Recent insights into lysosomal acid lipase deficiency.

Mutations in the LIPA gene cause LAL deficiency (LAL-D), a rare autosomal-recessive multiorgan condition with fatal outcome if residual lysosomal acid lipase (LAL) activity is below 1%. Early diagnosis is key in early-onset LAL-D, and the rapid, cost-effective, and minimally invasive dried-blood spot test is today's gold standard for diagnosis. Despite several limitations, enzyme replacement therapy with human recombinant LAL protein is currently the most effective treatment for LAL-D. Gene-therapy-treated autologous transplants in combination with dietary fat reduction and hematopoietic stem cell transplantation may provide the best clinical outcomes for patients by avoiding graft rejection and ensuring immunogenic tolerance of LAL. Although commonly used concentrations inhibit a number of intracellular neutral lipid hydrolases, lalistat1 or -2 can still be used in LAL-D diagnosis as samples are assayed at acidic pH. Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid storage disorders with complete or partial absence of LAL activity. This review discusses the consequences of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation. Early detection of LAL deficiency (LAL-D) is essential for disease management and survival. LAL-D must be considered in patients with dyslipidemia and elevated aminotransferase concentrations of unknown etiology. Enzyme replacement therapy, sometimes in combination with hematopoietic stem cell transplantation (HSCT), is currently the only therapy for LAL-D. New technologies based on mRNA and viral vector gene transfer are recent efforts to provide other effective therapeutic strategies. [ABSTRACT FROM AUTHOR]