Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene

doi:10.1016/j.ymgme.2009.02.007

Molecular Genetics and Metabolism

Volume 97, Issue 2, June 2009, Pages 143-148

https://doi.org/10.1016/j.ymgme.2009.02.007 Get rights and content

Abstract

Cholesteryl Ester Storage Disease (CESD) is a rare recessive disorder due to mutations in LIPA gene encoding the lysosomal acidic lipase (LAL). CESD patients have liver disease associated with mixed hyperlipidemia and low plasma levels of high-density lipoproteins (HDL). The aim of this study was the molecular characterization of three patients with CESD. LAL activity was measured in blood leukocytes.

In two patients (twin sisters) the clinical diagnosis of CESD was made at 9 years of age, following the fortuitous discovery of elevated serum liver enzymes in apparently healthy children. They had mixed hyperlipidemia, hepatosplenomegaly, reduced LAL activity (∼5% of control) and heteroalleic mutations in LIPA gene coding sequence: (i) the common c.894 G>A mutation and (ii) a novel nonsense mutation c.652 C>T (p.R218X). The other patient was an 80 year-old female who for several years had been treated with simvastatin because of severe hyperlipidemia associated with low plasma HDL. In this patient the sequence of major candidate genes for monogenic hypercholesterolemia and hypoalphalipoproteinemia was negative. She was found to be a compound heterozygote for two LIPA gene mutations resulting in 5% LAL activity: (i) c.894 G>A and (ii) a novel complex insertion/deletion leading to a premature termination codon at position 82.

These findings suggest that, in view of the variable severity of its phenotypic expression, CESD may sometimes be difficult to diagnose, but it should be considered in patients with severe type IIb hyperlipidemia associated with low HDL, mildly elevated serum liver enzymes and hepatomegaly.

Introduction

Lysosomal acid lipase (LAL)¹ (GenBank a.n. CAA83495) is a lysosomal enzyme which hydrolyzes cholesteryl esters (CE) and triglycerides (TG) internalized via receptor-mediated endocytosis of plasma lipoprotein particles [1], [2], [3], [4], [5], [6]. The LAL-mediated release of free cholesterol (FC) within the cell causes down-regulation of HMG-CoA reductase (HMGR) and LDL receptor (LDLR) genes and up-regulation of cholesterol esterification by the activation of ACAT enzyme [1], [5].

In humans LAL is encoded by the LIPA gene (GenBank a.n. NG008194) located on chromosome 10 (10q23.2-q23.3) [7], [8]. Homozygous and compound heterozygous mutations of this gene resulting in complete LAL deficiency are the cause of Wolman’s disease (OMIM +278000), a rare recessive disorder [9], characterized by massive storage of CE and TG in most tissues, failure to thrive and death, usually before one year of age [5], [10]. Subjects carrying mutations in the LIPA gene which result in residual LAL activity (i.e. 2–8% of controls in blood leukocytes) develop the less severe disorder known as Cholesteryl Ester Storage Disease (CESD) [5], [11], [12], [13]. CESD may be diagnosed in childhood or late in life, as its phenotypic expression shows a broad spectrum of severity of clinical manifestations [5], [12], [13]. The frequency of CESD in the population is presently unknown. A population survey of the heterozygous carriers of the most frequent LIPA gene mutation (c.894 G>A in exon 8) found in CESD patients suggests that the prevalence of CESD may be around 2.5/100,000 [14].

In the present work we report the molecular characterization of three patients with CESD, who were found to be compound heterozygous, carrying the common LIPA gene mutation (c.894 G>A, del p.S275_Q298), in combination with two novel mutations resulting in null alleles.

Section snippets

Family 1

The probands (subjects III.2 and III.3) (Fig. 1) were biovular twin sisters, in whom the clinical diagnosis of CESD was made at 9 years of age, when one of them was admitted to a paediatric hospital for mononucleosis infection. The first clue to the diagnosis was the finding of a persistent elevation of plasma liver enzymes and the presence of an otherwise unexplained hepatomegaly which required liver biopsy. The results of liver biopsy (see below) and of the assay of LAL activity in peripheral

Plasma lipids

Table 1 shows the pre-treatment plasma lipid levels in the two probands (III.2 and III.3) and their relatives. The affected sisters were found to have a marked elevation of TC, TG and ApoB, associated with a moderate reduction of HDL-C and apoA-I.

