Hyperlipoproteinemia Type III

Hyperlipoproteinemia Type III

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Hyperlipoproteinemia Type III 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.

Synonyms

  • Dysbetalipoproteinemia
  • Familial Dysbetalipoproteinemia
  • Broad Beta Disease
  • Remnant Removal Disease

Disorder Subdivisions

  • None

General Discussion

Hyperlipoproteinemia type III, also known as dysbetalipoproteinemia or broad beta disease, is a rare genetic disorder characterized by improper breakdown (metabolism) of certain fatty materials known as lipids, specifically cholesterol and triglycerides. This results in the abnormal accumulation of lipids in the body (hyperlipidemia). Affected individuals may develop multiple yellowish, lipid-filled bumps (papules) or plaques on the skin (xanthomas). Affected individuals may also develop the buildup of fatty materials in the blood vessels (artherosclerosis) potentially obstructing blood flow and resulting in coronary heart disease or peripheral vascular disease. Most cases of hyperlipoproteinemia type III are inherited as an autosomal recessive trait.

Symptoms

The symptoms of hyperlipoproteinemia type III may vary from case to case. Some individuals may not exhibit any apparent symptoms (asymptomatic). Symptoms of hyperlipoproteinemia type III usually do not appear unless a secondary genetic or environmental factor increases lipid levels. Such factors include diabetes, obesity, or hypothyroidsim.



The most consistent finding associated with hyperlipoproteinemia type III is the development of xanthomas, which are deposits of fatty materials (lipids) in the skin and subcutaneous tissue. Xanthomas appear as multiple yellowish bumps (papules) or plaques on or just beneath the skin. In individuals with hyperlipoproteinemia type III, xanthomas may form on the palms of the hands, a condition referred to as xanthoma striata palmaris. This symptom has not been reported to occur in any other disorder.



Xanthomas may also form on the elbows, knees, knuckles, arms, legs, and buttocks. Xanthomas may also occur within the tendons of the rear lower legs (Achilles tendon) and occasionally on the fingers. Some affected individuals may have fatty deposits within the corneas of the eyes (arcus lidus corneae).



Individuals with hyperlipoproteinemia type III may develop thickening and blockage of various blood vessels (atherosclerosis) due to the buildup of fatty material (e.g., lipids). Atherosclerosis may result in coronary heart disease or peripheral vascular disease. Coronary heart disease results from blockage or interruption of the blood supply to the heart potentially resulting in chest pain (angina) and heart attack. Peripheral vascular disease is a general term for disease of the blood vessels outside of the heart and brain. It results from blockage or interruption of the blood flow to various organs and the extremities. Decreased blood flow to the legs may result in cramping and cause a limp (claudication). Some individuals may have an abnormally enlarged liver or spleen (hepatosplenomegaly).



Individuals with hyperlipoproteinemia type III may eventually develop inflammation of the pancreas (pancreatitis). Chronic pancreatitis may result in back pain, diarrhea, jaundice, and potentially the development of diabetes.

Causes

Most cases of hyperlipoproteinemia type III are inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from 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% 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 and be genetically normal for that particular trait is 25%.



Symptoms of hyperlipoproteinemia type III develop due to the improper function or imbalance of special proteins in the blood (protein-lipid molecules known as apo E) that transport cholesterol and other fats from one area of the body to another and help clear fats from the blood.



The gene that is responsible for the production of apo E is located on the long arm of chromosome 19 (19q13). The gene occurs in many forms (alleles), the three most common of which are known as e2, e3 and e4. Every person had two apo E genes in some combination of these various forms. Physicians consider apo e3 the "normal" form of the gene; others are considered mutations of the apo E gene.



Most cases of recessively inherited hyperlipoproteinemia type III result from inheritance of two genes that code for apo e2. Apo e2 clears dietary fats from the body at a slower rate than apo e3. However, the presence of two apo e2-coding genes by itself usually does not result in the development of symptoms of hyperlipoproteinemia type III. In fact, fewer than 10 percent of individuals with two genes coding for apo e2 ever develop outward symptoms of hyperlipoproteinemia type III. Researchers believe that additional genetic, environmental, or hormonal factors play a role in the development of the disorder. These factors may include the presence of other disorders (e.g., hypothyroidism, diabetes), obesity, or age. In women, low estrogen levels may contribute to the development of symptoms, which is why the disorder occurs in women after menopause.



There are approximately 25 additional, extremely rare variants of apo E, some of which also cause hyperlipoproteinemia type III. These rare variants of the apo E gene are inherited as autosomal dominant traits.



Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.



Individuals with the dominant forms of hyperlipoproteinemia type III may experience symptoms from birth. Additional genetic, environmental and hormonal factors may determine the severity of the disorder.

