NORD gratefully acknowledges Sandro Muntoni, MD, PhD, Department of Biomedical Sciences, Faculty of Medicine, University of Cagliari, and Head of Centre for Metabolic Diseases and Atherosclerosis, The ME.DI.CO. Association, Cagliari, Italy, for assistance in the preparation of this report.
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 mutations in the lysosomal acid lipase (LIPA) gene and is inherited as an autosomal recessive trait.
CESD and Wolman disease are the two types of lysosomal acid lipase deficiency. LIPA gene mutations that cause CESD result in some enzyme activity, whereas LIPA gene mutations 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.
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.
CESD is caused by mutation of 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. Mutations of 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.
CESD 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 the LIPA gene. Regarding the frequency of CESD, in a German study population, Muntoni found in more than 2,000 individuals, an unexpected E8SJM allele frequency of 0.0025, which means that about one in every 200 people 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.
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 situ. Molecular genetic testing for mutations in the LIPA gene is also available. This is usually a two-step procedure where allele-specific testing for the highly prevalent E8SJM mutation is done first and, if needed, sequencing of the PCR-amplified gene is the second step.
In December 2015, the U.S. Food and Drug Administration (FDA) approved Kanuma (sebelipase alfa) as the first treatment for lysosomal acid lipase (LAL) deficiency. Kanuma is produced by Alexion Pharmaceuticals Inc.
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 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 is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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 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 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 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.
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:
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