Tangier disease

ALSO KNOWN AS: A-alphalipoprotein neuropathy; alpha high-density lipoprotein deficiency disease; analphalipoproteinemia; cholesterol thesaurismosis; familial high-density lipoprotein deficiency disease; familial hypoalphalipoproteinemia; HDL lipoprotein deficiency disease; lipoprotein deficiency disease, HDL, familial; Tangier disease neuropathy; Tangier hereditary neuropathy

DEFINITION Tangier disease is a rare, inherited disease that severely reduces blood concentrations of high-density lipoprotein. Cells lack the ability to export fats and cholesterol, and cholesterol accumulates inside cells, causing premature cardiovascular disease and other systemic pathologies.

Risk Factors

Because Tangier disease is a hereditary disease, it tends to run in families. A person cannot contract Tangier disease unless both biological parents have at least one mutant copy of the ABCA1 gene. This disease is quite rare, with less than one hundred cases known worldwide, but is it found in many different countries and occurs equally in men and women.

Etiology and Genetics

Mutations in the ABCA1 gene cause Tangier disease, and this disorder is inherited as an autosomal recessive trait. ABCA1 is located on the long arm of chromosome 9 in band 31.

To inherit Tangier disease, both parents must carry at least one mutant copy of the ABCA1 gene. Each sibling born to parents who both carry one mutant copy of the ABCA1 gene has a 25 percent chance of contracting Tangier disease.

The ABCA1 gene provides the instructions for the synthesis of a protein called the ATP-binding cassette transporter A1. This protein is inserted into cell membranes. The cell membrane delimits the interior of the cell from its exterior, and is composed of phosphate-containing lipids. To function properly, biological membranes must maintain a particular level of fluidity. Animal cells maintain the fluidity of their membranes by interspersing cholesterol molecules between the membrane lipid molecules. Cholesterol, however, is too bulky a molecule to move across cell membranes without a transport protein. The ATP-binding cassette transporter A1 protein serves as a cholesterol transporter, and it exports lipid and cholesterol molecules from cells.

Since human cells make their own cholesterol and use dietary cholesterol, they must dispose of excess cholesterol. A process called reverse cholesterol transport moves excess cholesterol from the peripheral tissues to the liver where it is converted into bile salts, secreted into the gastrointestinal tract, disposed of in feces. The ATP-binding cassette transporter A1 mediates reverse cholesterol transport.

Reverse cholesterol transport begins when the liver secretes a protein called apoA1 into the blood. ApoA1 binds to blood lipids and forms a nascent discoidal high-density lipoprotein (ndHDL). Cells use the ATP-binding cassette transporter A1 to export lipids and cholesterol into the extracellular spaces and ndHDLs absorb these molecules and use an enzyme called lecithin cholesterol acyltransferase (LCAT) to convert cholesterol into cholesterol esters. This enlarges the ndHDLs and transforms them into spherical, mature HDL particles, which are called HDL-C particles. HDL-C particles are taken up by the liver, and their cholesterol esters are converted into bile salts that are excreted into the small intestine for disposal.

Mutations in the ABCA1 gene that inactivate the ATP-binding cassette transporter A1 protein prevent cells from ridding themselves of excess cholesterol. Without the increased levels of cholesterol near the surfaces of cells, ApoA1 protein molecules never make HDL-C particles and are, instead, rapidly degraded. HDL levels in the blood are extremely low, and cholesterol builds up in cells throughout the body, eventually killing them.

Symptoms

The tonsils are greatly enlarged and have an orange or yellow color. Cholesterol buildup in nerves causes nervous system abnormalities (neuropathy). The large blood vessels show premature buildup of lipids and cholesterol within the inner lining of the vessel wall (atherosclerosis). Complications include an enlarged spleen (splenomegaly) and liver (hepatomegaly), clouding of the cornea of the eyes, and early-onset cardiovascular disease.

Screening and Diagnosis

Cholesterol deposits in the cornea of the eyes, tonsils, or rectal tissues are diagnostic, especially if combined with unexplained enlargement of the spleen or liver and neurological disturbances. Biochemically, patients show hypoalphalipoproteinemia, or unusually low blood HDL-C levels (less than 5 mg/dL). No commercially available DNA test exists to date, but particular research laboratories can detect mutations in the ABCA1 gene.

Treatment and Therapy

Presently, there is no cure for Tangier disease. Treatment regimes vary, but organs with excessive cholesterol deposits, like the tonsils and spleen, are usually removed. Treatment of arteriosclerosis requires angioplasty, and coronary artery disease is treated with bypass surgery. Medications typically show no efficacy.

Prevention and Outcomes

The prognosis for Tangier disease is, in most cases, positive. If patients develop heart disease, then they might have a decreased life span, but this depends on the severity of their disease and the quality of medical care they that receive.

Bibliography

Alshaikhli, Alfarooq, et al. Tangier Disease, StatPearls, 8 May 2023.

Grundy, Scott M. Atlas of Atherosclerosis and Metabolic Syndrome. New York: Springer, 2011. Print.

Kelly, Evelyn B. Encyclopedia of Human Genetics and Disease. Santa Barbara: Greenwood, 2013. Print.

Maxfield, Frederick R., and Ira Tabas. “Role of Cholesterol and Lipid Organization in Disease.” Nature 438.7068 (2005): 612–21. Print.

Oram, John. “Tangier Disease and ABCA1.” Biochimica et Biophysica Acta 1529 (2000): 321–30. Print.

"Tangier Disease." Cleveland Clinic, 5 Aug. 2022, my.clevelandclinic.org/health/diseases/23951-tangier-disease. Accessed 9 Sept. 2024.

“Tangier Disease.” Genetics Home Reference. Natl. Lib. of Medicine, Mar. 2010. Web. 25 Aug. 2014.