Wolman disease

Summary

Wolman disease (MONDO:0019148) is a disease with 3 cohort genes and 30 clinical trials. Top therapeutic interventions include sebelipase alfa, cyclophosphamide anhydrous, and alemtuzumab.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 505
• Phenotypes (HPO): 17
• Clinical trials: 30

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.19	Australia	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001399	Hepatic failure	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002570	Steatorrhea	Very frequent (80-99%)
HP:0003270	Abdominal distention	Very frequent (80-99%)
HP:0010512	Adrenal calcification	Very frequent (80-99%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001541	Ascites	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0004326	Cachexia	Frequent (30-79%)
HP:0004395	Malnutrition	Frequent (30-79%)
HP:0000846	Adrenal insufficiency	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002040	Esophageal varix	Occasional (5-29%)
HP:0004333	Bone-marrow foam cells	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Wolman disease
Mondo ID	MONDO:0019148
MeSH	C564736, D015223
OMIM	620151
Orphanet	75233
DOID	DOID:14497
ICD-11	520367511
NCIT	C61271
SNOMED CT	238074007, 82500001
UMLS	C0043208
MedGen	53088
GARD	0007899
MedDRA	10053687
NORD	1862
Is cancer (heuristic)	no

Also known as: familial xanthomatosis · liposomal acid lipase deficiency, Wolman type · lysosomal acid lipase deficiency · Wolman disease with hypolipoproteinemia and acanthocytosis · Wolman’s disease

Data availability: 505 ClinVar variants · 1 GenCC gene-disease record · 14 cell lines.

Disease family

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

Related subtypes (1): cholesteryl ester storage 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

505 retrieved; paginated sample, class counts are floors:

241 likely benign, 90 uncertain significance, 50 pathogenic, 50 conflicting classifications of pathogenicity, 35 likely pathogenic, 23 pathogenic/likely pathogenic, 8 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069094	NM_000235.4(LIPA):c.37del (p.Val13fs)	LIPA	Pathogenic	criteria provided, single submitter
1070183	NM_000235.4(LIPA):c.1067T>G (p.Leu356Ter)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070184	NM_000235.4(LIPA):c.980del (p.Thr327fs)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076884	NC_000010.10:g.(?91005423)(91007415_?)del	LIPA	Pathogenic	criteria provided, single submitter
1323236	NM_000235.4(LIPA):c.1180_1184del (p.Leu394fs)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350454	NM_000235.4(LIPA):c.1024G>C (p.Gly342Arg)	LIPA	Pathogenic	criteria provided, single submitter
1383305	NM_000235.4(LIPA):c.771_774del (p.Leu256_Cys257insTer)	LIPA	Pathogenic	criteria provided, single submitter
1404815	NM_000235.4(LIPA):c.951T>A (p.Tyr317Ter)	LIPA	Pathogenic	criteria provided, single submitter
1417455	NM_000235.4(LIPA):c.854del (p.Pro285fs)	LIPA	Pathogenic	criteria provided, single submitter
1455198	NM_000235.4(LIPA):c.929G>A (p.Trp310Ter)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457231	NC_000010.10:g.(?90974565)(91007425_?)del	LIPA	Pathogenic	criteria provided, single submitter
1458797	NC_000010.10:g.(?90982258)(90988165_?)del	LIPA	Pathogenic	criteria provided, single submitter
1459690	NM_000235.4(LIPA):c.600_603dup (p.Pro202fs)	LIPA	Pathogenic	criteria provided, single submitter
1459866	NM_000235.4(LIPA):c.652C>T (p.Arg218Ter)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1723279	NC_000010.10:g.(90986762_90987956)_(90988156_91005432)del	LIPA	Pathogenic	criteria provided, single submitter
1724570	NM_000235.4(LIPA):c.131G>A (p.Trp44Ter)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2002860	NM_000235.4(LIPA):c.618dup (p.Ala207fs)	LIPA	Pathogenic	criteria provided, single submitter
203361	NM_000235.4(LIPA):c.894G>A (p.Gln298=)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2085713	NM_000235.4(LIPA):c.511del (p.Val171fs)	LIPA	Pathogenic	criteria provided, single submitter
2113120	NM_000235.4(LIPA):c.890dup (p.Ser297fs)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2145326	NM_000235.4(LIPA):c.984C>A (p.Tyr328Ter)	LIPA	Pathogenic	criteria provided, single submitter
2192799	NM_000235.4(LIPA):c.694G>T (p.Glu232Ter)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2741248	NM_000235.4(LIPA):c.780_781del (p.Cys261fs)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
2746123	NM_000235.4(LIPA):c.78dup (p.Thr27fs)	LIPA	Pathogenic	criteria provided, single submitter
2808179	NM_000235.4(LIPA):c.964C>T (p.Gln322Ter)	LIPA	Pathogenic	criteria provided, single submitter
2836288	NM_000235.4(LIPA):c.618_627del (p.Ala207fs)	LIPA	Pathogenic	criteria provided, single submitter
2858809	NM_000235.4(LIPA):c.892del (p.Gln298fs)	LIPA	Pathogenic	criteria provided, single submitter
2865584	NM_000235.4(LIPA):c.245del (p.Val82fs)	LIPA	Pathogenic	criteria provided, single submitter
2877630	NM_000235.4(LIPA):c.293_295del (p.Asn98_Leu99delinsIle)	LIPA	Pathogenic	criteria provided, single submitter
2890181	NM_000235.4(LIPA):c.132G>A (p.Trp44Ter)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

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	Wolman disease	7
SCGB1D1	Supportive	Autosomal recessive	Wolman 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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

