742G>T (p.Glu248Ter)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1684031	NM_000543.5(SMPD1):c.668G>A (p.Cys223Tyr)	SMPD1	Pathogenic	criteria provided, single submitter
2446428	NM_000543.5(SMPD1):c.1390G>T (p.Glu464Ter)	SMPD1	Pathogenic	criteria provided, single submitter
2990	NM_000543.5(SMPD1):c.996del (p.Phe333fs)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
371218	NM_000543.5(SMPD1):c.193del (p.Ser65fs)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
632992	NM_000543.5(SMPD1):c.564dup (p.Lys189fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633426	NM_000543.5(SMPD1):c.1675_1676del (p.Val559fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
93318	NM_000543.5(SMPD1):c.1624C>T (p.Arg542Ter)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
4081802	NM_000543.5(SMPD1):c.1092-1G>A	SMPD1	Likely pathogenic	criteria provided, single submitter
556649	NM_000543.5(SMPD1):c.894_902del (p.Thr300_Thr302del)	SMPD1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMPD1	Orphanet:77292	Infantile neurovisceral acid sphingomyelinase deficiency
SMPD1	Orphanet:77293	Chronic visceral acid sphingomyelinase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMPD1	HGNC:11120	ENSG00000166311	P17405	Sphingomyelin phosphodiesterase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMPD1	Sphingomyelin phosphodiesterase	Converts sphingomyelin to ceramide.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMPD1	Enzyme (other)	yes	3.1.4.12	Calcineurin-like_PHP, SaposinB_dom, Saposin-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
stromal cell of endometrium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMPD1	262	ubiquitous	marker	type B pancreatic cell, stromal cell of endometrium, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMPD1	1,729

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMPD1	P17405	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid metabolism	1	300.5×	0.009	SMPD1
Glycosphingolipid catabolism	1	292.8×	0.009	SMPD1
Regulation of clotting cascade	1	233.1×	0.009	SMPD1
Sphingolipid metabolism	1	167.9×	0.009	SMPD1
Metabolism of lipids	1	31.6×	0.038	SMPD1
Metabolism	1	11.6×	0.086	SMPD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
termination of signal transduction	1	5617.3×	0.002	SMPD1
sphingomyelin metabolic process	1	3370.4×	0.002	SMPD1
sphingomyelin catabolic process	1	3370.4×	0.002	SMPD1
response to type I interferon	1	1872.4×	0.003	SMPD1
glycosphingolipid catabolic process	1	1532.0×	0.003	SMPD1
positive regulation of viral entry into host cell	1	1203.7×	0.003	SMPD1
positive regulation of endocytosis	1	802.5×	0.004	SMPD1
response to tumor necrosis factor	1	624.1×	0.004	SMPD1
plasma membrane repair	1	581.1×	0.004	SMPD1
response to cocaine	1	581.1×	0.004	SMPD1
response to interleukin-1	1	510.7×	0.004	SMPD1
ceramide biosynthetic process	1	421.3×	0.004	SMPD1
response to ionizing radiation	1	411.0×	0.004	SMPD1
symbiont entry into host cell	1	401.2×	0.004	SMPD1
negative regulation of MAPK cascade	1	300.9×	0.005	SMPD1
cellular response to UV	1	295.6×	0.005	SMPD1
wound healing	1	227.7×	0.006	SMPD1
cellular response to calcium ion	1	200.6×	0.006	SMPD1
cholesterol metabolic process	1	195.9×	0.006	SMPD1
response to virus	1	144.0×	0.008	SMPD1
response to xenobiotic stimulus	1	69.1×	0.017	SMPD1
positive regulation of apoptotic process	1	56.7×	0.019	SMPD1
nervous system development	1	45.9×	0.023	SMPD1
signal transduction	1	16.1×	0.062	SMPD1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SMPD1	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMPD1	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
FENDILINE	2	SMPD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SMPD1	42	Binding:40, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMPD1	3.1.4.12	sphingomyelin phosphodiesterase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
FENDILINE	2	SMPD1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SMPD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06949358	PHASE2	COMPLETED	A Study to Evaluate Safety and Tolerability of Olipudase Alfa in Pediatric and Adult Participants With Acid Sphingomyelinase Deficiency (ASMD) Who Completed the DFI12712 or the LTS13632 Study in France
NCT00410566	PHASE1	TERMINATED	Safety Study of rhASM Enzyme Replacement Therapy in Adults With Acid Sphingomyelinase Deficiency (Niemann-Pick Disease)
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT05992532	Not specified	RECRUITING	GammaGA: Prevalence of Acid Sphingomyelinase Deficiency Disease (ASMD) and Gaucher Disease in Patients With Monoclonal Gammopathies and/or Multiple Myeloma
NCT06192576	Not specified	RECRUITING	A Real-world Long-term Safety and Immunogenicity Study of Olipudase Alfa Therapy in Pediatric Patients Less Than 2 Years of Age With Acid Sphingomyelinase Deficiency (ASMD)
NCT06985212	Not specified	NOT_YET_RECRUITING	National Multicentre Study of the Natural History of Acid Sphingo-myelinase Deficiency in Adults and Children
NCT07274826	Not specified	ACTIVE_NOT_RECRUITING	Diagnostic Creteria of Acid Sphingomyelinase Deficiency (ASMD)
NCT04845958	Not specified	COMPLETED	A Non-Interventional National Study in Pediatric Patients With Unexplained Enlarged Spleen
NCT05359276	Not specified	COMPLETED	Data Analysis of Adult and Pediatric Participants With Acid Sphingomyelinase Deficiency (ASMD) on Early Access to Olipudase Alfa in France
NCT05641103	Not specified	COMPLETED	PREDIGA 2: Spanish Acronym of Educational and Diagnostic Project for Gaucher and ASMD

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OLIPUDASE ALFA	4	4