👪

Inheritance

1

Autosomal recessive HP:0000007

Wolman disease is inherited as an autosomal recessive disorder caused by biallelic LIPA pathogenic variants that severely reduce or abolish lysosomal acid lipase activity.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."

This review directly supports autosomal recessive inheritance and LIPA-mediated lysosomal acid lipase deficiency.

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Pathophysiology

9

LIPA Loss of Function

Biallelic pathogenic variants in LIPA reduce or abolish lysosomal acid lipase activity.

LIPA hgnc:6617

Downstream

Lysosomal Acid Lipase Deficiency Loss of LIPA function reduces or abolishes lysosomal acid lipase activity.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."

This review directly links LIPA mutations to reduced or absent lysosomal acid lipase activity.

Lysosomal Acid Lipase Deficiency

Lysosomal acid lipase activity is markedly reduced or absent, removing the essential lysosomal hydrolase required to cleave cholesteryl esters and triglycerides.

LIPA hgnc:6617

neutral lipid catabolic process GO:0046461 ↓ DECREASED triglyceride catabolic process GO:0019433 ↓ DECREASED

sterol ester esterase activity GO:0004771 ↓ DECREASED triacylglycerol lipase activity GO:0004806 ↓ DECREASED

lysosomal lumen GO:0043202

Downstream

Reduced lysosomal acid lipase activity LIPA pathogenic variants produce reduced or absent lysosomal acid lipase enzyme activity.

Impaired Lysosomal Cholesteryl Ester and Triglyceride Hydrolysis Deficient lysosomal acid lipase prevents normal lysosomal hydrolysis of cholesteryl esters and triglycerides.

Show evidence (2 references)

PMID:30866656 SUPPORT Human Clinical

"Lysosomal acid lipase (LAL), encoded by the lipase A ( LIPA) gene, hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell."

This review provides the core enzymatic function that is lost in Wolman disease.

PMID:36204319 SUPPORT Human Clinical

"Lysosomal acid lipase (LAL), encoded by the gene LIPA, is the sole neutral lipid hydrolase in lysosomes, responsible for cleavage of cholesteryl esters and triglycerides into their component parts."

This review independently supports lysosomal acid lipase as the key lysosomal hydrolase for cholesteryl ester and triglyceride cleavage.

Impaired Lysosomal Cholesteryl Ester and Triglyceride Hydrolysis

Failure of lysosomal acid lipase blocks lysosomal cleavage of cholesteryl esters and triglycerides into free cholesterol and fatty acids.

cholesterol metabolic process GO:0008203 ↓ DECREASED lipid metabolic process GO:0006629 ↓ DECREASED

Downstream

Lysosomal Cholesteryl Ester and Triglyceride Storage Undegraded cholesteryl esters and triglycerides accumulate in lysosomes.

Cholesteryl ester storage burden Blocked lysosomal neutral-lipid hydrolysis produces increased cholesteryl ester storage across affected tissues.

Triglyceride storage burden Blocked lysosomal neutral-lipid hydrolysis produces increased triglyceride storage across affected tissues.

Show evidence (1 reference)

PMID:30866656 SUPPORT Human Clinical

"Lysosomal acid lipase (LAL), encoded by the lipase A ( LIPA) gene, hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell."

Loss of this lysosomal hydrolysis step is the immediate biochemical consequence of lysosomal acid lipase deficiency.

Lysosomal Cholesteryl Ester and Triglyceride Storage

Cholesteryl esters and triglycerides accumulate within lysosomes of macrophages and parenchymal cells across multiple tissues, establishing the multisystem storage phenotype of Wolman disease.

macrophage CL:0000235 hepatocyte CL:0000182 enterocyte CL:0000584

liver UBERON:0002107 small intestine UBERON:0002108 lymph node UBERON:0000029

Downstream

Hepatic and Reticuloendothelial Lipid Storage Lipid-laden macrophages and parenchymal cells accumulate in liver and spleen.

Intestinal Lipid Storage Lipid storage in the gastrointestinal tract drives enteric dysfunction.

Adrenal Cortical Lipid Storage Adrenal cortical tissues accumulate stored lipids and become structurally abnormal.

Show evidence (2 references)

PMID:41599846 SUPPORT Human Clinical

"LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."

This review directly supports multisystem lysosomal cholesteryl ester and triglyceride storage in macrophages and parenchymal cells.

PMID:23624251 SUPPORT Human Clinical

"Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues."

This human translational study independently supports CE and TG accumulation in lysosomes across many tissues.

Hepatic and Reticuloendothelial Lipid Storage

Storage within hepatocytes and reticuloendothelial macrophages enlarges the liver and spleen and sets up rapidly progressive hepatic injury.

hepatocyte CL:0000182 macrophage CL:0000235

liver UBERON:0002107 spleen UBERON:0002106

Downstream

Progressive Liver Dysfunction Progressive hepatic storage contributes to liver dysfunction and eventual hepatic failure.

Hepatosplenomegaly Hepatic and reticuloendothelial lipid storage clinically manifests as marked hepatosplenomegaly.

Anemia Severe infantile hepatic and reticuloendothelial lipid-storage disease is accompanied by anemia within the systemic presentation.

Show evidence (1 reference)

PMID:28179030 SUPPORT Human Clinical

"Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"

This infant treatment study summarizes the core hepatic and reticuloendothelial disease burden before effective therapy.

Progressive Liver Dysfunction

Ongoing hepatic lipid storage causes liver dysfunction that can progress to hepatic failure during infancy.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Elevated hepatic transaminases Hepatocyte injury from progressive hepatic storage releases hepatic transaminases into circulation.

Hepatic failure Progressive hepatic dysfunction can advance to hepatic failure in the severe infantile phenotype.

Failure to thrive Severe hepatic failure contributes to the infantile failure-to-thrive phenotype.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months."

This review directly connects the severe infantile phenotype to progressive hepatic failure.

