Abstract

1. Deficient activity of lysosomal acid lipase (LAL) leads to the accumulation of cholesteryl esters and triglycerides in most tissue. These substrates of LAL highlight the central role of this enzyme in the modulation of cholesterol and triglyceride metabolism throughout the body. The deficiencies of LAL lead to a poorly defined continuum of diseases classically divided into Wolman disease and cholesteryl ester storage disease (CESD).

   
   

2. Wolman disease has its onset in the first month postpartum with a progressive course leading to death before 1 year of age. Hepatosplenomegaly, steatorrhea, abdominal distension, severe malabsorption and resultant malnutrition, and adrenal calcification are evident within the first months postpartum.

   
   

3. CESD has a less severe clinical course that is less well defined and highly variable. Isolated hepatomegaly and a hypercholesterolemia IIb pattern can be the presenting signs. Hepatic fibrosis with unpredictable progression to frank cirrhosis can occur. Premature atherosclerosis may occur. Malabsorption and adrenal calcifications are infrequent to rare.

   
   

4. Wolman disease and CESD are suspected by the clinical presentation and the diagnoses are confirmed by finding acid lipase deficiency in cultured skin fibroblasts, lymphocytes, or other tissues. Prenatal diagnosis is feasible by enzyme assay or molecular analyses of amniocytes or chorionic villus samples.

   
   

5. Wolman disease and CESD are autosomal recessive diseases, caused by mutations in the LIPA gene that maps to chromosome 10q23.2-q23.3 and encodes LAL. Many mutations of LIPA have been found in Wolman disease patients and lead to absence of LAL activity. In comparison, the many mutations of LIPA in CESD allow the expression of significant residual LAL activity. One common splice junction mutant allele (E8SJM-1) allows the expression of 3-8% percent of wild-type LAL activity and the apparent alleviation of the severity of Wolman disease.

   
   

6. No specific therapy is available for the LAL deficiencies. Enzyme therapy is successful in mouse models of LAL deficiency, and clinical trials in patients are currently underway. Bone marrow or hematopoietic stem cell transplantation has been successful in treating Wolman disease, but with very high mortality and morbidity rates. Use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to suppress cholesterol and apolipoprotein B production has been successful in treating the hyperlipidemia of CESD, but the long-term effects for the prevention and/or treatment of liver fibrosis/cirrhosis are unknown.

   
   

Purchase Chapter PDF

Access All of OMMBID

Already a user? Sign in here

Username:

Password:

Forgot your Username/Password?