Cholesteryl Ester Storage Disease

National Organization for Rare Disorders, Inc.

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It is possible that the main title of the report Cholesteryl Ester Storage Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


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

Disorder Subdivisions

  • None

General Discussion

Cholesteryl ester storage disease (CESD) is a rare genetic disorder characterized by subtotal defect of an enzyme known as lysosomal acid lipase (LIPA or LAL). This enzyme is essential for hydrolysis of triglycerides and cholesteryl esters in lysosomes. CESD is caused by mutations in the lysosomal acid lipase (LIPA) gene. The disorder is inherited as an autosomal recessive trait. Deficiency of the LIPA enzyme causes lipids storage in tissues and organs of the body potentially causing a variety of symptoms. In the liver the consequences are hepatomegaly due to hepatic steatosis and fibrosis that can lead to micronodular cirrhosis. Some individuals may not be diagnosed with CESD until adulthood.

While mutations causing Wolman disease produce an enzyme with no residual activity or no enzyme at all, CESD-causing mutations encode for LAL which retains some enzyme activity Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. CESD belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Defective lysosomal enzymes associated with CESD leads to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.


The symptoms and severity of cholesteryl ester storage disease (CESD) are highly variable from one individual to another. 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 cases, and sometimes the only clinical sign, is thus a mixed hyperlipidemia with low HDL-cholesterol levels; patients normally present an abnormally enlarged liver (hepatomegaly) due to hepatic steatosis. Hepatomegaly is 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 cases, the spleen may also be enlarged (splenomegaly).

In most cases, CESD is considered a benign condition, but in some cases 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 cases. 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.


Cholesteryl ester storage disease is caused by mutation of the lysosomal acid lipase (LIPA or LAL) gene. It is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

Investigators have determined that the LIPA gene is located on the long arm (q) of chromosome 10 (10q24-q25). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 10q24-q25" refers to bands 24-25 on the long arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

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. Mutations of the LIPA gene result deficient levels of active, functional LIPA enzyme. There is no direct linear relation between residual LAL activity in situ and the severity of the disease.

Affected Populations

Cholesteryl ester storage disease affects males and females in equal numbers. Approximately 50 cases have been reported in the medical literature. The majority of patients with CESD described to date present an exon 8 splice junction mutation [E8SJM], G to A transition at position 1 (E8SJM) as one of the defective alleles in LAL gene. Regarding the frequency of CESD, in a study population genetic screening in Germany, Muntoni found in more than 2,000 individuals an unexpected E8SJM allele frequency is of 0.0025, which means that about one in every 200 persons is an E8SJM carrier. In this paper, the prevalence of CESD homozygotes or compound heterozygotes among newborns has been estimated as 25 in one million, or a total of 366 cases among German youths until age 18. This data is in disagreement with the small number of CESD cases reported in the literature, probably due to CESD misdiagnoses.

Standard Therapies


A diagnosis of cholesteryl ester storage disease 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 enzyme lysosomal lipase acid (LIPA) in certain cells and tissues of the body. Test for CESD are easy to perform and reliable through the measurement of enzyme activity in circulating leukocytes. In these cells LAL activity is more severely depressed than in situ. Also, the structural integrity of the gene itself can be analyzed in a two-step genetic procedure, where allele-specific testing for the highly prevalent E8SJM is the first and, if needed, sequencing of the PCR-amplified gene is the second step.


A hypolipidemic diet and statins are the main therapeutic tools used against CESD. Among hypolipidemic agents, also fibrates, cholestyramine, ezetimibe can be used. The 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.

Few individuals with CESD who developed chronic liver disease were 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/or 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 his or her 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 may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Researchers are studying enzyme replacement therapy for lysosomal storage diseases such as cholesteryl ester storage disease. Enzyme replacement therapy involves replacing a missing enzyme in individuals who are deficient or lack the particular enzyme in question. Synthetic versions of missing enzymes have been developed and used to treat individuals with certain lysosomal diseases including Hurler syndrome, Fabry syndrome 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 in question. Given the permanent transfer of the normal gene, which is able to 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.

In 2010, Synageva BioPharma Corporation received orphan drug designation from the FDA for its program, SBC-102, which is an enzyme replacement therapy to treat cholesteryl ester storage disease. For more information, go to

Information on current clinical trials is posted on the Internet at 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


For information about clinical trials sponsored by private sources, contact:



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For a Complete Report

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