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Abstract

Abstract 

  1. Tangier disease is characterized by the virtual absence of high-density lipoproteins (HDL) in plasma and by the accumulation of cholesteryl esters in many tissues throughout the body. These include tonsils, liver, spleen, lymph nodes, thymus, intestinal mucosa, peripheral nerves, and the cornea. Tangier patients have a moderately increased risk for coronary heart disease.

  2. The major clinical signs are hyperplastic orange tonsils, hepatosplenomegaly, and relapsing neuropathy. Pathognomonic is the finding of HDL deficiency, low plasma cholesterol concentration accompanied by normal or elevated triglyceride levels in patients with hyperplastic orange-yellow tonsils, and adenoidal tissue.

  3. Plasma apolipoprotein (apo) A-I concentration is extremely low (<3 percent that of controls) due to the lack of mature, lipid-rich HDL, that is, α-HDL, which have electrophoretic alpha-mobility and represent the majority of HDL in normolipidemic plasma. Apparently normal amounts of apo A-I reside in a lipid-poor particle with electrophoretic pre-beta-mobility, that is, pre-β1-HDL, which in normal plasma represents approximately 5 percent of apo A-I and is a precursor of mature HDL.

  4. Tangier fibroblasts are characterized by defective lipid efflux and by disturbed signal transduction processes. Compared to normal fibroblasts, Tangier fibroblasts are completely defective in releasing phospholipids and cholesterol in the extracellular presence of lipid-free apolipoproteins and exhibit reduced capacity to release cholesterol in the presence of HDL. Agonist-mediated breakdown of phospholipids by phospholipases is disturbed in Tangier fibroblasts. Artificial increase of cellular levels of diacylglycerol or phosphatidic acid partially corrects the cholesterol efflux defect of Tangier fibroblasts.

  5. Obligate heterozygotes have no clinical manifestations and are characterized biochemically by half-normal serum concentrations of HDL-cholesterol, apo A-I, and apo A-II, and by half-normal lipid efflux from fibroblasts.

  6. Tangier disease is caused by mutations in the gene of the ATP-binding cassette transporter 1 (ABC1), which is located on the long arm of chromosome 9 (9q31).

  7. Although the pathomechanism is not known, the findings in Tangier disease demonstrate that ABC1 plays a pivotal role in the secretion of cellular lipids and in the formation of mature HDL. Defective lipid efflux appears to facilitate foam cell formation. Defective HDL maturation seems to underlie the enhanced catabolism of apo A-I and apo A-II resulting in HDL deficiency.

  8. There is no specific treatment for Tangier disease.

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