Cholesteryl Ester Storage Disease

Disease Overview

Summary
Cholesteryl ester storage disease (CESD) is a type of lysosomal acid lipase (LAL) deficiency; a rare genetic disorder characterized by a deficiency of the lysosomal acid lipase (LIPA or LAL) enzyme. This enzyme is essential for hydrolysis of triglycerides and cholesteryl esters in lysosomes. Deficiency of the LIPA enzyme causes accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body, potentially causing a variety of symptoms. In the liver, the consequences are abnormally enlarged liver (hepatomegaly) due to hepatic steatosis (fatty liver) and fibrosis that can lead to micronodular cirrhosis. Some individuals may not be diagnosed with CESD until adulthood. CESD is caused by changes (pathogenic variants or mutations) in the lysosomal acid lipase (LIPA) gene and is inherited in an autosomal recessive pattern.

Introduction
CESD and Wolman disease are the two types of lysosomal acid lipase deficiency. LIPA gene variants that cause CESD result in some enzyme activity, whereas LIPA gene variants that cause Wolman disease produce an enzyme with no residual activity or no enzyme at all. Genetic and biochemical evidence indicates that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity.

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Synonyms

• acid cholesteryl ester hydrolase deficiency, type 2
• CESD
• cholesterol ester hydrolase deficiency
• LAL deficiency, CESD type

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Signs & Symptoms

The symptoms and severity of CESD are highly variable. Some individuals may develop symptoms during childhood; others may have extremely mild cases that cause few symptoms. Still other individuals may not have any noticeable symptoms (asymptomatic) and may go undiagnosed until well into adulthood. It is important to note that affected individuals will not have all of the symptoms discussed below. The disorder often goes misdiagnosed or undiagnosed, making it difficult to determine its true frequency in the general population.

CESD is characterized by alterations of blood lipoprotein profile; patients present hypercholesterolemia, hypertriglyceridemia, HDL deficiency with abnormal lipid deposition in many organs. The primary finding in many patients, and sometimes the only clinical sign, is thus a mixed hyperlipidemia with low HDL-cholesterol levels. Patients normally present with hepatomegaly, often apparent at birth or during early childhood. In rare cases, it may not become apparent until the second decade of life. Hepatomegaly usually becomes progressively worse, eventually causing scarring (fibrosis) of the liver. In approximately one-third of patients, the spleen may also be enlarged (splenomegaly).

In most patients, CESD is considered a benign condition, but in some patients, significant complications may eventually develop including fatty liver (liver steatosis), fibrosis and finally micronodular cirrhosis with liver failure and esophageal varices due to altered hepatic venous circulation. The vessels swell and sometimes may rupture, causing potentially life-threatening bleeding. Abnormal enlargement of the adrenal glands (adrenomegaly) may also occur in few individuals. The adrenal glands are located on top of the kidneys and produce two hormones called epinephrine and norepinephrine. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. In rare cases, hardening of adrenal gland tissue due to the accumulation of calcium (calcification) may occur, but this finding is much more common in Wolman disease than in CESD.

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Causes

CESD is caused by pathogenic variants in the lysosomal acid lipase (LIPA) gene. The LIPA gene contains instructions for producing the enzyme lysosomal lipase acid. This enzyme is essential for breaking down (metabolizing) certain fats in the body, especially cholesteryl esters (a form of cholesterol) and to a lesser degree triglycerides. Without proper levels of this enzyme, these fats abnormally accumulate in and damage various tissues and organs of the body. Variants in the LIPA gene result deficient levels of active, functional LIPA enzyme. There is no direct linear relation between residual LAL activity and the severity of the disease.

CESD is inherited as an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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Affected populations

CESD affects males and females in equal numbers. Approximately 50 cases have been reported in the medical literature. It is likely that there are more patients with CESD who have been misdiagnosed with other conditions.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of cholesteryl ester storage disease. Comparisons may be useful for a differential diagnosis.

Wolman disease is a rare genetic disorder characterized by complete absence of the lysosomal acid lipase enzyme. It is often fatal within the first six months of life. Without the LIPA enzyme, certain lipids may abnormally accumulate in the tissues and organs of the body causing a variety of symptoms. Wolman disease causes adrenal calcifications and may lead to bloating or swelling of the stomach (abdominal distention), vomiting and significant enlargement of the liver or spleen (hepatosplenomegaly). Life-threatening complications often develop during early childhood. Wolman disease is caused by different variants in the LIPA gene that causes CESD. Wolman disease is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Wolman disease” as your search term in the Rare Disease Database.)

Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found mostly in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen and brain. Symptoms of type C occur because of impaired trafficking of large molecules within cells, which results in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) in tissues throughout the body. The metabolic defect in type C can lead to a secondary reduction in ASM activity in some cells. Symptoms common to all types of NPD include yellow discoloration of the skin, eyes and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities and hepatosplenomegaly. The different types of NPD are inherited in an autosomal recessive pattern. For more information on this disorder, choose “Niemann Pick” as your search term in the Rare Disease Database.

