Cholesteryl ester storage disease

Summary

Cholesteryl ester storage disease (MONDO:0019149) is a disease with 2 cohort genes and 9 clinical trials. Top therapeutic interventions include sebelipase alfa.

At a glance

• Prevalence: 1-9 / 1 000 000 (Specific population) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 61
• Phenotypes (HPO): 13
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.8	Specific population	Validated
Prevalence at birth	1-9 / 100 000	2.5	Germany	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0001399	Hepatic failure	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002634	Arteriosclerosis	Frequent (30-79%)
HP:0003124	Hypercholesterolemia	Frequent (30-79%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0002040	Esophageal varix	Occasional (5-29%)
HP:0010512	Adrenal calcification	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cholesteryl ester storage disease
Mondo ID	MONDO:0019149
OMIM	278000
Orphanet	75234
DOID	DOID:14502
ICD-11	894336362
SNOMED CT	57218003
UMLS	C0008384
MedGen	40266
GARD	0012099
NORD	929
Is cancer (heuristic)	no

Also known as: CESD · cholesterol ester hydrolase deficiency, partial · cholesterol ester storage disease · LAL deficiency, partial · LIPA deficiency, partial · lysosomal acid lipase deficiency, partial

Data availability: 61 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic dyslipidemia › lysosomal acid lipase deficiency › cholesteryl ester storage disease

Related subtypes (1): Wolman disease

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

61 retrieved; paginated sample, class counts are floors:

28 likely pathogenic, 14 pathogenic, 11 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 3 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1459866	NM_000235.4(LIPA):c.652C>T (p.Arg218Ter)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
203361	NM_000235.4(LIPA):c.894G>A (p.Gln298=)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2890181	NM_000235.4(LIPA):c.132G>A (p.Trp44Ter)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
289986	NM_000235.4(LIPA):c.398del (p.Leu132_Ser133insTer)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
552285	NM_000235.4(LIPA):c.482del (p.Asn161fs)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
553192	NM_000235.4(LIPA):c.684del (p.Phe228fs)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
554864	NM_000235.4(LIPA):c.419G>A (p.Trp140Ter)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
554874	NM_000235.4(LIPA):c.309C>A (p.Ser103Arg)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555337	NM_000235.4(LIPA):c.1024G>A (p.Gly342Arg)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
556450	NM_000235.4(LIPA):c.350_351insCC (p.Met117fs)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
556586	NM_000235.4(LIPA):c.892C>T (p.Gln298Ter)	LIPA	Pathogenic	criteria provided, single submitter
557940	NM_000235.4(LIPA):c.428+1G>A	LIPA	Pathogenic	criteria provided, single submitter
558291	NM_000235.4(LIPA):c.193C>T (p.Arg65Ter)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
648013	NM_000235.4(LIPA):c.111+1G>A	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
695039	NM_000235.4(LIPA):c.1033G>A (p.Asp345Asn)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
695056	NM_000235.4(LIPA):c.386A>C (p.His129Pro)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
695063	NM_000235.4(LIPA):c.253C>A (p.Gln85Lys)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
77	NM_000235.4(LIPA):c.599T>C (p.Leu200Pro)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
78	NM_000235.4(LIPA):c.796G>T (p.Gly266Ter)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
80	NM_000235.4(LIPA):c.594dup (p.Ala199fs)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
842105	NM_000235.4(LIPA):c.804del (p.Asn268fs)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
867231	NM_000235.4(LIPA):c.600G>A (p.Leu200=)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88770	NM_000235.4(LIPA):c.260G>T (p.Gly87Val)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
934943	NM_000235.4(LIPA):c.521C>T (p.Ser174Phe)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
937141	NM_000235.4(LIPA):c.1052ACG[1] (p.Asp352del)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1511921	NM_000235.4(LIPA):c.617_619dup (p.Val206dup)	LIPA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1517478	NM_000235.4(LIPA):c.675+2T>G	LIPA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725254	NM_000235.4(LIPA):c.871C>T (p.Gln291Ter)	LIPA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2981923	NM_000235.4(LIPA):c.230-2del	LIPA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239677	NM_000235.4(LIPA):c.663del (p.His222fs)	LIPA	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 2 · 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
LIPA	Supportive	Autosomal recessive	cholesteryl ester storage disease	7
SCGB1D1	Supportive	Autosomal recessive	cholesteryl ester storage disease	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LIPA	Orphanet:75233	Wolman disease
LIPA	Orphanet:75234	Cholesteryl ester storage disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCGB1D1	HGNC:18395	ENSG00000168515	O95968	Secretoglobin family 1D member 1	gencc,clinvar
LIPA	HGNC:6617	ENSG00000107798	P38571	Lysosomal acid lipase/cholesteryl ester hydrolase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCGB1D1	Secretoglobin family 1D member 1	May bind androgens and other steroids, may also bind estramustine, a chemotherapeutic agent used for prostate cancer.
LIPA	Lysosomal acid lipase/cholesteryl ester hydrolase	Catalyzes the deacylation of cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCGB1D1	Other/Unknown	no		Secretoglobin, Secretoglobin_sf
LIPA	Other/Unknown	no		AB_hydrolase_1, Lipase_euk, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood vessel layer	1
choroid plexus epithelium	1
right uterine tube	1
corpus callosum	1
duodenum	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCGB1D1	34	tissue_specific	marker	right uterine tube, blood vessel layer, choroid plexus epithelium
LIPA	300	ubiquitous	marker	jejunal mucosa, duodenum, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LIPA	1,912
SCGB1D1	707

