Wolman Disease

Wolman disease (WD) is an autosomal recessive storage disorder caused by very low (or absent) lysosomal acid lipase (LAL) activity. Deficiency of this enzyme leads to massive intracellular accumulation of cholesteryl esters and triglycerides. WD represents the severe form of LAL deficiency in which patients present in early infancy with steatorrhea, chronic emesis, failure to thrive, and hepatosplenomegaly. Without treatment, affected individuals usually die during the first year of life. A moderate phenotype of LAL deficiency, known as cholesteryl ester storage disease (CESD), correlates with higher residual LAL activity relative to WD. Patients with CESD present later in life with hepatomegaly, hyperlipoproteinemia and premature atherosclerosis. Both WD and CESD are diagnosed by enzymatic assay in fibroblasts and lymphocytes, and confirmed by mutational analysis of the lipase A, lysosomal acid, cholesterol esterase (LIPA) gene. Hematopoietic stem cell transplantation represents the only intervention capable of preventing hepatic failure and death in WD. Management of dyslipidemia and liver failure, on the other hand, constitute the mainstay therapy for CESD patients. Current efforts are directed towards reducing the complications associated with transplantation and towards novel therapeutic approaches such as enzyme replacement, gene transplant, and more effective lipid-lowering agents.