What is Lysosomal Acid Lipase?

Lysosomal acid lipase (LAL) is an enzyme located in lysosomes that helps break down cholesterol esters and triglycerides into fatty acids. The enzyme is encoded by the LIPA gene on chromosome 10 (10q23.31). Mutations in this gene reduce or eliminate LAL activity, causing lipid accumulation in liver, spleen, and other organs and impairing lysosomal function.

LAL deficiency is a monogenic metabolic disorder inherited in an autosomal recessive pattern.

Types of LAL Deficiency

There are two main phenotypes of LAL deficiency:

1. Wolman Disease (Early-Onset) 
   • Appears in infancy
   • Severe or complete lack of LAL activity
   • Rapidly progressive and life-threatening 
2. Cholesteryl Ester Storage Disease (CESD, Late-Onset) 
   • Residual enzyme activity remains
   • Occurs in older children or adults
   • Symptoms often milder and can be detected incidentally
     

Symptoms

Wolman Disease (Infants)

Symptoms usually appear within the first months of life and can include:

• Persistent vomiting and failure to thrive
• Hepatosplenomegaly (enlarged liver and spleen)
• Anemia and coagulopathy
• Abdominal distension and steatorrhea (fatty stools)
• Adrenal calcifications
• Cholestasis and elevated liver enzymes
• Hypertriglyceridemia 

Cholesteryl Ester Storage Disease (Older Children & Adults)

Symptoms are often subtle, which can delay diagnosis:

• Hepatomegaly and splenomegaly
• Abnormal lipid metabolism leading to early-onset atherosclerosis
• Mild liver enzyme elevations
• May mimic nonalcoholic fatty liver disease
• Many patients remain asymptomatic apart from organ enlargement
  

Diagnosis

LAL-D should be suspected in patients with dyslipidemia, hepatosplenomegaly, and elevated liver transaminases. Diagnostic methods include:

• Measuring LAL enzyme activity in leukocytes or fibroblasts
• Dried blood spot assays
• Molecular genetic testing to confirm LIPA mutations
• Chitotriosidase levels may be elevated
• Liver lipid analysis via thin-layer chromatography can also confirm LAL deficiency

Treatment

LAL deficiency is a chronic, progressive disease. Current available treatments are:

Enzyme Replacement Therapy (ERT)

• Sebelipase alfa is the only causal therapy
• Administered via intravenous infusion weekly or biweekly
• Normalizes liver enzyme levels and restores lipid balance
• Approved in Europe since 2015 

Supportive Care

• Nutritional management to prevent malnutrition and slow liver damage
• Corticosteroids for adrenal insufficiency
• Liver transplantation in end-stage liver failure
• Statins are ineffective for LAL-D

Prognosis

• Wolman disease: rapid progression, often fatal in infancy (usually before 6 months)
• Cholesteryl ester storage disease: milder course, onset can occur from childhood to adulthood
• Without treatment, prognosis is poor, especially in late-onset forms with delayed diagnosis
• In some countries (e.g., Poland), ERT is not yet reimbursed, limiting access

Sources:

• Lysosomal Acid Lipase Deficiency: Facts, Signs & Symptoms
• Lysosomal Acid Lipase Deficiency – GeneReviews® – NCBI Bookshelf
• Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies – PMC
• Lysosomal acid lipase: Roles in rare deficiency diseases, myeloid cell biology, innate immunity, and common neutral lipid diseases – ScienceDirect