Intestinal Lipid Storage

Storage in the gastrointestinal tract injures intestinal tissue and contributes to poor fat tolerance, vomiting, diarrhea, and downstream malabsorption.

enterocyte CL:0000584 macrophage CL:0000235

small intestine UBERON:0002108

Downstream

Malabsorption and Severe Gastrointestinal Dysfunction Intestinal storage produces gastrointestinal disturbance and impaired nutrient absorption.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."

This review supports direct lipid storage within gastrointestinal tissues as a core component of disease biology.

Malabsorption and Severe Gastrointestinal Dysfunction

Intestinal dysfunction produces persistent gastrointestinal symptoms and poor nutrient absorption, driving severe growth failure in infancy.

enterocyte CL:0000584

small intestine UBERON:0002108

Downstream

Malabsorption Severe gastrointestinal dysfunction includes malabsorption.

Diarrhea Gastrointestinal dysfunction commonly manifests as diarrhea.

Vomiting Severe gastrointestinal dysfunction begins early with persistent vomiting.

Failure to thrive Malabsorption and gastrointestinal dysfunction drive severe infantile growth failure.

Show evidence (2 references)

PMID:41599846 SUPPORT Human Clinical

"Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."

This review directly links gastrointestinal disturbance and growth failure to malabsorption in infantile Wolman disease.

PMID:34020687 SUPPORT Human Clinical

"The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved..."

Improvement in diarrhea, vomiting, fat tolerance, and villous structure after therapy supports intestinal pathology as a key disease mechanism.

Adrenal Cortical Lipid Storage

Lipid storage in the adrenal cortex produces adrenal enlargement and underlies the characteristic adrenal calcification seen in many infants.

adrenal cortex UBERON:0001235

Downstream

Adrenal calcification Adrenal cortical disease produces the characteristic adrenal calcification phenotype.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."

This review directly supports adrenal involvement with enlargement and calcification in rapidly progressive infantile disease.

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Pathograph

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Phenotypes

8

Blood 1

Anemia Anemia HP:0001903

Anemia accompanies the severe infantile systemic phenotype and improves with effective therapy.

Show evidence (1 reference)

PMID:28179030 SUPPORT Human Clinical

"Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"

This study directly identifies anemia as part of the severe infantile presentation.

Cardiovascular 1

Hepatosplenomegaly Hepatosplenomegaly HP:0001433

Often marked early in the course and coupled to progressive liver dysfunction.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."

This review directly identifies hepatosplenomegaly as a characteristic infantile manifestation.

Digestive 4

Hepatic failure Hepatic failure HP:0001399

Severe infantile hepatic disease can progress to hepatic failure within the first months of life.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months."

This review directly identifies hepatic failure in infantile Wolman disease.

Diarrhea Diarrhea HP:0002014

Persistent diarrhea reflects severe intestinal dysfunction and fat malabsorption.

Show evidence (1 reference)

PMID:28179030 SUPPORT Human Clinical

"Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"

This study directly documents diarrhea as part of the severe infantile phenotype.

Vomiting Vomiting HP:0002013

Persistent vomiting begins early and contributes to nutritional compromise.

Show evidence (1 reference)

PMID:24832708 SUPPORT Human Clinical

"In early onset LAL deficiency, clinical manifestations start in the first few weeks of life with persistent vomiting, failure to thrive, hepatosplenomegaly, liver dysfunction and hepatic failure."

This report directly supports persistent vomiting as an early manifestation of Wolman disease.

Malabsorption Malabsorption HP:0002024

Poor intestinal absorption is a major driver of growth failure and dietary intolerance.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."

This review explicitly identifies malabsorption as a driver of growth failure in infantile disease.

Growth 1

Failure to thrive Failure to thrive HP:0001508

Severe early growth failure driven by multisystem disease and malabsorption.

Show evidence (1 reference)

PMID:28179030 SUPPORT Human Clinical

"Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"

This study directly identifies failure to thrive as a hallmark manifestation of infantile Wolman disease.

Other 1

Adrenal calcification Adrenal calcification HP:0010512

Classic imaging clue when present, though not universal.

Show evidence (1 reference)

PMID:24832708 SUPPORT Human Clinical

"Adrenal calcification is a striking feature but is present in only about 50% of cases."

This case-based review directly supports adrenal calcification as a characteristic but not universal feature of Wolman disease.

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Genetic Associations

1

LIPA (Pathogenic Variants)

Gene: LIPA hgnc:6617

Show evidence (1 reference)

CGGV:assertion_1691be18-3aa2-46e7-b6a6-e7acafb9f998-2023-04-28T040000.000Z SUPPORT Other

ClinGen classifies the LIPA-lysosomal acid lipase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.

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Medical Actions

2

Sebelipase alfa enzyme replacement therapy

Action: enzyme replacement therapy Ontology label: enzyme replacement or supplementation therapy MAXO:0000933

Agent: sebelipase alfa NCIT:C152312

Recombinant human lysosomal acid lipase replacement restores proximal enzyme function and substantially improves survival, growth, liver parameters, and other major disease manifestations when started early.

Mechanism Target:

RESTORES Lysosomal Acid Lipase Deficiency — Sebelipase alfa replaces missing lysosomal acid lipase activity at the proximal defect.

Show evidence (1 reference)

PMID:28179030 SUPPORT Human Clinical

"Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency"

This phase 2/3 study supports enzyme replacement as proximal therapy for the underlying lysosomal acid lipase deficiency.

INHIBITS Lysosomal Cholesteryl Ester and Triglyceride Storage — Enzyme replacement lowers the stored neutral-lipid burden downstream of the LAL deficiency.

Show evidence (1 reference)

PMID:23624251 SUPPORT Model Organism

"A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa."

In a LAL-deficient animal model, sebelipase alfa reduced hepatic cholesteryl ester accumulation, supporting direct inhibition of the storage mechanism.

Target Phenotypes: Failure to thrive HP:0001508 Hepatosplenomegaly HP:0001433 Anemia HP:0001903

Show evidence (2 references)

PMID:34906190 SUPPORT Human Clinical

"Early ERT initiation allowed 100% survival with positive outcomes."

Long-term cohort follow-up supports strong clinical benefit from early sebelipase alfa initiation.