Liver biopsy

The liver biopsy was performed only in proband III.3 when she was 9 years old. Light-microscopy and immunohistochemistry showed massive vesicular steatosis, portal and septal fibrosis, portal infiltration of macrophages (CD68-positive) and lymphoid

Discussion

In this paper we describe three patients, from two families, affected by CESD. In the twin sisters of Family 1 the clinical diagnosis was made in the first decade of life, following the fortuitous observation of a persistent elevation of serum liver enzymes in apparently healthy children, which prompted the paediatrician to perform liver biopsy, followed by LAL activity assay in peripheral blood leukocytes. In striking contrast, the diagnosis of CESD in the proband of Family 2 was made late in

Acknowledgments

This work was supported by grants from the University of Genova (S.B.) and University of Modena and Reggio Emilia (S.C.).

References (31)

J.L. Goldstein et al.
Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease
J. Biol. Chem.
(1975)
G.N. Sando et al.
Recognition and receptor-mediated endocytosis of the lysosomal acid lipase secreted by cultured human fibroblasts
J. Lipid Res.
(1982)
S. Sheriff et al.
Characterization of lysosomal acid lipase by site-directed mutagenesis and heterologous expression
J. Biol. Chem.
(1995)
R.A. Anderson et al.
Cloning and expression of cDNA encoding human lysosomal acid lipase/cholesteryl ester hydrolase. Similarities to gastric and lingual lipases
J. Biol. Chem.
(1991)
R.A. Anderson et al.
In situ localization of the genetic locus encoding the lysosomal acid lipase/cholesteryl esterase (LIPA) deficient in Wolman disease to chromosome 10q23.2-q23.3
Genomics
(1993)
C. Aslanidis et al.
Genomic organization of the human lysosomal acid lipase gene (LIPA)
Genomics
(1994)
C. Aslanidis et al.
Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity
Genomics
(1996)
P. Lohse et al.
Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease
J. Lipid Res.
(2000)
L. Pisciotta et al.
Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia
Atherosclerosis
(2006)
J.E. Hixson et al.
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI
J. Lipid Res.
(1990)

F. Pagani et al.

New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease

J. Lipid Res.

(1998)

D. Ameis et al.

A 5’ splice-site mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease

J. Lipid Res.

(1995)

H. Du et al.

Molecular and enzymatic analyses of lysosomal acid lipase in cholesteryl ester storage disease

Mol. Genet. Metab.

(1998)

R.A. Anderson et al.

Lysosomal acid lipase mutations that determine phenotype in Wolman and Cholesteryl Ester Storage Disease

Mol. Genet. Metab.

(1999)

L. Pisciotta et al.

A novel mutation of apolipoprotein A-I gene in a family with familial combined hyperlipidemia

Atherosclerosis

(2008)

Cited by (66)

