Niemann-Pick disease type A

Summary

Niemann-Pick disease type A (MONDO:0009756) is a disease caused by SMPD1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: SMPD1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,033
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated
Prevalence at birth	1-9 / 1 000 000	0.25	Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Niemann-Pick disease type A
Mondo ID	MONDO:0009756
MeSH	D052536
OMIM	257200
Orphanet	77292
DOID	DOID:0070111
ICD-10-CM	E75.240
ICD-11	530611243
NCIT	C126561
SNOMED CT	52165006
UMLS	C0268242
MedGen	78650
GARD	0007206
Is cancer (heuristic)	no

Data availability: 1,033 ClinVar variants · 4 GenCC gene-disease records · 14 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Niemann-Pick disease type A

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

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

600 retrieved; paginated sample, class counts are floors:

315 likely benign, 69 pathogenic, 69 likely pathogenic, 52 uncertain significance, 45 conflicting classifications of pathogenicity, 31 pathogenic/likely pathogenic, 10 benign/likely benign, 9 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
198093	NM_000543.5(SMPD1):c.1826GCC[1] (p.Arg610del)	APBB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2018848	NM_000543.5(SMPD1):c.69del (p.Thr24fs)	LOC130005193	Pathogenic	criteria provided, single submitter
2921607	NC_000011.10:g.6390221_6390884del	LOC130005193	Pathogenic	criteria provided, single submitter
100731	NM_000543.5(SMPD1):c.739G>A (p.Gly247Ser)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073151	NM_000543.5(SMPD1):c.175del (p.Ala59fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076908	NM_000543.5(SMPD1):c.839A>C (p.Asp280Ala)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1173964	NM_000543.5(SMPD1):c.257G>A (p.Trp86Ter)	SMPD1	Pathogenic	criteria provided, single submitter
1173967	NM_000543.5(SMPD1):c.647T>G (p.Leu216Arg)	SMPD1	Pathogenic	criteria provided, single submitter
1173970	NM_000543.5(SMPD1):c.1088T>G (p.Leu363Arg)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173972	NM_000543.5(SMPD1):c.1148A>G (p.Asn383Ser)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173973	NM_000543.5(SMPD1):c.1171A>C (p.Asn391His)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173978	NM_000543.5(SMPD1):c.1598C>A (p.Pro533Gln)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173979	NM_000543.5(SMPD1):c.1699C>T (p.Gln567Ter)	SMPD1	Pathogenic	criteria provided, single submitter
1173981	NM_000543.5(SMPD1):c.1151del (p.Met384fs)	SMPD1	Pathogenic	criteria provided, single submitter
1173982	NM_000543.5(SMPD1):c.504dup (p.His169fs)	SMPD1	Pathogenic	criteria provided, single submitter
1173983	NM_000543.5(SMPD1):c.1071_1081del (p.Glu358fs)	SMPD1	Pathogenic	criteria provided, single submitter
1173984	NM_000543.5(SMPD1):c.933_936delinsGAC (p.Val312fs)	SMPD1	Pathogenic	criteria provided, single submitter
1353540	NM_000543.5(SMPD1):c.167G>A (p.Trp56Ter)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1370114	NM_000543.5(SMPD1):c.1032T>G (p.Tyr344Ter)	SMPD1	Pathogenic	criteria provided, single submitter
1372840	NM_000543.5(SMPD1):c.1216C>T (p.Gln406Ter)	SMPD1	Pathogenic	criteria provided, single submitter
1386053	NM_000543.5(SMPD1):c.43del (p.Ser15fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1399082	NM_000543.5(SMPD1):c.1576del (p.Ala526fs)	SMPD1	Pathogenic	criteria provided, single submitter
1420134	NM_000543.5(SMPD1):c.820del (p.Met274fs)	SMPD1	Pathogenic	criteria provided, single submitter
1427800	NM_000543.5(SMPD1):c.742G>T (p.Glu248Ter)	SMPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1430049	NM_000543.5(SMPD1):c.1643_1644insA (p.Asn549fs)	SMPD1	Pathogenic	criteria provided, single submitter
1451535	NM_000543.5(SMPD1):c.193dup (p.Ser65fs)	SMPD1	Pathogenic	criteria provided, single submitter
1452305	NM_000543.5(SMPD1):c.742G>C (p.Glu248Gln)	SMPD1	Pathogenic	criteria provided, single submitter
1452689	NM_000543.5(SMPD1):c.477_483dup (p.Leu162fs)	SMPD1	Pathogenic	criteria provided, single submitter
1453617	NM_000543.5(SMPD1):c.572del (p.Pro191fs)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455924	NM_000543.5(SMPD1):c.1363C>T (p.Gln455Ter)	SMPD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SMPD1	Definitive	Autosomal recessive	Niemann-Pick disease	9

