Tangier Disease
by Jackie Newman

Tangier Disease is an extremely rare autosomal recessive metabolic disorder. Documentation shows that as of 1988, 27 cases of Tangier Disease had been reported (Makrides pg.465) and in 1992 the reported cases were still fewer than 50 persons worldwide (Thoene pg.265). The majority of the cases tend to localize in one single area of the U.S., Tangier Island, Virginia. The fact that most of the people that are affected by Tangier disease all live in close proximity to one another could be due to Founder's effect. The original settlers to the island came in 1686 and it is possible that one or two of them were carriers of the disease or actually had the symptoms and passed it down through the blood line.
Characteristics of Tangier Disease include increased levels or even a complete absence of high-density lipoproteins (HDL) concentrations in one's plasma, low cholesterol levels in the plasma, increased cholesteryl esters in the tonsils, spleen, liver, skin and lymph nodes. One easily visual characteristic usually found in children with Tangier disease is the presence of enlarged, yellow-orange tonsils.
Initial research of Tangier disease showed a marked decrease in the HDL concentrations when compared to normal controls. In some cases the reduction was as great as 50% (Schmitz pg.6306). Scientists studied the HDL concentrations and looked for any possible links in its involvement with the disease. They specifically looked at the apo A-I (apolipoprotein) concentrations, which is a major protein component of HDL.
The main hypothesis was that apo A-I was structurally abnormal. Studies proved that this was incorrect because the DNA- derived protein sequence for Tangier apo A-I was identical to the control groups apo A-I sequence (Makrides pg.468). Scientists discovered that the cause of Tangier disease is involved with the intracellular membrane trafficking of the HDL. Normally macrophages inside the cell have receptors that bind the HDL. After the HDL is bound it is transported into the endosomes. The endosome is transported through the cell without any degradation by the lysosome and the HDL is eventually resecreted from the cell. It is during this cycle that there are problems for the Tangier disease people. When the HDL is allowed to bind to the receptor monocyte, the two stick together but they never separate. The HDL is not resecreted outside the cell (Schmitz pg.6308) The data suggest that there is a deficiency in the cellular metabolism of HDL in the Tangier monocytes. The HDL-monocyte unit together also supports the observed condition of high concentrations of excess cholesterol in body tissues.
Currently the treatment for Tangier patients is dependent on the various symptoms, ranging from heart surgery to removal of organs. Gene therapy has been proposed as a possible treatment but is difficult because there isn't anything wrong specifically with the gene involved in the HDL conversion. The problem is in the cellular transportation. Many of the specific processes within the cell are still not known so any extensive treatment is still investigational.

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