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Lysosomal acid lipase deficiency: Wolman disease/cholesteryl ester storage disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Wolman and colleagues [1] reported first one, then two more siblings in the same family, in whom the accumulation of cholesterol and triglycerides was associated with abdominal distension, hepatosplenomegaly, and calcification of the adrenals. Death occurred within the first three months of life. The molecular defect in this disease is the lysosomal acid lipase (EC 3.1.1.13) [2]. This lipase, first demonstrated to be defective in the liver and spleen, is a 46 kDa glycoprotein active on both triglycerides and cholesteryl esters (Figure 94.1). The enzyme is also defective in cholesteryl ester storage disease. The two diseases are allelic, caused by mutations at the LIPA locus on chromosome 10q23.2-q23.3 [3]. In general, the mutations in patients with Wolman disease are major alterations that lead to absence of enzyme activity [4–6]. Most patients with cholesteryl ester storage disease have at least one copy of a single mutant allele, a G934A mutation at the exon 8 splice junction, which leads to exon skipping and the loss of codons 254–277 [7, 8].
Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
HDL2 may be related to estrogens, since its amount in premenopausal women is about three times greater than in men. This lipid:protein ratio is about 1:1, and it contains 32% cholesterol, 10% triglycerides and 51% phospholipids. In the HDL2 component, lecithin constitutes 70 to 80% of the total sphingomyelin (12 to 14%). The predominant fatty acid in cholesteryl esters is linoleic acid. The concentration of HDL lecithin is influenced by risk factors, including coronary heart disease.567
Lipid Metabolism in the Intestinal Tract and Its Modification by Ethanol
Published in Victor R. Preedy, Ronald R. Watson, Alcohol and the Gastrointestinal Tract, 2017
Luminal PCs, most of which are secreted in the bile, are hydrolyzed by pancreatic phospholipase A2 to lysophosphatidylcholine (LPC) and fatty acids.7 Phospholipase A2 has an absolute requirement for Ca2+ ions to function.8 Cholesteryl esters are hydrolyzed to cholesterol by the cholesterol esterase contained in pancreatic juice. Pancreatic cholesterol esterase appears to be the same enzyme as pancreatic nonspecific lipase (carboxylic lipase).9 The enzyme has broad substrate specificity from water-soluble carboxyl esters to insoluble esters dispersed in bile salt micelles.10
Recommendations for overcoming challenges in the diagnosis of lysosomal acid lipase deficiency
Published in Expert Opinion on Orphan Drugs, 2022
Pilar Giraldo, Laura López de Frutos, Jorge J Cebolla
Lysosomal acid lipase deficiency (LALD; MIM#278000) is also known as acid cholesterol ester hydrolase deficiency. It is an ultrarare lysosomal storage disease (LSD) with a wide range of phenotypic variability and age of onset. Classically, the onset of the severe phenotype called Wolman disease (WD) is in the first days of life, and it can cause death in the first 12 months of life if it is not treated. On the other hand, the mild phenotype, also called cholesteryl ester storage disease (CESD), can arise from infancy to the fifth and sixth decade of life, with cardiovascular disease in the absence of liver failure being the main cause of death [1]. The estimated incidence of WD is 1 in 500,000 live births, and this is possibly higher for CESD, which tends to go more unnoticed. Using the prevalence of the most frequent genetic variant in CESD (NM_000235.3:c.894 G >A), the prevalence of CESD in the Caucasian and Hispanic populations has been estimated to be about ~0.8 per 100,000 (~1 in 130,000; 95% CI: ~1 in 90,000 to 1 in 170,000) [2].
Safety of sebelipase alfa for the treatment of lysosomal acid lipase deficiency
Published in Expert Opinion on Drug Safety, 2022
Lysosomal acid lipase (LAL) deficiency (LAL-D) (OMIM 278000) is an autosomal recessive lysosomal storage disease that is caused by mutations in the LIPA gene [1–3]. The extent of tissue deposition of cholesteryl esters and triglycerides appears to be directly proportional to the severity of the disease and inversely proportional to the age of presentation. There is a clinical spectrum from a severe form in early childhood to a mild form in adulthood. In infants with no or very minimal LAL activity (Wolman’s disease, infantile onset LALD), progression is very rapid, with early death generally by six months of age. The estimated incidence is 1 in 500,000 live births. It is characterized by massive hepatosplenomegaly, malabsorption, growth retardation, liver failure, and adrenal calcification [2,4]. In older patients with some residual LAL activity (cholesteryl ester storage disease, childhood/adult onset LALD), progression of the disease leads to hepatomegaly, splenomegaly, abdominal distension, dyslipidaemia, abnormal liver function tests, and gastrointestinal disturbances. The disorder can lead to jaundice, multiorgan failure, and death in childhood or later in life. The estimated incidence is about 1 in 40,000 [1,2].
An update on emerging drugs for the treatment of hypercholesterolemia
Published in Expert Opinion on Emerging Drugs, 2021
Adam J Nelson, Kristen Bubb, Stephen J Nicholls
Cholesteryl ester transfer protein (CETP) plays an important role in the regulation of lipid metabolism, promoting transfer of esterified cholesterol from HDL to VLDL and LDL particles, in exchange for triglycerides [62]. CETP inhibitors were originally developed on the basis of their ability to raise HDL cholesterol levels [62] and atheroprotective properties of CETP inhibition in rabbit models [63–66]. However, the clinical development of small molecule CETP inhibitors has proven challenging. The first agent, torcetrapib, was demonstrated to produce an increase cardiovascular events and all-cause mortality [67]. Subsequent analyses revealed that torcetrapib possessed a number of off-target toxicities, including elevation of blood pressure, adrenal synthesis of cortisol and aldosterone and aortic wall expression of endothelin [67–69]. The ability to demonstrate a lack of such effects would permit other CETP inhibitors to proceed in development. However, outcomes trials of the modest CETP inhibitor, dalcetrapib, and the potent CETP inhibitor, evacetrapib, demonstrated clinical futility with no impact on cardiovascular events [70,71]. Anacetrapib, an additional potent CETP inhibitor, was demonstrated to produce a significant reduction in cardiovascular events, with the degree of benefit directly proportional to the extent of lowering levels of atherogenic lipoproteins [72]. Clinical development of this agent was halted due to the finding of adipose tissue accumulation.