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
IFIT1B	HGNC:23442	ENSG00000204010	Q5T764	Protein IFIT1 homolog B	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.
IFIT1B	Protein IFIT1 homolog B	IFIT1B is likely non-functional, lacking the critical antiviral role of IFIT1.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

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
IFIT1B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt

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
blood vessel layer	1
choroid plexus epithelium	1
right uterine tube	1
corpus callosum	1
duodenum	1
jejunal mucosa	1
blood	1
bone marrow	1
bone marrow cell	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
IFIT1B	25	tissue_specific	marker	bone marrow cell, bone marrow, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LIPA	1,912
IFIT1B	1,538
SCGB1D1	707

Structural data

PDB: 1 · AlphaFold-only: 2 · 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
IFIT1B	Q5T764	93.41
SCGB1D1	O95968	89.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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 2 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	8426.0×	0.002	LIPA
respiratory burst involved in inflammatory response	1	4213.0×	0.002	LIPA
defecation	1	4213.0×	0.002	LIPA
triglyceride-rich lipoprotein particle clearance	1	4213.0×	0.002	LIPA
cell proliferation in bone marrow	1	4213.0×	0.002	LIPA
liver morphogenesis	1	4213.0×	0.002	LIPA
lipid import into cell	1	4213.0×	0.002	LIPA
macrophage homeostasis	1	2808.7×	0.002	LIPA
fat cell proliferation	1	2808.7×	0.002	LIPA
response to rapamycin	1	2106.5×	0.003	LIPA
blood vessel endothelial cell differentiation	1	1685.2×	0.003	LIPA
vitamin A metabolic process	1	1203.7×	0.004	LIPA
cholesterol storage	1	1203.7×	0.004	LIPA
lipoprotein catabolic process	1	1203.7×	0.004	LIPA
myeloid cell apoptotic process	1	1053.2×	0.004	LIPA
common myeloid progenitor cell proliferation	1	936.2×	0.004	LIPA
reactive oxygen species biosynthetic process	1	936.2×	0.004	LIPA
acute inflammatory response	1	842.6×	0.004	LIPA
bone marrow development	1	766.0×	0.004	LIPA
tissue remodeling	1	648.1×	0.004	LIPA
T cell apoptotic process	1	648.1×	0.004	LIPA
response to dietary excess	1	561.7×	0.005	LIPA
response to vitamin A	1	526.6×	0.005	LIPA
adaptive thermogenesis	1	526.6×	0.005	LIPA
ATP biosynthetic process	1	495.6×	0.005	LIPA
low-density lipoprotein particle clearance	1	495.6×	0.005	LIPA
sterol metabolic process	1	421.3×	0.005	LIPA
TOR signaling	1	383.0×	0.005	LIPA
positive regulation of T cell receptor signaling pathway	1	383.0×	0.005	LIPA
myeloid cell differentiation	1	324.1×	0.006	LIPA

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Sebelipase Alfa	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Busulfan.

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
IFIT1B	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: 3; 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	3	SCGB1D1, LIPA, IFIT1B

Undrugged target profiles

3 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	—
IFIT1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 30.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	19
PHASE2	5
PHASE2/PHASE3	2
PHASE1	2
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT01371825	PHASE2/PHASE3	COMPLETED	Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency
NCT01757184	PHASE3	COMPLETED	Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
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
NCT02112994	PHASE2	COMPLETED	Safety and Efficacy Study of Sebelipase Alfa in Participants With Lysosomal Acid Lipase Deficiency
NCT02193867	PHASE2	TERMINATED	Clinical Study In Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency
NCT04532047	PHASE1	RECRUITING	PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT01633489	Not specified	RECRUITING	Lysosomal Acid Lipase (LAL) Deficiency Registry
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT05619900	Not specified	RECRUITING	Registry of Patients Diagnosed With Lysosomal Storage Diseases
NCT07455864	Not specified	RECRUITING	Lysosomal Acid Lipase Deficiency in Risk Groups
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT01358370	Not specified	COMPLETED	A Retrospective Natural History Study of Patients With Lysosomal Acid Lipase Deficiency/Wolman Phenotype
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
NCT01884220	Not specified	COMPLETED	Wolman/CESD Natural History Chart Review and Longitudinal Follow-Up
NCT02345421	Not specified	TERMINATED	A Study to Identify and Characterize LAL-D Patients in High-risk Populations
NCT02376751	Not specified	NO_LONGER_AVAILABLE	An Expanded Access Protocol for Sebelipase Alfa for Patients With Lysosomal Acid Lipase Deficiency
NCT02926872	Not specified	TERMINATED	Screening for Lysosomal Acid Lipase Deficiency
NCT03564002	Not specified	UNKNOWN	Metabolic Effects of Very Low Carbohydrate Ketogenic Diet in Subjects With Severe Obesity
NCT03984149	Not specified	UNKNOWN	Lipa Gene Mutation in PED-LIPIGEN (Pediatric FH Subjects)
NCT04652713	Not specified	COMPLETED	Breakfast for Young Women
NCT04792671	Not specified	UNKNOWN	Prevalence and Risk Factors of Women Mental Health Disorders
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06287658	Not specified	UNKNOWN	The Effect of Kegel Exercise and Ba Duan Jin Applications on Premenopausal Women With Urinary Incontinence

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SEBELIPASE ALFA	4	7
CYCLOPHOSPHAMIDE ANHYDROUS	4	2
ALEMTUZUMAB	4	1
BUSULFAN	4	1
CLOFARABINE	4	1
HYDROXYUREA	4	1
LARONIDASE	4	1