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  • 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 the metabolisms of cholesterol and triglyceride throughout the body. Deficiency of LAL (LALD) leads to a continuum of diseases historically divided into infantile-onset LALD (Wolman disease) and childhood/adult-onset LALD (cholesteryl ester storage disease).

  • Infantile-onset LALD presents in the first month postpartum with a rapidly progressive course leading to death before 1 year of age. Hepatosplenomegaly, steatorrhea, abdominal distention, severe malabsorption and resultant malnutrition, and adrenal enlargement with or without calcification are evident within the first months postpartum.

  • Childhood/adult-onset LALD has a less severe clinical course that is highly variable. The majority of patients present in the pediatric age group with significantly progressive disease. There has been a paucity of patients identified in the third to fourth decades. Isolated hepatomegaly and hypercholesterolemia 2b or mixed dyslipidemia patterns can be the presenting signs. Hepatic fibrosis with progression to bridging fibrosis and frank cirrhosis occurs. Premature atherosclerosis may occur. Malabsorption and adrenal calcifications are infrequent to rare.

  • Infantile-onset LALD and childhood/adult-onset LALD are suspected by the clinical presentation, and the diagnoses are confirmed by finding LALD in cultured skin fibroblasts, lymphocytes, other tissues, or dried blood spot assays. Prenatal diagnosis is feasible using amniocytes or chorionic villus samples for enzyme assay or molecular analyses in genetically characterized families.

  • Infantile-onset and childhood/adult-onset LALD are autosomal recessive diseases, caused by mutations in LIPA that maps to chromosome 10q23.2–q23.3 and encodes LAL. Many mutations of LIPA have been found in infantile-onset LALD patients, and these lead to severe deficiency or absence of LAL activity. In comparison, the many mutations of LIPA in childhood/adult-onset LALD allow the expression of significant residual LAL activity. A splice junction mutant allele, E8SJM-1 (c.894G>A), that is common in the Western World allows the expression of 3–8% of wild-type LAL activity and the apparent attenuation of the extreme manifestations of infantile-onset LALD.

  • Therapies have included hematopoietic stem cell transplantation in infantile-onset LALD, but the outcomes have been highly variable, with very high mortality and morbidity rates. In childhood/adult-onset LALD, 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 childhood/adult-onset LALD, but these have little if any effect on the progressive hepatic disease.

  • Specific enzyme therapy with human recombinant LAL has been approved by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA) and the Japan Ministry of Health, Labour and Welfare (MHLW) for amelioration and treatment of infantile-onset and childhood/adult LALD.


Severe malnutrition, hepatosplenomegaly, calcified adrenal glands, and death of children within the first few months of life were described in a family, and the designation Wolman disease was applied to these.1 Cholesteryl esters and triglycerides accumulated in the liver, spleen, adrenal glands, ...

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