PMID:33407676 SUPPORT Human Clinical

"The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated,..."

Final pooled study results confirm durable benefit on survival, growth, hematologic measures, and liver disease.

Nutritional management with dietary lipid reduction

Action: dietary intervention MAXO:0000088

Nutritional management is used alongside enzyme replacement therapy to reduce dietary lipid substrate burden, improve gastrointestinal tolerance, and support growth in infants with severe intestinal disease.

Mechanism Target:

MODULATES Malabsorption and Severe Gastrointestinal Dysfunction — Dietary substrate reduction and GI-focused nutritional management reduce intestinal stress and improve absorption and growth.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"Dietary substrate (lipid) reduction, known as substrate reduction therapy, is essential for optimal management in LAL-D."

This review directly supports dietary substrate reduction as part of optimal management of infantile LAL deficiency.

Target Phenotypes: Malabsorption HP:0002024 Failure to thrive HP:0001508 Diarrhea HP:0002014 Vomiting HP:0002013

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"Treatment takes the two-pronged approach of sebelipase alfa, a human lysosomal acid lipase enzyme replacement therapy (ERT) that improves lipid metabolism, combined with nutritional management."

This review directly frames nutritional management as a standard co-therapy with enzyme replacement in infantile disease.

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Biochemical Markers

4

Reduced lysosomal acid lipase activity (DECREASED)

Context: Reduced or absent lysosomal acid lipase activity is the proximal diagnostic enzyme abnormality caused by LIPA pathogenic variants.

Pathograph Readouts

Readout Of Lysosomal Acid Lipase Deficiency Negative Diagnostic

Low LAL enzyme activity reports the proximal lysosomal acid lipase deficiency.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"Lysosomal acid lipase deficiency-which can be diagnosed using dry blood spot testing-is often misdiagnosed as non-alcoholic fatty liver disease"

Dry blood spot LAL enzyme activity assay is the established diagnostic test for the proximal LAL deficiency, supporting low enzyme activity as the diagnostic readout.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."

This review directly supports reduced or absent LAL activity as the defining biochemical enzyme abnormality.

Cholesteryl ester storage burden (INCREASED)

Context: Cholesteryl ester storage is a chemical readout of the LAL deficiency neutral-lipid storage lesion.

Pathograph Readouts

Readout Of Lysosomal Cholesteryl Ester and Triglyceride Storage Positive Diagnostic

Increased cholesteryl ester storage reports the core lysosomal neutral-lipid storage lesion.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes"

LAL deficiency causes intra-lysosomal accumulation of cholesteryl esters, supporting CE burden as a direct readout of the lysosomal neutral-lipid storage lesion.

Readout Of Hepatic and Reticuloendothelial Lipid Storage Positive Monitoring

Cholesteryl ester burden reports hepatic and reticuloendothelial storage biology.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes"

Accumulation in liver and macrophages (reticuloendothelial system) and lymph nodes supports the cholesteryl ester readout reporting on hepatic and reticuloendothelial storage biology.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."

This review supports cholesteryl ester storage as a disease biochemical readout.

Triglyceride storage burden (INCREASED)

Context: Triglyceride storage accompanies cholesteryl ester storage when LAL deficiency blocks lysosomal neutral-lipid hydrolysis.

Pathograph Readouts

Readout Of Lysosomal Cholesteryl Ester and Triglyceride Storage Positive Diagnostic

Increased triglyceride burden reports impaired lysosomal neutral-lipid hydrolysis.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes"

LAL deficiency causes intra-lysosomal triglyceride accumulation alongside cholesteryl esters, supporting TG burden as a direct readout of the impaired lysosomal neutral-lipid hydrolysis lesion.

Show evidence (1 reference)

PMID:41599846 SUPPORT Human Clinical

"LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."

This review supports triglyceride storage as part of the disease biochemical profile.

Elevated hepatic transaminases (INCREASED)

Context: Transaminitis is a circulating biochemical correlate of hepatic involvement across the LAL deficiency spectrum.

Pathograph Readouts

Readout Of Progressive Liver Dysfunction Positive Monitoring

Elevated transaminases report ongoing hepatocellular injury downstream of hepatic lipid storage.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"although the two diseases share many common features, including dyslipidaemia and transaminitis."

Transaminitis is a shared feature across the LAL deficiency spectrum, supporting elevated transaminases as a circulating readout of progressive hepatocellular injury.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"although the two diseases share many common features, including dyslipidaemia and transaminitis."

This review supports transaminitis as a biochemical manifestation of LAL deficiency.

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Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Wolman Disease:

Cholesteryl ester storage disease MONDO:0019149

Overlapping Features Later-onset lysosomal acid lipase deficiency phenotype that shares LIPA causation and cholesteryl ester/triglyceride storage biology but is clinically less severe and usually presents beyond infancy with chronic liver disease and dyslipidemia.

Show evidence (1 reference)

PMID:28786388 SUPPORT Human Clinical

"Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis."

This review directly supports CESD as the later-onset, less severe sibling phenotype on the same LAL deficiency spectrum.