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
NPC1	Orphanet:216972	Niemann-Pick disease type C, severe perinatal form
NPC1	Orphanet:216975	Niemann-Pick disease type C, severe early infantile neurologic onset
NPC1	Orphanet:216978	Niemann-Pick disease type C, late infantile neurologic onset
NPC1	Orphanet:216981	Niemann-Pick disease type C, juvenile neurologic onset
NPC1	Orphanet:216986	Niemann-Pick disease type C, adult neurologic onset

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMPD1	HGNC:11120	ENSG00000166311	P17405	Sphingomyelin phosphodiesterase	gencc,clinvar
APBB1	HGNC:581	ENSG00000166313	O00213	Amyloid beta precursor protein binding family B member 1	clinvar
NPC1	HGNC:7897	ENSG00000141458	O15118	NPC intracellular cholesterol transporter 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMPD1	Sphingomyelin phosphodiesterase	Converts sphingomyelin to ceramide.
APBB1	Amyloid beta precursor protein binding family B member 1	Transcription coregulator that can have both coactivator and corepressor functions.
NPC1	NPC intracellular cholesterol transporter 1	Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Scaffold/PPI	1	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

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
APBB1	Scaffold/PPI	no		WW_dom, PTB/PI_dom, PH-like_dom_sf
NPC1	Other/Unknown	no		SSD, NPC1-like, NPC1_N

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
stromal cell of endometrium	1
type B pancreatic cell	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
adrenal tissue	1
oocyte	1
secondary oocyte	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
APBB1	242	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NPC1	292	ubiquitous	marker	secondary oocyte, oocyte, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APBB1	2,826
NPC1	2,648
SMPD1	1,729