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LIPA	P38571	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCGB1D1	O95968	89.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
LDL clearance	1	543.8×	0.004	LIPA
Plasma lipoprotein clearance	1	475.8×	0.004	LIPA
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.006	LIPA
Transport of small molecules	1	25.1×	0.040	LIPA

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
multicellular organismal-level chemical homeostasis	1	16852.0×	1e-03	LIPA
respiratory burst involved in inflammatory response	1	8426.0×	1e-03	LIPA
defecation	1	8426.0×	1e-03	LIPA
triglyceride-rich lipoprotein particle clearance	1	8426.0×	1e-03	LIPA
cell proliferation in bone marrow	1	8426.0×	1e-03	LIPA
liver morphogenesis	1	8426.0×	1e-03	LIPA
lipid import into cell	1	8426.0×	1e-03	LIPA
macrophage homeostasis	1	5617.3×	0.001	LIPA
fat cell proliferation	1	5617.3×	0.001	LIPA
response to rapamycin	1	4213.0×	0.001	LIPA
blood vessel endothelial cell differentiation	1	3370.4×	0.002	LIPA
vitamin A metabolic process	1	2407.4×	0.002	LIPA
cholesterol storage	1	2407.4×	0.002	LIPA
lipoprotein catabolic process	1	2407.4×	0.002	LIPA
myeloid cell apoptotic process	1	2106.5×	0.002	LIPA
common myeloid progenitor cell proliferation	1	1872.4×	0.002	LIPA
reactive oxygen species biosynthetic process	1	1872.4×	0.002	LIPA
acute inflammatory response	1	1685.2×	0.002	LIPA
bone marrow development	1	1532.0×	0.002	LIPA
tissue remodeling	1	1296.3×	0.002	LIPA
T cell apoptotic process	1	1296.3×	0.002	LIPA
response to dietary excess	1	1123.5×	0.002	LIPA
response to vitamin A	1	1053.2×	0.002	LIPA
adaptive thermogenesis	1	1053.2×	0.002	LIPA
ATP biosynthetic process	1	991.3×	0.002	LIPA
low-density lipoprotein particle clearance	1	991.3×	0.002	LIPA
sterol metabolic process	1	842.6×	0.003	LIPA
TOR signaling	1	766.0×	0.003	LIPA
positive regulation of T cell receptor signaling pathway	1	766.0×	0.003	LIPA
myeloid cell differentiation	1	648.1×	0.003	LIPA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCGB1D1	0	0
LIPA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LIPA	10	Binding:10

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	SCGB1D1, LIPA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SCGB1D1	0	—
LIPA	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE1/PHASE2	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01307098	PHASE1/PHASE2	COMPLETED	Safety, Tolerability and Pharmacokinetics of SBC-102 (Sebelipase Alfa) in Adult Participants With Lysosomal Acid Lipase Deficiency
NCT01488097	PHASE2	COMPLETED	Extension Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of SBC-102 (Sebelipase Alfa) in Adult Subjects With Lysosomal Acid Lipase Deficiency
NCT01633489	Not specified	RECRUITING	Lysosomal Acid Lipase (LAL) Deficiency Registry
NCT01528917	Not specified	COMPLETED	An Observational Study of Patients With Lysosomal Acid Lipase Deficiency/Cholesteryl Ester Storage Disease Phenotype
NCT01716728	Not specified	UNKNOWN	Identification of Undiagnosed Lysosomal Acid Lipase Deficiency
NCT01791452	Not specified	UNKNOWN	Novel Association of Cholesterol Ester Storage Disease Due to Lysosomal Acid Lipase Deficiency and Non-Alcoholic Fatty Liver Disease: A Prospective Clinical Study
NCT01884220	Not specified	COMPLETED	Wolman/CESD Natural History Chart Review and Longitudinal Follow-Up
NCT02372513	Not specified	COMPLETED	National Lysosomal Acid Lipase Deficiency Study
NCT02383641	Not specified	WITHDRAWN	Biomarker for Wolman Disease (BioWolman)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SEBELIPASE ALFA	4	2