{ }

Source YAML

click to show

name: Wolman Disease
creation_date: '2026-04-14T19:53:03Z'
updated_date: '2026-05-20T04:07:56Z'
category: Mendelian
description: >
  Wolman disease is the rapidly progressive infantile phenotype of lysosomal acid
  lipase deficiency caused by biallelic pathogenic variants in LIPA. Near-complete
  loss of lysosomal acid lipase activity blocks lysosomal hydrolysis of cholesteryl
  esters and triglycerides, causing multisystem lipid storage in macrophages and
  parenchymal cells, especially in liver, intestine, spleen, lymphoid tissues,
  and adrenal cortex. The resulting hepatic dysfunction, malabsorption, failure
  to thrive, hepatosplenomegaly, anemia, and adrenal calcification lead to fatal
  multiorgan failure in infancy if untreated. Wolman disease is distinct from the
  later-onset cholesteryl ester storage disease phenotype on the same lysosomal
  acid lipase deficiency spectrum.
disease_term:
  preferred_term: Wolman disease
  term:
    id: MONDO:0019148
    label: Wolman disease
parents:
- Lysosomal Storage Disease
inheritance:
- name: Autosomal recessive
  description: >
    Wolman disease is inherited as an autosomal recessive disorder caused by
    biallelic LIPA pathogenic variants that severely reduce or abolish lysosomal
    acid lipase activity.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:28786388
    reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."
    explanation: This review directly supports autosomal recessive inheritance and LIPA-mediated lysosomal acid lipase deficiency.
progression:
- phase: Neonatal/Early infancy onset
  age_range: first weeks to months of life
  notes: >
    Symptoms begin in early infancy with persistent vomiting, failure to thrive,
    hepatosplenomegaly, liver dysfunction, and progressive gastrointestinal disease.
  evidence:
  - reference: PMID:24832708
    reference_title: "Infant case of lysosomal acid lipase deficiency: Wolman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In early onset LAL deficiency, clinical manifestations start in the first few weeks of life with persistent vomiting, failure to thrive, hepatosplenomegaly, liver dysfunction and hepatic failure."
    explanation: This infant case report and review directly supports early infantile onset with gastrointestinal and hepatic manifestations.
- phase: Untreated rapid progression
  age_range: first year of life
  notes: >
    Without treatment, disease progresses rapidly to multiorgan failure and death
    in infancy.
  evidence:
  - reference: PMID:34906190
    reference_title: "Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age."
    explanation: This nationwide cohort study summarizes the untreated natural history as rapidly progressive multiorgan failure in infancy.
pathophysiology:
- name: LIPA Loss of Function
  description: >
    Biallelic pathogenic variants in LIPA reduce or abolish lysosomal acid lipase
    activity.
  genes:
  - preferred_term: LIPA
    term:
      id: hgnc:6617
      label: LIPA
  downstream:
  - target: Lysosomal Acid Lipase Deficiency
    description: Loss of LIPA function reduces or abolishes lysosomal acid lipase activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28786388
      reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."
      explanation: This review directly connects LIPA mutations to reduced or absent lysosomal acid lipase activity.
  evidence:
  - reference: PMID:28786388
    reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."
    explanation: This review directly links LIPA mutations to reduced or absent lysosomal acid lipase activity.
- name: Lysosomal Acid Lipase Deficiency
  description: >
    Lysosomal acid lipase activity is markedly reduced or absent, removing the
    essential lysosomal hydrolase required to cleave cholesteryl esters and triglycerides.
  genes:
  - preferred_term: LIPA
    term:
      id: hgnc:6617
      label: LIPA
  molecular_functions:
  - preferred_term: sterol ester esterase activity
    term:
      id: GO:0004771
      label: sterol ester esterase activity
    modifier: DECREASED
  - preferred_term: triacylglycerol lipase activity
    term:
      id: GO:0004806
      label: triacylglycerol lipase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: neutral lipid catabolic process
    term:
      id: GO:0046461
      label: neutral lipid catabolic process
    modifier: DECREASED
  - preferred_term: triglyceride catabolic process
    term:
      id: GO:0019433
      label: triglyceride catabolic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: lysosomal lumen
    term:
      id: GO:0043202
      label: lysosomal lumen
  downstream:
  - target: Reduced lysosomal acid lipase activity
    description: LIPA pathogenic variants produce reduced or absent lysosomal acid lipase enzyme activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28786388
      reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."
      explanation: The review directly supports reduced or absent LAL activity as the enzyme readout of the genetic defect.
  - target: Impaired Lysosomal Cholesteryl Ester and Triglyceride Hydrolysis
    description: Deficient lysosomal acid lipase prevents normal lysosomal hydrolysis of cholesteryl esters and triglycerides.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36204319
      reference_title: "Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lysosomal acid lipase (LAL), encoded by the gene LIPA, is the sole neutral lipid hydrolase in lysosomes, responsible for cleavage of cholesteryl esters and triglycerides into their component parts."
      explanation: This review defines LAL as the lysosomal hydrolase responsible for cleaving cholesteryl esters and triglycerides, supporting the hydrolysis block caused by deficiency.
  evidence:
  - reference: PMID:30866656
    reference_title: "Lysosomal Acid Lipase in Lipid Metabolism and Beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysosomal acid lipase (LAL), encoded by the lipase A ( LIPA) gene, hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell."
    explanation: This review provides the core enzymatic function that is lost in Wolman disease.
  - reference: PMID:36204319
    reference_title: "Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysosomal acid lipase (LAL), encoded by the gene LIPA, is the sole neutral lipid hydrolase in lysosomes, responsible for cleavage of cholesteryl esters and triglycerides into their component parts."
    explanation: This review independently supports lysosomal acid lipase as the key lysosomal hydrolase for cholesteryl ester and triglyceride cleavage.
- name: Impaired Lysosomal Cholesteryl Ester and Triglyceride Hydrolysis
  description: >
    Failure of lysosomal acid lipase blocks lysosomal cleavage of cholesteryl esters
    and triglycerides into free cholesterol and fatty acids.
  biological_processes:
  - preferred_term: cholesterol metabolic process
    term:
      id: GO:0008203
      label: cholesterol metabolic process
    modifier: DECREASED
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: cholesteryl ester
    term:
      id: CHEBI:17002
      label: cholesteryl ester
  - preferred_term: triglyceride
    term:
      id: CHEBI:17855
      label: triglyceride
  downstream:
  - target: Lysosomal Cholesteryl Ester and Triglyceride Storage
    description: Undegraded cholesteryl esters and triglycerides accumulate in lysosomes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23624251
      reference_title: "Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues."
      explanation: Human LAL deficiency data directly support lysosomal cholesteryl ester and triglyceride storage downstream of reduced LAL activity.
  - target: Cholesteryl ester storage burden
    description: Blocked lysosomal neutral-lipid hydrolysis produces increased cholesteryl ester storage across affected tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
      explanation: The review directly supports cholesteryl ester storage downstream of LAL deficiency in affected tissues.
