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A rare genetic disorder pinpointed // A molecule crucial to cholesterol metabolism found // Possible treatments for heart disease and Alzheimer’s explored.

Tangier Disease: One Island’s Treasure

By Cathryn Delude // Illustrations by Stuart Bradford // Fall 2009
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tangier disease

Stuart Bradford

The surgeon who removed the five-year-old boy’s tonsils in 1959 had never seen anything like them. Instead of pinkish lobes, the boy’s tonsils were huge and orange. Thinking that their extraordinary appearance might signal a rare malignancy, the surgeon sent the tonsils to the Armed Forces Pathology Institute in Washington, D.C. Though researchers there found no cancer, they did discover the reason for the tissue’s abnormal size and color: Its cells were bloated with cholesterol. That prompted a call to a leading cholesterol expert, the National Heart Institute’s Don Fredrickson, who packed his medicine bag and took a ferry to the boy’s home on Tangier Island, 12 miles off the coast of Virginia.

John Smith, of Jamestown fame, discovered the island in 1608, its stretches of pale sand reminding him of North Africa’s Tangier. To Fredrickson, 350 years later, the island seemed a likely place for a rare, inherited condition to become more prevalent than it could ever be in a more diverse, widely dispersed population. A handful of families had settled Tangier in 1686, and its inhabitants had remained physically and genetically isolated. After a cholera epidemic forced the island’s evacuation in 1866, many families never returned, and the gene pool became even smaller.

Looking down the throats of almost everyone on the island, Fredrickson found only one other set of big orange tonsils, in the boy’s sister. That told him this was probably a recessive genetic condition that followed the inheritance pattern first defined by Gregor Mendel in his famous pea experiments. In the case of Huntington’s disease and a few other Mendelian maladies, the defect is dominant, and children who inherit a copy of the affected gene from just one parent will develop the disease. In other conditions, including cystic fibrosis and sickle cell anemia, the gene is recessive: Both parents must pass it along for the child to get sick.

Tangier disease, as the boy’s condition came to be known, was indeed recessive. “The kids with two copies of the defective gene had no HDL [high-density lipids], the good form of cholesterol, in their blood,” says Mason Freeman, an expert on cholesterol metabolism at Massachusetts General Hospital. “The parents, with just one defective copy each, had some HDL, but much lower levels than the average person.” HDL normally helps cells get rid of their excess cholesterol; without HDL, too much cholesterol accumulates—leading, in this case, to swollen orange tonsils.

Fredrickson was intrigued because scientists already knew HDL was associated with heart disease risk—low levels were bad and high levels were protective—but didn’t understand why. If he could find additional cases like those of the boy and his sister, they might lead researchers to the gene responsible for the condition, and the chance to learn more about HDL. Fredrickson began a hunt that ended up taking 40 years, in part because it proved quite difficult to find other people with cholesterol-laden tonsils. To date, only about 100 people with Tangier disease have been identified worldwide.

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1. “Tangier Disease: Still More Questions Than Answers,” by Jerzy-Roch Nofer and Alan T. Remaley, Cellular and Molecular Life Sciences, October 2005. A historical journey from the discovery of the ABCA1 gene, a mutation of which causes Tangier disease, to the growing understanding of its essential role in transporting cholesterol and its potential to reduce heart disease risk.

2. “Greasing the Wheels of Abeta Clearance in Alzheimer’s Disease: The Role of Lipids and Apolipoprotein E,” by Jianjia Fan, James Donkin and Cheryl Wellington, BioFactors, June 2009. A concise overview of the recently appreciated role of ABCA1 in forestalling Alzheimer’s disease.

3. “The Cell Cholesterol Exporter ABCA1 as a Protector From Cardiovascular Disease and Diabetes,” by Chongren Tang and John F. Oram, Biochimica et Biophysica Acta, July 2009. Oram, a discoverer of ABCA1, describes a crucial function of the gene: regulating the inflammatory process that can contribute to heart disease and Alzheimer’s, as well as diabetes and other disorders.

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