Recent insights into lysosomal acid lipase deficiency
2023, Trends in Molecular Medicine
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.
Lysosomal acid lipase: Roles in rare deficiency diseases, myeloid cell biology, innate immunity, and common neutral lipid diseases
2022, Cholesterol: From Chemistry and Biophysics to the Clinic
Lysosomal acid lipase (LAL) is a unique mammalian lipase that cleaves cholesteryl esters (CEs) and triacylglycerols (TGs) in its single active site. Following LAL hydrolysis of CEs and TGs, free cholesterol (FC) and free fatty acids (FFAs) exit the lysosome into the intra- and extracellular spaces where they or their synthesized metabolites have major effects on neutral lipid metabolism, myeloid cell activation, and PPARγ-mediated inflammation. Inherited inadequate LAL activity causes rare lethal/severe disease with hepatic fibrosis or failure, early atherosclerosis, myeloid dysfunction, and chronic inflammation. These can be reversed by supplying sufficient exogenous recombinant LAL. Other diseases of myeloid dysfunction, inadequate TG hydrolysis (NAFLD/NASH), cryptogenic cirrhosis, cancer progression, and coronary artery disease have also been linked to LAL dysfunction and disease progression. In this chapter, a historical background for LAL is followed by discussion of its structure, properties, and biology as well as its deficiency diseases. The molecular genetics and mutations causal to the genetic etiology and clinical disease phenotypes are delineated. Finally, the developing roles of LALs are examined for selected common acquired diseases.
Lysosomal acid lipase deficiency in pediatric patients: a scoping review
2022, Jornal de Pediatria
Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review.
Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020.
The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases.
Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy.
Lysosomal Storage Disorders
2020, Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Metabolic Disorders
Lysosomal storage disorders are a diverse group of complex-molecule disorders characterized by the accumulation of undegraded or partially substrate(s) within lysosomes, most often due to deficiency of a catabolic enzyme. Clinical manifestations are sundry, affecting nearly every organ system in the body. The understanding of natural history continues to evolve, particularly as disorders are added to newborn screening panels. In the last decade, the advancement of therapeutics for lysosomal storage disorders has been unparalleled in its rapidity and innovation. Current treatments include enzyme replacement therapy, substrate reduction therapy, chaperone therapy, and others. Gene therapy for many disorders will likely be available in the next few years. In this chapter, we review the clinical manifestations, genetic and metabolic basis, diagnosis, and management of lysosomal storage disorders.
The Adrenal Cortex and Its Disorders
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and Print
The adrenal cortex produces dozens of steroids having varying degrees of glucocorticoid, mineralocorticoid, and androgenic activity. Cortisol, the principal glucocorticoid, and aldosterone, the principal mineralocorticoid, are essential for normal physiology. Steroidogenesis entails more than 25 enzymes and cofactors arrayed in complex pathways that differ among the various types of steroidogenic cells; some important pathways are newly described. Evaluation of adrenal function entails steroid measurements in basal, stimulated, and inhibited states. Many technologies are used for steroid measurements, yielding different results; the endocrinologist must be familiar with the assay technologies used and normal values by age and sex. Adrenal insufficiency (Addison disease) may be attributable to autoimmune, infectious, or genetic causes. Glucocorticoid excess (Cushing syndrome) may be caused by adrenocorticotropic hormone (ACTH) of pituitary or tumor origin, or caused by adrenal genetic disorders or tumors. Mineralocorticoid excess (hyperaldosteronism) may be caused by adrenal tumors (Conn syndrome) associated with genetic disorders of potassium channels. Steroid hormones act via nuclear receptors; genetic disorders affecting these may mimic steroidal excess or deficiency states. In all, over 100 genes relevant to steroid hormone production, metabolism, or action may be seen as adrenal disorders. Deficiency states are known for most of these, yielding complex clinical phenotypes attributable to deficient hormonal products and accumulated hormonal precursors. Many apparently unrelated medical conditions and commonly used drugs may increase or decrease steroid metabolism. Steroids are widely used as therapeutic agents; the relative activities of different agents as glucocorticoids, mineralocorticoids, and growth suppressants are discordant. Withdrawal from long-term glucocorticoid treatment may be difficult and require substantial time.
Genetic Causes of Liver Disease: When to Suspect a Genetic Etiology, Initial Lab Testing, and the Basics of Management
2019, Medical Clinics of North America

View all citing articles on Scopus

View full text

Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene

Abstract

Introduction

Section snippets

Family 1

Plasma lipids

Liver biopsy

Discussion

Acknowledgments

J. Biol. Chem.

J. Lipid Res.

J. Biol. Chem.

J. Biol. Chem.

Genomics

Genomics

Genomics

J. Lipid Res.

Atherosclerosis

J. Lipid Res.

J. Lipid Res.

J. Lipid Res.

Mol. Genet. Metab.

Mol. Genet. Metab.

Atherosclerosis