  - target: Triglyceride storage burden
    description: Blocked lysosomal neutral-lipid hydrolysis produces increased triglyceride storage across affected tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
      explanation: The review directly supports triglyceride storage downstream of LAL deficiency in affected tissues.
  evidence:
  - reference: PMID:30866656
    reference_title: "Lysosomal Acid Lipase in Lipid Metabolism and Beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysosomal acid lipase (LAL), encoded by the lipase A ( LIPA) gene, hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell."
    explanation: Loss of this lysosomal hydrolysis step is the immediate biochemical consequence of lysosomal acid lipase deficiency.
- name: Lysosomal Cholesteryl Ester and Triglyceride Storage
  description: >
    Cholesteryl esters and triglycerides accumulate within lysosomes of macrophages
    and parenchymal cells across multiple tissues, establishing the multisystem
    storage phenotype of Wolman disease.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  - preferred_term: lymph node
    term:
      id: UBERON:0000029
      label: lymph node
  chemical_entities:
  - preferred_term: cholesteryl ester
    term:
      id: CHEBI:17002
      label: cholesteryl ester
  - preferred_term: triglyceride
    term:
      id: CHEBI:17855
      label: triglyceride
  downstream:
  - target: Hepatic and Reticuloendothelial Lipid Storage
    description: Lipid-laden macrophages and parenchymal cells accumulate in liver and spleen.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
      explanation: The review directly identifies lipid storage in macrophages and parenchymal cells, including liver and lymphoid tissues.
  - target: Intestinal Lipid Storage
    description: Lipid storage in the gastrointestinal tract drives enteric dysfunction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
      explanation: The same tissue-distribution statement directly supports gastrointestinal tract lipid storage.
  - target: Adrenal Cortical Lipid Storage
    description: Adrenal cortical tissues accumulate stored lipids and become structurally abnormal.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
      explanation: The review supports adrenal structural disease in rapidly progressive LAL-D, consistent with adrenal cortical lipid storage as a direct tissue-specific extension of multisystem neutral-lipid storage.
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
    explanation: This review directly supports multisystem lysosomal cholesteryl ester and triglyceride storage in macrophages and parenchymal cells.
  - reference: PMID:23624251
    reference_title: "Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues."
    explanation: This human translational study independently supports CE and TG accumulation in lysosomes across many tissues.
- name: Hepatic and Reticuloendothelial Lipid Storage
  description: >
    Storage within hepatocytes and reticuloendothelial macrophages enlarges the
    liver and spleen and sets up rapidly progressive hepatic injury.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  downstream:
  - target: Progressive Liver Dysfunction
    description: Progressive hepatic storage contributes to liver dysfunction and eventual hepatic failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28179030
      reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"
      explanation: The infant treatment study links hepatosplenomegaly and rapidly progressive liver disease in the severe LAL-D phenotype.
  - target: Hepatosplenomegaly
    description: Hepatic and reticuloendothelial lipid storage clinically manifests as marked hepatosplenomegaly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28179030
      reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"
      explanation: The study identifies massive hepatosplenomegaly as a hallmark manifestation of infantile LAL-D.
  - target: Anemia
    description: Severe infantile hepatic and reticuloendothelial lipid-storage disease is accompanied by anemia within the systemic presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:28179030
    reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"
    explanation: This infant treatment study summarizes the core hepatic and reticuloendothelial disease burden before effective therapy.
- name: Progressive Liver Dysfunction
  description: >
    Ongoing hepatic lipid storage causes liver dysfunction that can progress to
    hepatic failure during infancy.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:28786388
    reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months."
    explanation: This review directly connects the severe infantile phenotype to progressive hepatic failure.
  downstream:
  - target: Elevated hepatic transaminases
    description: Hepatocyte injury from progressive hepatic storage releases hepatic transaminases into circulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28786388
      reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "although the two diseases share many common features, including dyslipidaemia and transaminitis."
      explanation: The review identifies transaminitis as a shared biochemical feature of the LAL deficiency spectrum, supporting elevated hepatic transaminases downstream of hepatic disease.
  - target: Hepatic failure
    description: Progressive hepatic dysfunction can advance to hepatic failure in the severe infantile phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28786388
      reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months."
      explanation: The review directly links the severe infantile phenotype to hepatic failure.
  - target: Failure to thrive
    description: Severe hepatic failure contributes to the infantile failure-to-thrive phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - severe infantile multisystem disease
    - impaired growth and nutritional status
    evidence:
    - reference: PMID:28786388
      reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months."
      explanation: The review links the severe infantile hepatic phenotype with failure to thrive.
- name: Intestinal Lipid Storage
  description: >
    Storage in the gastrointestinal tract injures intestinal tissue and contributes
    to poor fat tolerance, vomiting, diarrhea, and downstream malabsorption.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Malabsorption and Severe Gastrointestinal Dysfunction
    description: Intestinal storage produces gastrointestinal disturbance and impaired nutrient absorption.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
      explanation: The review links infantile LAL-D gastrointestinal disturbance with malabsorption-driven growth failure.
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
    explanation: This review supports direct lipid storage within gastrointestinal tissues as a core component of disease biology.
- name: Malabsorption and Severe Gastrointestinal Dysfunction
  description: >
    Intestinal dysfunction produces persistent gastrointestinal symptoms and poor
    nutrient absorption, driving severe growth failure in infancy.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
    explanation: This review directly links gastrointestinal disturbance and growth failure to malabsorption in infantile Wolman disease.
  - reference: PMID:34020687
    reference_title: "Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure."
    explanation: Improvement in diarrhea, vomiting, fat tolerance, and villous structure after therapy supports intestinal pathology as a key disease mechanism.
  downstream:
  - target: Malabsorption
    description: Severe gastrointestinal dysfunction includes malabsorption.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
      explanation: The review explicitly states that malabsorption drives growth failure in rapidly progressive infantile LAL-D.
  - target: Diarrhea
