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  • Updated 03.04.2021
  • Released 04.28.1997
  • Expires For CME 03.04.2024

Wolman disease

Introduction

Overview

The etiology of lysosomal acid lipase deficiency, which is known as Wolman disease in its most severe form and historically as cholesteryl storage disease in its milder form is the deficient activity of acid lipase (E.C. 3.1.1.13), a hydrolase that cleaves cholesteryl esters and triglycerides under acid conditions, with an autosomal recessive mode of inheritance. It has been referred to as lysosomal acid lipase, acid lipase, or acid esterase. The abnormal accumulation of cholesteryl esters and triglycerides is the biological basis of lysosomal acid lipase deficiency. Due to apparently complete absence of enzyme activity in the most severe form, Wolman disease, the accumulation in that disorder is more severe and affects a larger variety of tissues, whereas the slight residual enzyme activity in the milder cholesteryl ester storage disease offers some protection. The incidence of both conditions can be diminished by genetic counseling, familial carrier testing, and preimplantation genetic diagnostics. The demonstration of deficient acid lipase activity or molecular diagnosis can serve as the definitive diagnostic tests. Intravenous enzyme replacement therapy has emerged as a therapeutic option with some success.

Key points

• Wolman disease was first described in Iranian-Jewish children. It is the infantile form of autosomal recessive lysosomal acid lipase deficiency.

• Characteristically, Wolman disease presents in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands.

• Without treatment, hepatic failure followed by death occurs within the first year of life.

• Milder lysosomal acid lipase deficiency, historically described as cholesteryl ester storage disease, is characterized by hepatic steatosis and dyslipidemia.

• Enzyme replacement therapy has emerged as a therapeutic option.

Historical note and terminology

In 1956, Abramov and colleagues described an infant with abdominal distension, hepatosplenomegaly, and massive calcification of the adrenal gland who died at 3 months of age (01). In 1961, Wolman and colleagues reported the same clinical findings in 2 siblings of the first patient and also demonstrated that the accumulated lipids consisted mainly of cholesterol esters and triglycerides (74). The name "Wolman disease" was introduced by Crocker and colleagues in 1965 (21). In 1969, Patrick and Lake demonstrated a deficient activity of a lysosomal acid lipase catalyzing the hydrolysis of cholesterol ester and triglycerides in the liver and spleen of patients with Wolman disease (56), and this led to diagnostic assays in cultured fibroblasts (20) and lymphocytes (18). Anderson and Sando cloned human lysosomal acid lipase in 1991 (04). The crystal structure has been described (59).

Defective activity of lysosomal acid lipase is also a feature in cholesteryl ester storage disease (09), a somewhat milder disorder characterized by hepatomegaly and hyperlipoproteinemia that is compatible with survival to the second decade or adulthood. It is now clear that Wolman disease and cholesteryl ester storage disease are allelic and describe a continuum of lysosomal acid lipase deficiency. A variety of mutations in the gene that encode lysosomal acid lipase have been reported for both disorders (02; 54; 53; 47; 07).

In 2015, a phase 3 trial of sebelipase alfa, a recombinant human enzyme replacement therapy, demonstrated that this therapeutic option could result in reduction of several measures of disease severity in children and adults (15). This drug has since been approved for use both in Europe and by the FDA in the United States (55).

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