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.

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.

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.

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.

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.

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.