    description: Gastrointestinal dysfunction commonly manifests as diarrhea.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28179030
      reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"
      explanation: The infant LAL-D study directly lists diarrhea among the severe gastrointestinal manifestations.
  - target: Vomiting
    description: Severe gastrointestinal dysfunction begins early with persistent vomiting.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24832708
      reference_title: "Infant case of lysosomal acid lipase deficiency: Wolman's disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In early onset LAL deficiency, clinical manifestations start in the first few weeks of life with persistent vomiting, failure to thrive, hepatosplenomegaly, liver dysfunction and hepatic failure."
      explanation: This case-based review directly supports persistent vomiting as an early gastrointestinal manifestation.
  - target: Failure to thrive
    description: Malabsorption and gastrointestinal dysfunction drive severe infantile growth failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
      explanation: The review directly connects malabsorption to growth failure in infantile-onset LAL-D.
- name: Adrenal Cortical Lipid Storage
  description: >
    Lipid storage in the adrenal cortex produces adrenal enlargement and underlies
    the characteristic adrenal calcification seen in many infants.
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
    explanation: This review directly supports adrenal involvement with enlargement and calcification in rapidly progressive infantile disease.
  downstream:
  - target: Adrenal calcification
    description: Adrenal cortical disease produces the characteristic adrenal calcification phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24832708
      reference_title: "Infant case of lysosomal acid lipase deficiency: Wolman's disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adrenal calcification is a striking feature but is present in only about 50% of cases."
      explanation: This case-based review directly supports adrenal calcification as a characteristic adrenal manifestation of Wolman disease.
phenotypes:
- name: Failure to thrive
  category: Growth
  notes: Severe early growth failure driven by multisystem disease and malabsorption.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:28179030
    reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"
    explanation: This study directly identifies failure to thrive as a hallmark manifestation of infantile Wolman disease.
- name: Hepatosplenomegaly
  category: Gastrointestinal
  diagnostic: true
  notes: Often marked early in the course and coupled to progressive liver dysfunction.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
    explanation: This review directly identifies hepatosplenomegaly as a characteristic infantile manifestation.
- name: Hepatic failure
  category: Hepatic
  notes: Severe infantile hepatic disease can progress to hepatic failure within the first months of life.
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:28786388
    reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months."
    explanation: This review directly identifies hepatic failure in infantile Wolman disease.
- name: Diarrhea
  category: Gastrointestinal
  notes: Persistent diarrhea reflects severe intestinal dysfunction and fat malabsorption.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:28179030
    reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"
    explanation: This study directly documents diarrhea as part of the severe infantile phenotype.
- name: Vomiting
  category: Gastrointestinal
  notes: Persistent vomiting begins early and contributes to nutritional compromise.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:24832708
    reference_title: "Infant case of lysosomal acid lipase deficiency: Wolman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In early onset LAL deficiency, clinical manifestations start in the first few weeks of life with persistent vomiting, failure to thrive, hepatosplenomegaly, liver dysfunction and hepatic failure."
    explanation: This report directly supports persistent vomiting as an early manifestation of Wolman disease.
- name: Malabsorption
  category: Gastrointestinal
  notes: Poor intestinal absorption is a major driver of growth failure and dietary intolerance.
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation."
    explanation: This review explicitly identifies malabsorption as a driver of growth failure in infantile disease.
- name: Adrenal calcification
  category: Endocrine
  diagnostic: true
  notes: Classic imaging clue when present, though not universal.
  phenotype_term:
    preferred_term: Adrenal calcification
    term:
      id: HP:0010512
      label: Adrenal calcification
  evidence:
  - reference: PMID:24832708
    reference_title: "Infant case of lysosomal acid lipase deficiency: Wolman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adrenal calcification is a striking feature but is present in only about 50% of cases."
    explanation: This case-based review directly supports adrenal calcification as a characteristic but not universal feature of Wolman disease.
- name: Anemia
  category: Hematologic
  notes: Anemia accompanies the severe infantile systemic phenotype and improves with effective therapy.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:28179030
    reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life"
    explanation: This study directly identifies anemia as part of the severe infantile presentation.
biochemical:
- name: Reduced lysosomal acid lipase activity
  presence: DECREASED
  context: >
    Reduced or absent lysosomal acid lipase activity is the proximal diagnostic
    enzyme abnormality caused by LIPA pathogenic variants.
  readouts:
  - target: Lysosomal Acid Lipase Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low LAL enzyme activity reports the proximal lysosomal acid lipase deficiency.
    evidence:
    - reference: PMID:28786388
      reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lysosomal acid lipase deficiency-which can be diagnosed using dry blood spot testing-is often misdiagnosed as non-alcoholic fatty liver disease"
      explanation: Dry blood spot LAL enzyme activity assay is the established diagnostic test for the proximal LAL deficiency, supporting low enzyme activity as the diagnostic readout.
  evidence:
  - reference: PMID:28786388
    reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme."
    explanation: This review directly supports reduced or absent LAL activity as the defining biochemical enzyme abnormality.
- name: Cholesteryl ester storage burden
  presence: INCREASED
  context: >
    Cholesteryl ester storage is a chemical readout of the LAL deficiency
    neutral-lipid storage lesion.
  biomarker_term:
    preferred_term: cholesteryl ester
    term:
      id: CHEBI:17002
      label: cholesteryl ester
  readouts:
  - target: Lysosomal Cholesteryl Ester and Triglyceride Storage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased cholesteryl ester storage reports the core lysosomal neutral-lipid storage lesion.
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes"
      explanation: LAL deficiency causes intra-lysosomal accumulation of cholesteryl esters, supporting CE burden as a direct readout of the lysosomal neutral-lipid storage lesion.
  - target: Hepatic and Reticuloendothelial Lipid Storage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Cholesteryl ester burden reports hepatic and reticuloendothelial storage biology.
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes"
      explanation: Accumulation in liver and macrophages (reticuloendothelial system) and lymph nodes supports the cholesteryl ester readout reporting on hepatic and reticuloendothelial storage biology.
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
    explanation: This review supports cholesteryl ester storage as a disease biochemical readout.
