Wolman disease

Seth I Berger MD PhD (

Dr. Berger of Children’s National Health System has no relevant financial relationships to disclose.

)
Kimberly A Chapman MD PhD (

Dr. Chapman of Children’s National Health System has no relevant financial relationships to disclose.

)
AHM M Huq MD PhD, editor. (Dr. Huq of Wayne State University has no relevant financial relationships to disclose.)
Originally released April 28, 1997; last updated February 12, 2018; expires February 12, 2021

This article includes discussion of Wolman disease, Wolman syndrome, cholesteryl ester storage disease, and lysosomal acid lipase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The etiology of Wolman disease and of cholesteryl storage disease 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 both Wolman disease and cholesteryl ester storage disease. Due to apparently complete absence of enzyme activity in Wolman disease, the accumulation in that disorder is more severe and affects a larger variety of tissues, whereas the slight residual enzyme activity in 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 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.

 

• Cholesteryl ester storage disease is a milder disorder 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 (Abramov et al 1956). 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 (Wolman et al 1961). The name "Wolman disease" was introduced by Crocker and colleagues in 1965 (Crocker et al 1965). 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 (Patrick and Lake 1969), and this led to diagnostic assays in cultured fibroblasts (Cortner et al 1976) and lymphocytes (Coates et al 1979). Anderson and Sando cloned human lysosomal acid lipase in 1991 (Anderson and Sando 1991).

Defective activity of lysosomal acid lipase is also a feature in cholesteryl ester storage disease (Beaudet et al 1977), 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. A variety of mutations in the gene that encode lysosomal acid lipase have been reported for both disorders (Anderson et al 1994; Pagani et al 1994; Pagani et al 1996; Maslen et al 1995; Aslanidis et al 1996).

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 (Burton et al 2015). This drug has since been approved for use both in Europe and by the FDA in the United States.

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