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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].
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 unusual case of hypercholesterolaemia with liver dysfunction
Published in Journal of Endocrinology, Metabolism and Diabetes of South Africa, 2020
Zareena Angamia, Frederick J Raal
Cholesteryl ester storage disease (CESD) is a rare, autosomal recessive lysosomal storage disorder, resulting from a deficiency in lysosomal acid lipase (LAL) activity. LAL deficiency results in accumulation of cholesteryl esters and triglycerides in multiple body tissues, the clinical manifestations and complications of which can present from as early as the first year of life. Although a rare condition, the likelihood is that many patients go unrecognised or are misdiagnosed. In this report, we present a case of an adult female who initially presented, and was subsequently diagnosed, at the age of four years.