- name: Triglyceride storage burden
  presence: INCREASED
  context: >
    Triglyceride storage accompanies cholesteryl ester storage when LAL
    deficiency blocks lysosomal neutral-lipid hydrolysis.
  biomarker_term:
    preferred_term: triglyceride
    term:
      id: CHEBI:17855
      label: triglyceride
  readouts:
  - target: Lysosomal Cholesteryl Ester and Triglyceride Storage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased triglyceride burden reports impaired lysosomal neutral-lipid hydrolysis.
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes"
      explanation: LAL deficiency causes intra-lysosomal triglyceride accumulation alongside cholesteryl esters, supporting TG burden as a direct readout of the impaired lysosomal neutral-lipid hydrolysis lesion.
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system."
    explanation: This review supports triglyceride storage as part of the disease biochemical profile.
- name: Elevated hepatic transaminases
  presence: INCREASED
  context: >
    Transaminitis is a circulating biochemical correlate of hepatic involvement
    across the LAL deficiency spectrum.
  readouts:
  - target: Progressive Liver Dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Elevated transaminases report ongoing hepatocellular injury downstream of hepatic lipid storage.
    evidence:
    - reference: PMID:28786388
      reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "although the two diseases share many common features, including dyslipidaemia and transaminitis."
      explanation: Transaminitis is a shared feature across the LAL deficiency spectrum, supporting elevated transaminases as a circulating readout of progressive hepatocellular injury.
  evidence:
  - reference: PMID:28786388
    reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "although the two diseases share many common features, including dyslipidaemia and transaminitis."
    explanation: This review supports transaminitis as a biochemical manifestation of LAL deficiency.
genetic:
- name: LIPA
  gene_term:
    preferred_term: LIPA
    term:
      id: hgnc:6617
      label: LIPA
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_1691be18-3aa2-46e7-b6a6-e7acafb9f998-2023-04-28T040000.000Z
    reference_title: "LIPA / lysosomal acid lipase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LIPA | HGNC:6617 | lysosomal acid lipase deficiency | MONDO:0800449 | AR | Definitive"
    explanation: ClinGen classifies the LIPA-lysosomal acid lipase deficiency gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Sebelipase alfa enzyme replacement therapy
  description: >
    Recombinant human lysosomal acid lipase replacement restores proximal enzyme
    function and substantially improves survival, growth, liver parameters, and
    other major disease manifestations when started early.
  treatment_term:
    preferred_term: enzyme replacement therapy
    term:
      id: MAXO:0000933
      label: enzyme replacement or supplementation therapy
    therapeutic_agent:
    - preferred_term: sebelipase alfa
      term:
        id: NCIT:C152312
        label: Sebelipase Alfa
  target_mechanisms:
  - target: Lysosomal Acid Lipase Deficiency
    treatment_effect: RESTORES
    description: Sebelipase alfa replaces missing lysosomal acid lipase activity at the proximal defect.
    evidence:
    - reference: PMID:28179030
      reference_title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency"
      explanation: This phase 2/3 study supports enzyme replacement as proximal therapy for the underlying lysosomal acid lipase deficiency.
  - target: Lysosomal Cholesteryl Ester and Triglyceride Storage
    treatment_effect: INHIBITS
    description: Enzyme replacement lowers the stored neutral-lipid burden downstream of the LAL deficiency.
    evidence:
    - reference: PMID:23624251
      reference_title: "Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa."
      explanation: In a LAL-deficient animal model, sebelipase alfa reduced hepatic cholesteryl ester accumulation, supporting direct inhibition of the storage mechanism.
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  - preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:34906190
    reference_title: "Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early ERT initiation allowed 100% survival with positive outcomes."
    explanation: Long-term cohort follow-up supports strong clinical benefit from early sebelipase alfa initiation.
  - reference: PMID:33407676
    reference_title: "Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated, with an acceptable safety profile."
    explanation: Final pooled study results confirm durable benefit on survival, growth, hematologic measures, and liver disease.
- name: Nutritional management with dietary lipid reduction
  description: >
    Nutritional management is used alongside enzyme replacement therapy to reduce
    dietary lipid substrate burden, improve gastrointestinal tolerance, and support
    growth in infants with severe intestinal disease.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Malabsorption and Severe Gastrointestinal Dysfunction
    treatment_effect: MODULATES
    description: Dietary substrate reduction and GI-focused nutritional management reduce intestinal stress and improve absorption and growth.
    evidence:
    - reference: PMID:41599846
      reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dietary substrate (lipid) reduction, known as substrate reduction therapy, is essential for optimal management in LAL-D."
      explanation: This review directly supports dietary substrate reduction as part of optimal management of infantile LAL deficiency.
  target_phenotypes:
  - preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  - preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  - preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:41599846
    reference_title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment takes the two-pronged approach of sebelipase alfa, a human lysosomal acid lipase enzyme replacement therapy (ERT) that improves lipid metabolism, combined with nutritional management."
    explanation: This review directly frames nutritional management as a standard co-therapy with enzyme replacement in infantile disease.
differential_diagnoses:
- name: Cholesteryl ester storage disease
  description: >
    Later-onset lysosomal acid lipase deficiency phenotype that shares LIPA causation
    and cholesteryl ester/triglyceride storage biology but is clinically less severe
    and usually presents beyond infancy with chronic liver disease and dyslipidemia.
  disease_term:
    preferred_term: cholesteryl ester storage disease
    term:
      id: MONDO:0019149
      label: cholesteryl ester storage disease
  evidence:
  - reference: PMID:28786388
    reference_title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis."
    explanation: This review directly supports CESD as the later-onset, less severe sibling phenotype on the same LAL deficiency spectrum.
references:
- reference: PMID:28786388
  title: "Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency."
- reference: PMID:30866656
  title: "Lysosomal Acid Lipase in Lipid Metabolism and Beyond."
- reference: PMID:36204319
  title: "Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease."
- reference: PMID:41599846
  title: "Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion."
- reference: PMID:23624251
  title: "Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance."
- reference: PMID:28179030
  title: "Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study."
- reference: PMID:34906190
  title: "Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up."
- reference: PMID:33407676
  title: "Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies."
- reference: PMID:24832708
  title: "Infant case of lysosomal acid lipase deficiency: Wolman's disease."
- reference: PMID:34020687
  title: "Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease."

📚

References & Deep Research

References

10

PMID:28786388

Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency.

No top-level findings curated for this source.

PMID:30866656

Lysosomal Acid Lipase in Lipid Metabolism and Beyond.

No top-level findings curated for this source.

PMID:36204319

Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease.

No top-level findings curated for this source.

PMID:41599846

Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion.

No top-level findings curated for this source.

PMID:23624251

Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance.

No top-level findings curated for this source.

PMID:28179030

Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study.

No top-level findings curated for this source.

PMID:34906190

Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up.

No top-level findings curated for this source.

PMID:33407676

Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies.

No top-level findings curated for this source.

PMID:24832708

Infant case of lysosomal acid lipase deficiency: Wolman's disease.

No top-level findings curated for this source.

PMID:34020687

Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease.

No top-level findings curated for this source.

Deep Research

1

Codex Local Synthesis ▸

Wolman Disease Curation Synthesis

gpt-5 9 citations 2026-04-14T19:53:03Z

Wolman Disease Curation Synthesis

MONDO and ClinGen checks

MONDO:0019148 exact label: Wolman disease (MONDO/OLS).
MONDO:0800449 exact label: lysosomal acid lipase deficiency (MONDO/OLS).
MONDO:0019149 exact label: cholesteryl ester storage disease (MONDO/OLS).
MONDO/OLS description for MONDO:0019148: Wolman disease represents the most severe manifestation of lysosomal acid lipase deficiency. Milder phenotypes as a whole are referred to as cholesterol ester storage disease.
Local ClinGen cache cross-check: cache/clingen/gene_validity.csv records LIPA -> lysosomal acid lipase deficiency (MONDO:0800449) as Definitive by the Lysosomal Diseases Gene Curation Expert Panel on 2023-04-28.
Curation implication: anchor the disease file to the specific child term Wolman disease, while making the broader lysosomal acid lipase deficiency umbrella and the later-onset sibling phenotype cholesteryl ester storage disease explicit in the narrative and differential framing.

Exact PMID-backed quote inventory

Core disease framing

PMID:28786388
Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme.
Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months.
Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis.

Proximal enzymatic defect

PMID:30866656
Lysosomal acid lipase (LAL), encoded by the lipase A ( LIPA) gene, hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell.
In humans, loss-of-function mutations of LIPA cause rare lysosomal disorders, Wolman disease and cholesteryl ester storage disease, in which LAL enzyme-replacement therapy has shown significant benefits in a phase 3 clinical trial.
PMID:36204319
Lysosomal acid lipase (LAL), encoded by the gene LIPA, is the sole neutral lipid hydrolase in lysosomes, responsible for cleavage of cholesteryl esters and triglycerides into their component parts.
Inherited forms of complete (Wolman Disease, WD) or partial LAL deficiency (cholesteryl ester storage disease, CESD) are fortunately rare.

Storage biology and tissue distribution

PMID:41599846
LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system.
Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation.
PMID:23624251
Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues.

Natural history and severe infantile phenotype

PMID:28179030
Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life
Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency
PMID:34906190
Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age.
Early ERT initiation allowed 100% survival with positive outcomes.
PMID:33407676
The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated, with an acceptable safety profile.
PMID:24832708
In early onset LAL deficiency, clinical manifestations start in the first few weeks of life with persistent vomiting, failure to thrive, hepatosplenomegaly, liver dysfunction and hepatic failure.
Adrenal calcification is a striking feature but is present in only about 50% of cases.

Curation decisions derived from the evidence

Use a connected proximal chain:
LIPA loss of function
Lysosomal acid lipase deficiency
Impaired lysosomal cholesteryl ester and triglyceride hydrolysis
Lysosomal cholesteryl ester and triglyceride storage
Split downstream tissue dysfunction rather than shortcutting directly to symptoms:
Hepatic and reticuloendothelial lipid storage -> Progressive liver dysfunction
Intestinal lipid storage -> Malabsorption and severe gastrointestinal dysfunction
Adrenal cortical lipid storage
Keep phenotype assertions at the disease level and do not encode frequency unless the abstract supports the quantitative band directly.
Connect sebelipase alfa to the proximal deficiency/storage nodes with target_mechanisms, and add dietary management separately because the literature frames treatment as a two-pronged ERT plus nutritional-management approach.

Term shortlist used for grounding

Disease terms:
MONDO:0019148 Wolman disease
MONDO:0019149 cholesteryl ester storage disease
Gene:
hgnc:6617 LIPA
Molecular functions:
GO:0004771 sterol ester esterase activity
GO:0004806 triacylglycerol lipase activity
Cellular component:
GO:0043202 lysosomal lumen
Biological processes:
GO:0006629 lipid metabolic process
GO:0008203 cholesterol metabolic process
Chemicals:
CHEBI:17002 cholesteryl ester
CHEBI:17855 triglyceride
Cell types:
CL:0000235 macrophage
CL:0000182 hepatocyte
CL:0000584 enterocyte
Anatomical locations:
UBERON:0002107 liver
UBERON:0002106 spleen
UBERON:0002108 small intestine
UBERON:0001235 adrenal cortex
UBERON:0000029 lymph node
Phenotypes:
HP:0001508 Failure to thrive
HP:0001433 Hepatosplenomegaly
HP:0002014 Diarrhea
HP:0002013 Vomiting
HP:0002024 Malabsorption
HP:0010512 Adrenal calcification
HP:0001903 Anemia
Treatments:
MAXO:0000933 enzyme replacement or supplementation therapy
NCIT:C152312 Sebelipase Alfa
MAXO:0000088 dietary intervention

Wolman Disease

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References & Deep Research

References

Deep Research

Wolman Disease Curation Synthesis

MONDO and ClinGen checks

Exact PMID-backed quote inventory

Core disease framing

Proximal enzymatic defect

Storage biology and tissue distribution

Natural history and severe infantile phenotype

Curation decisions derived from the evidence

Term shortlist used for grounding