Lysosomal Acid Lipase Deficiency and Cholesteryl Ester Storage Disease

Lysosomal acid lipase deficiency is an inherited disorder arising from mutations in the gene encoding lysosomal acid lipase, an enzyme responsible for hydrolysing cholesteryl esters and triglycerides within lysosomes. The clinical spectrum ranges from the rapidly progressive infantile form, often fatal within months, to the attenuated form known as cholesteryl ester storage disease, which presents later with hepatomegaly, dyslipidaemia and accelerated atherosclerosis. Pathologically, lipid-laden macrophages and hepatocytes accumulate neutral lipids, triggering inflammation, fibrosis and multi-organ dysfunction. Diagnosis relies on enzyme assays and genetic testing, while management encompasses enzyme replacement, emerging gene therapy approaches and supportive care. Improved understanding of lysosomal lipid trafficking has illuminated links to metabolic regulation, immune activation and cardiovascular risk, underscoring global significance despite the rarity of the condition.

Research from Nature Portfolio

Recent preclinical work has demonstrated that a single administration of a recombinant adeno-associated virus serotype 8 vector carrying the human lysosomal acid lipase transgene under a hepatocyte-specific promoter can fully correct lipid accumulation in a murine model. By defining the minimal effective dose, researchers achieved stable long-term enzyme expression, reversal of cholesteryl ester and triglyceride deposition across multiple organs and functional recovery of mitochondrial pathways disrupted by lipid overload. This gene therapy strategy offers a potential one-time curative approach that surpasses the limitations of lifelong enzyme infusions.

Lysosomal Acid Lipase Deficiency and Cholesteryl Ester Storage Disease publication trend

The graph below shows the total number of articles in lysosomal acid lipase deficiency and cholesteryl ester storage disease across all publications each year (not limited to Nature Index journals).

Technical terms

Lysosomal acid lipase (LAL): Enzyme that hydrolyses cholesteryl esters and triglycerides within lysosomes to generate free cholesterol and fatty acids.

Lysosomal acid lipase deficiency (LAL-D): Autosomal recessive disorder characterised by insufficient LAL activity, leading to intralysosomal lipid storage and organ damage.

Cholesteryl ester storage disease (CESD): A milder, late-onset form of LAL-D with residual enzyme activity causing progressive lipid deposition.

Enzyme replacement therapy (ERT): Treatment involving regular intravenous administration of recombinant enzyme to restore deficient lysosomal function.

Recombinant adeno-associated virus (rAAV) vector: Viral delivery system engineered to transport therapeutic genes into target cells, notably hepatocytes, with long-term expression.

References

1. Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer. Communications Medicine (2025).
2. Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants. Genetics in Medicine (2015).
3. Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (2019).
4. Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice*. Journal of Lipid Research (2008).
5. 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. Orphanet Journal of Rare Diseases (2021).