Lysosomal acid lipase deficiency

Summary

Lysosomal acid lipase deficiency (MONDO:0800449) is a disease with 2 cohort genes and 19 clinical trials. Top therapeutic interventions include sebelipase alfa.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 241
• Phenotypes (HPO): 49
• Clinical trials: 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.27	Czech Republic	Validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0000991	Xanthomatosis	Very frequent (80-99%)
HP:0001395	Hepatic fibrosis	Very frequent (80-99%)
HP:0001399	Hepatic failure	Very frequent (80-99%)
HP:0001410	Decreased liver function	Very frequent (80-99%)
HP:0001414	Microvesicular hepatic steatosis	Very frequent (80-99%)
HP:0001433	Hepatosplenomegaly	Very frequent (80-99%)
HP:0001922	Vacuolated lymphocytes	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0002570	Steatorrhea	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0003124	Hypercholesterolemia	Very frequent (80-99%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Very frequent (80-99%)
HP:0003270	Abdominal distention	Very frequent (80-99%)
HP:0006583	Fatal liver failure in infancy	Very frequent (80-99%)
HP:0010512	Adrenal calcification	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0001114	Xanthelasma	Frequent (30-79%)
HP:0001297	Stroke	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002040	Esophageal varix	Frequent (30-79%)
HP:0004416	Precocious atherosclerosis	Frequent (30-79%)
HP:0001677	Coronaryartery atherosclerosis	Frequent (30-79%)
HP:0000127	Renal salt wasting	Occasional (5-29%)
HP:0008207	Primary adrenal insufficiency	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0001941	Acidosis	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001971	Hypersplenism	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002153	Hyperkalemia	Occasional (5-29%)
HP:0002361	Psychomotor deterioration	Occasional (5-29%)
HP:0002615	Hypotension	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0012605	Hypernatriuria	Occasional (5-29%)
HP:0004326	Cachexia	Occasional (5-29%)
HP:0004333	Bone-marrow foam cells	Occasional (5-29%)
HP:0004395	Malnutrition	Occasional (5-29%)
HP:0011106	Hypovolemia	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012598	Abnormal urine potassium concentration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lysosomal acid lipase deficiency
Mondo ID	MONDO:0800449
MeSH	C531854
OMIM	278000
Orphanet	275761
DOID	DOID:0080217
ICD-11	381622932
SNOMED CT	715923003
UMLS	C5574740
MedGen	1807768
GARD	0012097
Is cancer (heuristic)	no

Also known as: LAL deficiency

Data availability: 241 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (28): familial apolipoprotein C-II deficiency, sitosterolemia, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata type 1, apparent mineralocorticoid excess, GM1 gangliosidosis type 1, familial lipoprotein lipase deficiency, sea-blue histiocyte syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, CHIME syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, Barth syndrome, CHILD syndrome, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, Krabbe disease due to saposin A deficiency, lipoprotein glomerulopathy, hereditary spastic paraplegia 39, PHARC syndrome, congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome, hyperlipoproteinemia, type 1D, intellectual disability, autosomal recessive 53, hyperphosphatasia-intellectual disability syndrome, mevalonate kinase deficiency, fatty acid hydroxylase-associated neurodegeneration, nephrotic syndrome 14, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction, peroxisome biogenesis disorder due to PEX5 defect in the PEX7-binding domain

Subtypes (2): Wolman disease, 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

241 retrieved; paginated sample, class counts are floors:

69 uncertain significance, 54 likely pathogenic, 38 conflicting classifications of pathogenicity, 22 pathogenic, 20 pathogenic/likely pathogenic, 20 likely benign, 10 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
1323236	NM_000235.4(LIPA):c.1180_1184del (p.Leu394fs)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455198	NM_000235.4(LIPA):c.929G>A (p.Trp310Ter)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459866	NM_000235.4(LIPA):c.652C>T (p.Arg218Ter)	LIPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1685926	NM_000235.4(LIPA):c.647T>A (p.Leu216Ter)	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
203361	NM_000235.4(LIPA):c.894G>A (p.Gln298=)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208594	NM_000235.4(LIPA):c.253C>T (p.Gln85Ter)	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
2741248	NM_000235.4(LIPA):c.780_781del (p.Cys261fs)	LIPA	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
3572000	NM_000235.4(LIPA):c.347G>A (p.Trp116Ter)	LIPA	Pathogenic	criteria provided, single submitter
4069969	NM_000235.4(LIPA):c.538+1G>A	LIPA	Pathogenic	criteria provided, single submitter
4081718	NC_000010.11:g.89215060CT[1]	LIPA	Pathogenic	criteria provided, single submitter
4081719	NM_000235.4(LIPA):c.966+2T>G	LIPA	Pathogenic	criteria provided, single submitter
430634	NM_000235.4(LIPA):c.894G>C (p.Gln298His)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4691978	NM_000235.4(LIPA):c.294C>A (p.Asn98Lys)	LIPA	Pathogenic/Likely 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
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
695052	NM_000235.4(LIPA):c.455T>C (p.Leu152Pro)	LIPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
695055	NM_000235.4(LIPA):c.386A>G (p.His129Arg)	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

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
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	clinvar
LIPA	HGNC:6617	ENSG00000107798	P38571	Lysosomal acid lipase/cholesteryl ester hydrolase	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: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE2	3
PHASE2/PHASE3	1
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
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
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
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
NCT07455864	Not specified	RECRUITING	Lysosomal Acid Lipase Deficiency in Risk Groups
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
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)
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SEBELIPASE ALFA	4	7