Lysosomal acid lipase deficiency in all siblings of the same parents

Highlights

• Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed lipid disorder.

• Consider LAL-D in a patient with idiopathic significant hypercholesterolemia and liver enzyme elevation.

• Tuberous xanthomas and periorbital dark circles are a clinical sign in some patients with LAL-D.

• Sebelipase alfa is the enzyme-replacement therapy for LAL-D.

Abstract

We present 4 normal-weight sibling children with lysosomal acid lipase deficiency (LAL-D). LAL-D was considered in the differential diagnosis based on the absence of secondary causes and primary inherited traits for their marked hyperlipidemia, together with unexplained hepatic transaminase elevation. Residual lysosomal acid lipase activity confirmed the diagnosis. DNA sequencing of LIPA indicated that the siblings were compound heterozygotes (c.894G>A and c.428+1G>A). This case describes the unusual occurrence of all offspring from the same nonconsanguineous mother and father inheriting compound heterozygosity of a recessive trait and the identification of an apparently unique LIPA mutation (c.428+1G>A). It highlights the collaborative effort between a lipidologist and gastroenterologist in developing a differential diagnosis leading to the confirmatory diagnosis of this rare, life-threatening disease. With the availability of an effective enzyme replacement therapy (sebelipase alfa), LAL-D should be entertained in the differential diagnosis of children, adolescents, and young adults with idiopathic hyperlipidemia and unexplained hepatic transaminase elevation.

Introduction

Lysosomal acid lipase deficiency (LAL-D; Online Mendelian Inheritance in Man, Trademark John Hopkins University [OMIM]: 278000) is a rare autosomal recessive lipid disorder characterized by progressive accumulation of cholesteryl ester (CE) and to a lesser extent triglyceride (TG), in liver, spleen, intestine, adrenal glands, and macrophages throughout the body including those in the subendothelial spaces of arteries.1, 2 The involvement of these organs and cells appears to correlate with their participation in the receptor-mediated endocytosis and lysosomal degradation of lipoproteins.2, 3 Classically, LAL-D is divided into 2 phenotypes: the fulminant, infantile-onset, Wolman disease, and the less severe, later-onset, CE storage disease.1, 2 The variable rates of onset and severity are presumed to be the result of the different disease-causing mutations in the lysosomal acid lipase (LAL) gene (LIPA; OMIM: 613497) resulting in different degrees of impaired enzyme activity.4, 5 LIPA contains 10 exons and is localized to chromosome 10q23.2-23.3.⁶ More than 40 LIPA mutations have been identified.1, 2, 7

The infantile-onset phenotype of LAL-D is thought to occur as a result of the absence of LAL activity and affected infants generally present within 1 month of age with significant hepatomegaly, vomiting, diarrhea, inanition, failure to thrive, and calcification of the adrenal glands.8, 9 The total cholesterol and TG plasma levels are usually normal.¹ Death occurs within the first 6 to 12 months of life as a result of malabsorption, cachexia, growth retardation, and severe liver disease.1, 8, 10

Later-onset LAL-D usually presents in early childhood to adolescence with LAL activity ranging from <0.1% to 12% of normal.1, 11, 12 The progressive hepatic accumulation of CE leads to the characteristic liver (ie, mixed steatosis and fibrosis) and spleen pathology, and serum transaminase elevation. Significant lysosomal TG accumulation is not characteristic of later-onset LAL-D because the catalytic activity of LAL has a significant preference for TGs, diglycerides, and monoglycerides compared with CE.¹³ This substrate preference and the presence of residual amounts of normal LAL in the cells of most patients with later-onset LAL-D is a biologically plausible explanation for why TG and CE accumulate in the lysosomes of patients with infantile-onset LAL-D and only CE in those with the later-onset phenotype.¹

Residual LAL activity in the later-onset phenotype mitigates the release of free cholesterol (FC) from lysosomes causing a drop in its cytoplasmic concentration. This stimulates the transcriptional activity of nuclear sterol regulatory element-binding proteins leading to increased synthesis of cholesterol and fatty acids14, 15 and enhanced secretion of apolipoprotein B-100–containing lipoproteins from the liver.¹⁶ The low FC cytoplasmic concentration also reduces the transcriptional activity of nuclear liver X receptors, thereby decreasing the expression of hepatic cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) and the efflux of nascent high-density lipoproteins (HDL) into the blood.¹⁷ These derangements in cellular cholesterol homeostasis caused by LAL-D lead to the characteristic dyslipidemia of elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and low levels of HDL cholesterol (HDL-C).18, 19 The morbidity and premature death associated with later-onset LAL-D are caused by either accelerated atherosclerotic cardiovascular disease (ASCVD) secondary to the dyslipidemia or liver failure.2, 20, 21