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPC1	O15118	20
APBB1	O00213	11
SMPD1	P17405	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LDL clearance	1	181.3×	0.023	NPC1
DNA Double Strand Break Response	1	158.6×	0.023	APBB1
Glycosphingolipid metabolism	1	100.2×	0.023	SMPD1
Glycosphingolipid catabolism	1	97.6×	0.023	SMPD1
DNA Double-Strand Break Repair	1	82.8×	0.023	APBB1
Regulation of clotting cascade	1	77.7×	0.023	SMPD1
Sphingolipid metabolism	1	56.0×	0.028	SMPD1
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	48.8×	0.028	APBB1
DNA Repair	1	32.8×	0.037	APBB1
Metabolism of lipids	1	10.5×	0.101	SMPD1
Metabolism	1	3.9×	0.237	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
symbiont entry into host cell	2	267.5×	0.001	SMPD1, NPC1
cholesterol metabolic process	2	130.6×	0.002	SMPD1, NPC1
cyclodextrin metabolic process	1	5617.3×	0.004	NPC1
termination of signal transduction	1	1872.4×	0.006	SMPD1
intracellular lipid transport	1	1872.4×	0.006	NPC1
sphingomyelin metabolic process	1	1123.5×	0.006	SMPD1
sphingomyelin catabolic process	1	1123.5×	0.006	SMPD1
membrane raft organization	1	1123.5×	0.006	NPC1
response to xenobiotic stimulus	2	46.0×	0.006	SMPD1, NPC1
positive regulation of apoptotic process	2	37.8×	0.006	SMPD1, APBB1
sterol transport	1	936.2×	0.006	NPC1
cholesterol storage	1	802.5×	0.006	NPC1
negative regulation of cell cycle G1/S phase transition	1	802.5×	0.006	APBB1
response to type I interferon	1	624.1×	0.007	SMPD1
establishment of protein localization to membrane	1	624.1×	0.007	NPC1
glycosphingolipid catabolic process	1	510.7×	0.008	SMPD1
intestinal cholesterol absorption	1	468.1×	0.008	NPC1
programmed cell death	1	432.1×	0.008	NPC1
intracellular cholesterol transport	1	432.1×	0.008	NPC1
positive regulation of viral entry into host cell	1	401.2×	0.008	SMPD1
negative regulation of epithelial cell apoptotic process	1	401.2×	0.008	NPC1
negative regulation of macroautophagy	1	374.5×	0.008	NPC1
cellular response to steroid hormone stimulus	1	351.1×	0.008	NPC1
bile acid metabolic process	1	330.4×	0.008	NPC1
cellular response to low-density lipoprotein particle stimulus	1	295.6×	0.009	NPC1
smooth muscle contraction	1	267.5×	0.009	APBB1
positive regulation of endocytosis	1	267.5×	0.009	SMPD1
cholesterol transport	1	244.2×	0.009	NPC1
response to cadmium ion	1	244.2×	0.009	NPC1
lysosomal transport	1	234.1×	0.009	NPC1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
NPC1	NABUMETONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPC1	90	4
SMPD1	3	4
APBB1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
NABUMETONE	4	NPC1
PHENELZINE	4	NPC1
AMLEXANOX	4	NPC1
IDARUBICIN	4	NPC1
RABEPRAZOLE SODIUM	4	NPC1
NITAZOXANIDE	4	NPC1
NICLOSAMIDE	4	NPC1
NITROXOLINE	4	NPC1
NICARDIPINE	4	NPC1
DAUNORUBICIN HYDROCHLORIDE	4	NPC1
INDOPROFEN	4	NPC1
CYCLOSPORINE	4	NPC1
TERFENADINE	4	NPC1
DIGOXIN	4	NPC1
PRAZOSIN	4	NPC1
MAPROTILINE	4	NPC1
DIGITOXIN	4	NPC1
HYDRALAZINE	4	NPC1
EBASTINE	4	NPC1
DEQUALINIUM	4	NPC1
DOXORUBICIN HYDROCHLORIDE	4	NPC1
VINBLASTINE SULFATE	4	NPC1
FLUOXETINE	4	NPC1
DITHIAZANINE IODIDE	4	NPC1
TRIFLUOPERAZINE	4	NPC1
PACLITAXEL	4	NPC1
NORTRIPTYLINE	4	NPC1
MIBEFRADIL	4	NPC1

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
NPC1	18	Binding:13, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMPD1	3.1.4.12	sphingomyelin phosphodiesterase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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
NABUMETONE	4	NPC1
PHENELZINE	4	NPC1
AMLEXANOX	4	NPC1
IDARUBICIN	4	NPC1
RABEPRAZOLE SODIUM	4	NPC1
NITAZOXANIDE	4	NPC1
NICLOSAMIDE	4	NPC1
NITROXOLINE	4	NPC1
NICARDIPINE	4	NPC1
DAUNORUBICIN HYDROCHLORIDE	4	NPC1
INDOPROFEN	4	NPC1
CYCLOSPORINE	4	NPC1
TERFENADINE	4	NPC1
DIGOXIN	4	NPC1
PRAZOSIN	4	NPC1
MAPROTILINE	4	NPC1
DIGITOXIN	4	NPC1
HYDRALAZINE	4	NPC1
EBASTINE	4	NPC1
DEQUALINIUM	4	NPC1
DOXORUBICIN HYDROCHLORIDE	4	NPC1
VINBLASTINE SULFATE	4	NPC1
FLUOXETINE	4	NPC1
DITHIAZANINE IODIDE	4	NPC1
TRIFLUOPERAZINE	4	NPC1
PACLITAXEL	4	NPC1
NORTRIPTYLINE	4	NPC1
MIBEFRADIL	4	NPC1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SMPD1, NPC1
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	1	APBB1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APBB1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns