Cholesterol Storage Disease - Symptoms, Causes, Treatment | NORTH (2023)

Overview of diseases

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

Introduction
CESD and Wolman's disease are the two types of lysosomal acid lipase deficiency.VETgene variants causing CESD result in some enzyme activity, whileVETgene 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 differentiated by residual lysosomal acid lipase activity.

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Synonyms

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

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Signs and Symptoms

The symptoms and severity of CESD vary widely. Some people may develop symptoms during childhood. others may have extremely mild cases that cause few symptoms. Other people may have no obvious symptoms (asymptomatic) and may not be diagnosed until adulthood. It is important to note that affected individuals will not have all of the symptoms listed below. The condition is often misdiagnosed or misdiagnosed, making it difficult to determine its true prevalence in the general population.

CESD is characterized by changes in the blood lipoprotein profile. patients present with hypercholesterolemia, hypertriglyceridemia, HDL deficiency with abnormal fat deposition in multiple organs. The primary finding in many patients, and sometimes the only clinical sign, is therefore mixed hyperlipidemia with low HDL cholesterol levels. Patients usually present with hepatomegaly, often apparent at birth or during early childhood. In rare cases, it does not become apparent until the second decade of life. Hepatomegaly usually gets worse and eventually causes scarring (fibrosis) of the liver. In about a third of patients, the spleen may also be enlarged (splenomegaly).

In most patients, CESD is considered to be a benign condition, but significant complications may eventually develop in some patients, such as fatty liver disease (hepatic steatosis), fibrosis, and finally micronodular cirrhosis with liver failure and esophageal varices due to impaired hepatic venous circulation. The vessels swell and can sometimes rupture, causing potentially life-threatening bleeding. Abnormal enlargement of the adrenal glands (adrenomegaly) can also occur in a few people. 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 regulate fluid and electrolyte balance in the body. In rare cases, hardening of the adrenal tissue due to calcium buildup (calcification) can occur, but this finding is much more common in Wolman disease than in CESD.

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Reasons

CESD is caused by pathogenic variants in lysosomal acid lipase (VET) gen. TheVETgene contains instructions for producing the enzyme lysosomal acid lipase. This enzyme is needed to break down (metabolize) certain fats in the body, especially cholesterol esters (a form of cholesterol) and to a lesser extent triglycerides. Without proper levels of this enzyme, these fats build up abnormally and damage various body tissues and organs. Variations opVETgene results in deficient levels of active, functional LIPA enzyme. There is no direct linear relationship between residual LAL activity and disease severity.

CESD is inherited as an autosomal recessive disorder. Recessive genetic disorders occur when a person inherits two copies of an abnormal gene for the same trait, one from each parent. If a person inherits one normal gene and one gene for the disease, the person is a carrier of the disease, but usually shows no symptoms. The risk of two carrier parents both passing on the altered gene and having an affected child is 25% in any pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance that a child will inherit normal genes from both parents is 25%. The risk is the same for men and women.

Parents who are closely related (consanguineous) are more likely than non-consanguineous parents to both carry the same abnormal gene, which increases the risk of having children with a residual genetic disorder.

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Populations affected

CESD affects men and women equally. About 50 cases have been reported in the medical literature. It is likely that there are more patients with CESD who are misdiagnosed with other conditions.

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Conditions with similar symptoms

Symptoms of the following conditions may be similar to those of cholesterol storage disease. Comparisons can be useful for differential diagnosis.

Wolman disease is a rare genetic disorder characterized by a complete absence of the enzyme lysosomal acid lipase. It is often fatal within the first six months of life. Without the LIPA enzyme, certain lipids can build up abnormally in the tissues and organs of the body and cause a variety of symptoms. Wolman's disease causes calcifications of the adrenal glands and can lead to bloating or swelling of the stomach (abdominal distension), vomiting, and significant enlargement of the liver or spleen (hepatosplenomegaly). Life-threatening complications often arise during early childhood. Wolman's disease is caused by several variants in theVETgene causing CESD. Wolman disease is inherited in an autosomal recessive pattern. (For more information on this condition, select "Wolman disease" as a search term in the Rare Disease Database.)

Niemann-Pick disease (NPD) is a group of rare hereditary disorders of fat metabolism. At least five types of Niemann-Pick disease (NPD types A, B, C, D, and E) have been recognized. Type A and B symptoms occur due to a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found primarily in the brain and nervous system. This deficiency results in the abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body, such as the liver, spleen, and brain. Type C symptoms occur due to impaired movement of large molecules within cells, resulting in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) in tissues throughout the body. The metabolic defect in type C may lead to a secondary decrease in ASM activity in some cells. Symptoms common to all types of NPD include yellowing 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 condition, select "Niemann Pick" as a search term in the Rare Disease Database.

