NORD gratefully acknowledges Dillon Davis, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Hyperlipoproteinemia type III is a genetic disorder that causes the body to breakdown (metabolize) fats (lipids) incorrectly. This results in the buildup of lipids in the body (hyperlipidemia) and can lead to the development of multiple small, yellow skin growths (xanthomas). Affected individuals may also develop the buildup of fatty materials in the blood vessels (atherosclerosis) blocking blood flow and potentially leading to heart attack or stroke. Hyperlipoproteinemia type III affects 1-5,000 to 1 in 10,000 people in the general population. Without treatment, affected individuals are 5-10 times more likely to develop cardiovascular disease.
The symptoms of hyperlipoproteinemia type III may vary from person to person. Some individuals may not show any symptoms (asymptomatic). Symptoms of hyperlipoproteinemia type III often do not appear unless additional conditions are present such as diabetes, obesity, or hypothyroidism.
The most common feature associated with hyperlipoproteinemia type III is the development of xanthomas, which are deposits of fatty materials (lipids) in the skin and appear as multiple yellow bumps (papules) on or just beneath the skin. Xanthomas may form on different parts of the body including the hands, elbows, knees, knuckles, arms, legs, and buttocks. Xanthomas on the palms of the hands, a condition called xanthoma striata palmaris, is specific to hyperlipoproteinemia type III and has not been reported in any other disorder. Xanthomas can also develop 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).
The risk for developing coronary heart disease is 5-10 times higher for an individual with hyperlipoproteinemia type III compared to the general population. Individuals with hyperlipoproteinemia type III may develop thickening and blockage of various blood vessels (atherosclerosis) due to the buildup of fatty material (lipids). Atherosclerosis may result in coronary heart disease or peripheral vascular disease. Coronary heart disease results from blockage 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 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, yellow-colored skin (jaundice), and potentially the development of diabetes. Pancreatitis can also lead to the development of pancreatic cancer.
Hypolipoproteinemia type III is a genetic condition caused by changes in the APOE gene. The APOE gene provides instructions for making a protein called apolipoprotein E. This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats, carrying them through the bloodstream, and helping clear them from the bloodstream.
There are different versions (alleles) of the APOE gene. The major versions are called e2, e3, and e4. Every person has two copies of the APOE gene in some combination of these different versions. The most common version is e3, which is found in more than half of the general population. The APOE e2 version has been shown to increase the risk of hyperlipoproteinemia type III. APO e2 clears dietary fats from the body at a slower rate than apo e3. Also, of note, the APOE gene is associated with Alzheimer’s disease. However, individuals with two copies of the APO e2 variant have a low risk to develop the disease.
The presence of two APO e2 genes by itself usually does not result in the development of symptoms of hyperlipoproteinemia type III. In fact, about 10-15 percent of individuals with two copies of the APO e2 variant 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.
Hyperlipoproteinemia type III is most often inherited in an autosomal recessive pattern. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. 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 blood 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.
About 10% of hyperlipoproteinemia type III is caused by versions of the APOE gene that are inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
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.
Hyperlipoproteinemia type III affects males more often than females. Of the 10-15% of people who develop symptoms, this most often happens in early adulthood. Most people begin to experience symptoms in early adulthood, although some individuals have symptoms begining in childhood or late adulthood. Women are rarely affected until after menopause.
Hyperlipoproteinemia type III is estimated to affect approximately 1 in 5,000-10,000 people in the general population
A diagnosis of hyperlipoproteinemia type III can be made based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings such as xanthoma striata palmaris. Arterial imaging and a cardiac stress test can identify signs of silent atherosclerosis in young adults.
Certain tests can be performed that can identify increased blood levels of certain lipids (hyperlipidemia), specifically cholesterol and triglycerides, and increased blood levels of very low-density lipoproteins (VLDLs), a lipoprotein that is elevated in hyperlipoproteinemia type III. An increased ratio of VLDLs to plasma triglycerides is also suggestive of hyperlipoproteinemia type III. A test known as electrophoresis may be used to show 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.
Genetic testing of the APOE gene can confirm diagnosis of hyperlipoproteinemia type III. If genetic testing identifies two e2 versions of the APOE gene in an individual who is experiencing symptoms (xanthomas, high cholesterol and triglycerides), then a diagnosis of hyperlipoproteinemia type III can be made.
Most individuals with hyperlipoproteinemia type III respond well 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.
Certain drugs can also help lower lipid levels. Drugs that have shown to be effective for reducing lipid levels include statin, fibrates, and nicotinic acid. Other drugs, such as cholestyramine and colestipol are not effective for the treatment of hyperlipoproteinemia type III; they may actually raise blood levels of beta-lipoproteins.
Xanthomas can sometimes be removed surgically. Cardiovascular disease is treated according to the symptoms that present. Because estrogen improves the clearance of specific lipids associated with hyperlipoproteinemia type III from the bloodstream, estrogen therapy may help some postmenopausal women with this disorder.
Genetic counseling is recommended for people with hyperlipoproteinemia type III and their families. Other treatment is symptomatic and supportive.
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:
Toll-free: (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:
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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