NORD gratefully acknowledges Emily Fishman, NORD Editorial Intern, and Michael Shapiro, DO, Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, for assistance in the preparation of this report.
Tangier disease is a rare inherited disorder characterized by significantly reduced levels of high-density lipoproteins (HDL) in the blood. HDL-cholesterol (HDL-C) is often referred to as the “good cholesterol” as it can facilitate the removal of cholesterol out of the walls of arteries, particularly the coronary (heart) arteries. Classic features of Tangier disease include fatty accumulations that present as enlarged and yellow- or orange-colored tonsils, or enlarged liver (hepatomegaly), spleen (splenomegaly), or lymph nodes. Tangier disease may also be associated with an increased risk of cardiovascular disease, moderate elevation in triglycerides (hypertriglyceridemia), nerve disturbances (neuropathy), and rarely an opaqueness in the covering of the eye (corneal clouding). This disorder was originally named after the location in which it was first discovered – Tangier Island in the Chesapeake Bay. Later, the disease was further characterized as more individuals were found to have the disease in other areas of the United States and around the globe.
Symptoms of Tangier disease are variable and depend on which organs are involved and the severity of those manifestations. Tangier disease is most often characterized by enlarged orange- or yellow-colored tonsils. This discoloration is due to fatty deposits accumulating in the tonsils. Fatty deposits can also form in other organs causing enlargement of the throat, liver, spleen, or lymph nodes. Fat accumulations in nerves can cause disturbances and loss-of-sensation called peripheral neuropathy. Discoloration may also occur in the digestive system, particularly the rectum and large intestine. Cardiovascular disease has been reported in adults with Tangier disease. In rare cases, a clouding of the cornea of the eye can occur, but is generally mild and does not cause vision impairment.
Tangier disease is an autosomal recessive genetic disorder. 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 Tangier disease, the individual will be a carrier for the disease but will not show the classic characteristics. However, carriers of Tangier disease often are found to have relatively low levels of HDL-C.
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.
The gene that causes Tangier disease has been identified as ABCA1 (ATP-binding cassette transporter A1). ABCA1 codes for a cell surface protein that is important in the process of reverse cholesterol transport, which allows the movement of cholesterol from inside the cell to apolipoprotein AI (apoA-I), the major protein constituent of HDL. When two ABCA1 gene mutations are present, the cell is no longer able to efflux cholesterol out of the cell to ApoA-I.
Cholesterol is a soft, waxy substance found among the lipids (fats) in the bloodstream and in all the cells in our body. Cholesterol is essential to the formation of cell membranes, hormones, and other cellular functions. Cholesterol and other fats cannot dissolve in the blood and have to be transported to and from the cells by special carriers called lipoproteins. There are several types of lipoproteins that vary in density, but the most clinically important types are low-density lipoprotein (LDL) and HDL. About one-third to one-fourth of blood cholesterol is carried by HDL. HDL is commonly called the “good” cholesterol because it may be involved with the removal of cholesterol from the artery walls and ultimate disposal to the liver. On the other hand, LDL deposits cholesterol in the artery walls, causing the formation of cholesterol plaque.
Patients with Tangier disease have been found to have a severe reduction in HDL levels. Without sufficient HDL to help clear arteries of plaques, individuals are more susceptible to having excess lipid deposits on organs of the body such as liver, heart, spleen, lymph nodes, and brain.
Tangier disease is a rare disorder with only approximately 100 cases diagnosed worldwide. Tangier disease is thought to be present at birth, but the age of diagnosis can be highly variable (from infancy through 7th decade) due to the nature of symptoms.
Diagnosis of Tangier disease is achieved through clinical evaluation and can be confirmed through genetic testing involving the sequencing of the ABCA1 gene. HDL-C deficiency and an extremely low apolipoprotein A1 (ApoA1) level are typical diagnostic criteria.
Treatment of Tangier disease is supportive and based on specific disease manifestations in a given individual. There are no known specific treatments for Tangier disease. Surgical removal of the spleen, tonsils, or other enlarged tissues may become necessary in some patients. It is suggested that management of Tangier disease should include regular assessment of cardiovascular risk and neurological and ophthalmological examination.
Genetic counseling is recommended for families of patients with Tangier disease.
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Hooper AJ, Mccormick SPA, Hegele RA, Burnett JR. Clinical utility gene card for: Tangier disease. European Journal of Human Genetics. 2017;25(7). doi:10.1038/ejhg.2017.72.
Bale PM, Clifton-Bligh P, Benjamin BNP, Whyte HM. Pathology of Tangier disease. Journal of Clinical Pathology. 1971;24(7):609-616. doi:10.1136/jcp.24.7.609.
Shapiro MD. Rare Genetic Disorders Altering Lipoproteins. Endotext. Last Update: December 6, 2015. https://www.ncbi.nlm.nih.gov/books/NBK326744/#_NBK326744_pubdet. Accessed July 10, 2017.
Genetics Home Reference. Tangier disease. Reviewed March 2010. https://ghr.nlm.nih.gov/condition/tangier-disease#resources Accessed June 19, 2017.
Orphanet .Tangier disease. http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=9288&Disease_Disease_Search_diseaseGroup=anal&Disease_Disease_Search_diseaseType=Pat&Disease%28s%29%2Fgroup of diseases=Tangier-disease–Analphalipoproteinemia-&title=Tangier-disease–Analphalipoproteinemia-&search=Disease_Search_Simple. Published December 2013. Accessed June 19, 2017.
Online Inheritance in Man (OMIM).Tangier Disease. Entry # 205400. https://www.omim.org/entry/205400?search=tangier%20disease&highlight=tangier%20disease#6. Last update: 07/09/2016. Accessed June 19, 2017.
Genetic Testing Registry. Genetic Testing Registry. https://www.ncbi.nlm.nih.gov/gtr/conditions/C0039292/ Accessed June 19, 2017.
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