Chanarin Dorfman syndrome is a rare genetic disorder of lipid metabolism (lipids). It is characterized by flaky skin (ichthyosis), muscle degeneration (myopathy), and abnormal white blood cells with small spaces (vacuum) filled with fat (lipids). Additional symptoms such as hearing loss, visual abnormalities, hepatomegaly and hepatic steatosis may occur. Cognitive decline may occur in some affected individuals. Chanarin Dorfman syndrome is inherited in an autosomal recessive pattern. (For more information on this condition, select "Chanarin Dorfman" as your search term in the Rare Disease Database.)

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

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Diagnose

The diagnosis of CESD may be suspected based on the identification of hallmark symptoms such as abnormal enlargement of the liver. The diagnosis can be confirmed by a thorough clinical evaluation, a detailed patient history (including family history), and specialized tests that reveal insufficient activity of the LIPA enzyme in certain cells and tissues of the body. Screening for CESD is simple and reliable by measuring enzyme activity in circulating leukocytes using dry blood spot (DBS) technology. In these cells, LAL activity is more severe than in the body. Molecular genetic screening for variants inVETgene is also available. This is usually a two-step process of first testing for the common E8SJM variant and sequencing if necessary.VETgene is the second step.

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Standard treatments

Therapy
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. Of the lipid-lowering agents, fibrates, cholestyramine and ezetimibe can also be used. Other CESD treatments focus on the specific symptoms evident in each individual. Some people have been treated with a lipid-lowering diet and statins that lower plasma cholesterol levels. The combination of diet and drug administration has resulted in dramatic reductions in the levels of lipids such as cholesterol and triglycerides in the blood of affected individuals.

Some people with CESD who develop chronic liver disease have been treated with a liver transplant with positive results. Specific treatment procedures such as liver transplant depend on many factors such as the severity of the disease, the person's age and general health, and other factors. Decisions about specific treatments should be made by physicians and other members of the healthcare team in careful consultation with the patient based on the specifics of their case. thorough discussion of potential benefits and risks, including potential side effects and long-term effects; patient preference; and other relevant factors.

Genetic counseling is recommended for affected individuals and their families. Other treatments are 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 people who are deficient or deficient in that enzyme. Synthetic versions of missing enzymes have been developed and used to treat people with certain lysosomal diseases, such as Hurler's syndrome, Fabry's disease, and Gaucher's disease.

Gene therapy is also being studied as another possible treatment approach for some lysosomal storage diseases. In gene therapy, the defective gene in a patient is replaced with a normal gene to enable the production of an active enzyme and prevent the development and progression of the disease. Given the permanent transfer of the normal gene, which can produce an active enzyme at all disease sites, this form of treatment theoretically has a better chance of 'curing'. At present, however, there are many technical issues that must be overcome before gene therapy can succeed.

Information on current clinical trials is published online atwww.clinicaltrials.gov.

All studies that receive funding from the US government, and some are supported by the private sector, are published on this government website.

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

Toll Free: (800) 411-1222
TTY: (866) 411-1010
E-MAIL:[emailprotected]

Some ongoing clinical trials are also published 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 on privately funded clinical trials, please contact:
www.centerwatch.com

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

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bibliographic references

School books
Scriver CR, Beaudet AL, Sly WS, et al. Eds. The metabolic molecular basis of hereditary 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 Basis of Inherited Disease (8th ed): New York, NY: McGraw Hill; 2001:3551-3572.

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

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

Muntoni S, Wiebusch H, Jansen-Rust M, et al. Prevalence of cholesterol storage disease. Arterioscleral 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 Kind 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 cholesterol storage disease diagnosed by histological and ultrastructural examination of intestinal and liver biopsy. Pathol Res practice. 2004? 200:231-240.

Pagani F, Pariyarath R, Garcia R, et al. Novel mutated lysosomal acid lipase genes explain Wolman disease and cholesterol storage disease phenotype. J Lipid Res. 1998, 39:1382-1388.

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

INTERNET
Online Mendelian Inheritance in Humans (OMIM). Johns Hopkins University. Lysosomal acid lipase deficiency. Participation number: 278000. Last update 24/08/2021. Available in:http://omim.org/entry/278000Accessed February 27, 2023.

Medline Plus. Lysosomal acid lipase deficiency. Review: February 2017.https://medlineplus.gov/genetics/condition/lysosomal-acid-lipase-deficiency/. Accessed February 27, 2023.

Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal acid lipase deficiency. July 30, 2015 [updated September 1, 2016]. 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 February 27, 2023.

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