Affected Populations

Hyperlipoproteinemia type III affects males more often than females. The majority of cases occur during early adulthood, although cases have been reported in children and the elderly. Women are rarely affected until after menopause.



The incidence of hyperlipoproteinemia is unknown. It is estimated to affect approximately 1 in 5,000-10,000 people in the general population.

Standard Therapies

Diagnosis

There is no specific diagnostic test for hyperlipoproteinemia type III. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings such as xanthoma striata palmaris. Tests may be performed that demonstrate elevated levels of cholesterol and triglycerides (hyperlipidemia), which occurs after fasting; reveal the presence of very low density lipoproteins (VLDLs), a type of lipoprotein that is elevated in individuals with hyperlipoproteinemia type III; and demonstrate an increased ratio between VLDLs to plasma triglycerides. A test known as electrophoresis may be used to demonstrate abnormal lipoproteins. Electrophoresis is a laboratory test that measures protein levels in the blood or urine by using an electric current to separate proteins by molecular size.



Genotyping is a test that determines what form (allele) of gene is present. A simple blood test can determine whether an individual has two apo e2 genes. When these genes are found a person with characteristic symptoms, it is diagnostic of hyperlipoproteinemia type III.



Treatment

Most individuals with hyperlipoproteinemia type III respond to dietary therapy that consists of a diet that is low in cholesterol and saturated fat. The reduction of the intake of dietary cholesterol and other fats generally prevents xanthomas and high lipid levels in the blood (hyperlipidemia). Exercise in addition to dietary therapy may help lower lipid levels.



In individuals in whom dietary modification does not lower lipid levels, certain drugs may be used. These drugs include niacin, gemfibrozil, clofibrate, and/or lovastatin. Other drugs, such as cholestyramine and colestipol are not effective for the treatment of Broad Beta Disease; they may actually raise blood levels of beta-lipoproteins.



Xanthomas can sometimes be removed surgically. Treatment of cardiovascular disease is symptomatic. Because estrogen improves the clearance of specific lipids associated with hyperlipoproteinemia type III, estrogen therapy may help some postmenopausal women with this disorder.



Genetic counseling may be of benefit for people with hyperlipoproteinemia type III and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

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 website.



For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



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

www.centerwatch.com

References

TEXTBOOKS

Demacker PNM, Stalenhoef AFH. Familial Dysbetalipoproteinemia. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:559.



Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:2835-62.



Behrman RE., ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:383.



Magalini SI, et al., eds. Dictionary of Medical Syndromes. 4th ed.New York, NY: Lippincott-Raven Publishers; 1997:397.



JOURNAL ARTICLES

Lugo-Somolinos A, Sanchez JE. Xanthomas: a marker for hyperlipidemias. Bol Asoc Med PR. 2003;95:12-6.



Rolleri M, Vivona N, Emmanuele G, et al., Two Italian kindreds carrying the Arg136-->Ser mutation of the Apo E gene: development of premature and severe atherosclerosis in the presence of epsilon 2 as second allele. Nutr Metab Cardiovasc Dis. 2003;13:93-9.



Ishigami M, Yamashita S, Sakai N, et al., Atorvastatin markedly improves type III hyperlipoproteinemia in associated with reduction of both exogenous and endogenous apolipoproteinemia B-containing lipoproteins. Atherosclerosis. 2003;168:359-66.



Smelt AH. From gene to disease; apolipoproteinemia E2 and familial dysbetalipoproteinemia. Ned Tijdschr Geneeskd. 2003;147:157-9.



Blom DJ, Byrnes P, Jones S, Marais AD. Dysbetalipoproteinemia - clinical and pathophysiological features. S Afr Med J. 2002;92:892-7.



Mahley RW, Huang Y, Rall Jr. SC. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes. J Lipid Res. 1999;40:1933-49.



FROM THE INTERNET

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:107741; Last Update:6/10/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107741 Accessed on: February 1, 2005.



Friday KE. Dysbetalipoproteinemia. Emedicine. 2004. Available at: http://www.emedicine.com/med/topic596.htm Accessed on: February 1, 2005.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



American Heart Association

7272 Greenville Avenue

Dallas, TX 75231

Tel: (214)784-7212

Fax: (214)784-1307

Tel: (800)242-8721

Email: Review.personal.info@heart.org

Internet: http://www.heart.org



NIH/National Heart, Lung and Blood Institute

P.O. Box 30105

Bethesda, MD 20892-0105

Tel: (301)592-8573

Fax: (301)251-1223

Email: nhlbiinfo@rover.nhlbi.nih.gov

Internet: http://www.nhlbi.nih.gov/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

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