Chanarin Dorfman syndrome is a rare genetic disorder of fat (lipid) metabolism. It is characterized by scaly skin (ichthyosis), degeneration of the muscles (myopathy) and abnormal white blood cells with small spaces (vacuoles) filled with fat (lipids). Additional symptoms may occur including hearing loss, vision abnormalities, hepatomegaly and liver steatosis. Cognitive decline may occur in some affected individuals. Chanarin Dorfman syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Chanarin Dorfman” as your search term in the Rare Disease Database.)

There are several types of metabolic disorders in which secondary accumulation of certain fats (triglycerides) occur in the body. These disorders include galactosemia, fructose intolerance and specific disorders amino acid metabolism. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

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Diagnosis

A diagnosis of CESD may be suspected based upon identification of characteristic symptoms such as abnormally enlarged liver. A diagnosis may be confirmed by a thorough clinical evaluation, a detail patient history (including family history) and specialized tests that reveal deficient activity of the LIPA enzyme in certain cells and tissues of the body. Testing for CESD is easy to perform and reliable through the measurement of enzyme activity in circulating leukocytes using dry blood spot (DBS) technology. In these cells, LAL activity is more severely depressed than in the body. Molecular genetic testing for variants in the LIPA gene is also available. This is usually a two-step procedure where testing for the highly prevalent E8SJM variant is done first and, if needed, sequencing of the LIPA gene is the second step.

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Standard Therapies

Treatment
In 2015, the U.S. Food and Drug Administration (FDA) approved Kanuma (sebelipase alfa) as the first treatment for lysosomal acid lipase (LAL) deficiency.

A hypolipidemic diet and statins are other therapeutic tools used against CESD. Among hypolipidemic agents, also fibrates, cholestyramine, ezetimibe can be used. Other treatment of CESD is directed toward the specific symptoms that are apparent in each individual. Some individuals have been treated with a hypolipidic diet and statins that reduce plasma cholesterol levels. The combination of diet and drug administration has led to dramatic reductions in the levels of lipids such as cholesterol and triglycerides in the blood of affected individuals.

A few individuals with CESD who developed chronic liver disease have been treated with a liver transplant with positive results. Specific therapeutic procedures such as a liver transplant depend upon numerous factors, such as disease severity, an individual’s age and general health, and other factors. Decisions concerning specific treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

Researchers are studying enzyme replacement therapy for lysosomal storage diseases such as CESD. Enzyme replacement therapy involves replacing a missing enzyme in individuals who are deficient or lack the enzyme in question. Synthetic versions of missing enzymes have been developed and used to treat individuals with certain lysosomal diseases including Hurler syndrome, Fabry disease and Gaucher disease.

Gene therapy is also being studied as another possible approach to therapy for some lysosomal storage disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent the development and progression of the disease. Given the permanent transfer of the normal gene, which can produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure”. However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.

All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill Companies; 2001:3551-3572.

Assmann G. and Seedorf U. Acid lipase deficiency: Wolman disease and cholesterol ester storage disease. In: Sciver, C. R. Beuadet L. A. Sly W. S. Valle D. The Metabolic & Molecular Bases of Inherited Disease (8th edition): New York, NY: McGraw Hill; 2001:3551-3572.

JOURNAL ARTICLES
Carter A, Brackley SM, Gao J, Mann JP. The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD.
Journal of Hepatology 2019; vol. 70 j 142–150.

Fang Li, Zhang H. Lysosomal acid lipase in lipid metabolism and beyond. Arterioscler Thromb. Arterioscler Thromb Vasc Biol. 2019; 39:850- 856. DOI: 10.1161/ATVBAHA.119.312136.

Muntoni S, Wiebusch H, Jansen-Rust M, et al. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol. 2007;27(8):1866-8.

Bindu PS, Taly AB, Christopher R, et al. Cholesterol ester storage disease with unusual neurological manifestations in two siblings: a report from south India. J Child Neurol. 2007:22:1401-1404.

Drebber U, Andersen M, Kasper HU, et al. Severe chronic diarrhea and weight loss in cholesterol ester storage disease: a case report. World J Gastroenterol. 2005;11:2364-2366.

Boldrini R, Devito R, Biselli R, Filocamo M, Bosman C. Wolman disease and cholesteryl ester storage disease diagnosed by histological and ultrastructural examination of intestinal and liver biopsy. Pathol Res Pract. 2004;200:231-240.

Pagani F, Pariyarath R, Garcia R, et al. New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease. J Lipid Res. 1998;39:1382-1388.

Aslanidis C, Ries S, Fehringer P, et al. Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. Genomics. 1996;33:85-93.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lysosomal Acid Lipase Deficiency. Entry No: 278000. Last Update 08/24/2021. Available at: https://omim.org/entry/278000 Accessed Feb 27, 2023.

MedlinePlus. Lysosomal acid lipase deficiency. Reviewed: February 2017. https://medlineplus.gov/genetics/condition/lysosomal-acid-lipase-deficiency/. Accessed Feb 27, 2023.

Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal Acid Lipase Deficiency. 2015 Jul 30 [Updated 2016 Sep 1]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK305870/ Accessed Feb 27, 2023.

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