Tangier disease

Tangier disease is a rare genetic disorder with an estimated 100 known cases worldwide. It is characterized by very low levels of high-density lipoprotein (HDL or “good” cholesterol). The complications of this disease can be very serious, especially when it goes undiagnosed.

Definition & Facts

Tangier disease is named after Tangier Island, Virginia, where the first case was diagnosed in 1959. The disease is caused by a genetic mutation in chromosome 9q31. This mutation leads to a defective ABCA1 transporter. If functioning properly, the ABCA1 transporter removes cholesterol from cells into the bloodstream.

The extreme inefficiency of the ABCA1 transporter in people with Tangier disease creates two major health problems. First, there is a toxic build-up of cholesterol within the cells. Second, because HDL functions to remove “bad” cholesterol from the body via the liver, the lack of HDL in the bloodstream increases a patient’s risk for coronary artery disease, atherosclerosis, and stroke.

Symptoms & Complaints

There are several external symptoms of Tangier disease. One of the most obvious is orange or yellowish-grey tonsils that are extremely enlarged. Lipid accumulation in the corneas can cause them to appear hazy or clouded. Swollen lymph nodes all throughout the body are common. Some patients present with small, pimple-like skin lesion‘s that are not pus-producing.

The internal symptoms of Tangier disease largely depend on the duration of the disease. The older the patient is when diagnosed the greater the damage caused by the HDL deficiency and the corresponding cholesterol build-up. Most adults who are diagnosed with Tangier disease seek medical attention for neuropathy, or the numbness or weakness caused by damage to the peripheral nerves. The disease can also cause an enlarged liver (hepatomegaly) or enlarged spleen (splenomegaly). Anemia, gastrointestinal disorders, slightly elevated fat content in the bloodstream and deficiencies in blood platelets are also common.

Causes

Tangier disease is caused by a recessive gene mutation that must be present in both parents to manifest. Most genetic carriers of the chromosome 9q31 mutation, who have only one copy of the mutated gene, do not have symptoms of the disease. The disease is not sex linked. Because it is recessive, there is only a 25% chance that two carrier parents will produce offspring with the disease.

There is a 50 percent chance that these same parents will produce carrier offspring. The 9q31 chromosome is part of the ATP-Binding Cassette transporter A1 (ABCA1) gene. This gene encodes the ABCA1 membrane transporter. This transporter is a protein that regulates cellular cholesterol removal and the homeostasis of the lipids that form cell membranes.

When the ABCA1 protein is not functioning properly, there is insufficient HDL cholesterol to combat the body’s low-density lipoprotein (LDL), or bad cholesterol. The symptoms and manifestations of Tangier disease arise from this imbalance.

Arteries can get clogged from excess lipids (fats) in the bloodstream and these fats can also be deposited in organs, including the heart, spleen, liver, lymph nodes and brain. The characteristic nerve damage caused by Tangier disease seems to be related to engorged Schwann cells that cannot properly execute their role in keeping nerve fibers alive.

Diagnosis & Tests

Because of its rarity, Tangier disease is often misdiagnosed. There are, however, specific indications that the disease is likely. Tangier disease is indicated by extremely low HDL cholesterol levels, especially in combination with normal or high triglycerides and low total plasma cholesterol (less than 150 mg/dl). Body tissues, including the liver, the spleen, the tonsils, peripheral nerves, bone marrow and lymph nodes can be tested for the accumulation of cholesterol esters (fats).

The presence of fat-laden foam cells in rectal mucosa and skin biopsies can signify Tangier disease. Premature onset of atherosclerosis, heart attacks and stroke can also indicate Tangier disease. Because it is hereditary, a family history of the disease is a strong indicator. Definitive diagnosis of Tangier disease is made by sequencing the ABCA1 gene to expose the expected mutation of the 9q31 chromosome. 

Treatment & Therapy

There is currently no specific treatment for Tangier disease. Therapeutic strategies should focus on increasing HDL concentration. Unfortunately, most common drugs known to increase HDL are ineffective in Tangier disease patients. The recently designed drugs dalcetrapib and anacetrapib, which are both cholesterylester transfer protein (CETP) inhibitors, may reduce cardiovascular and neuropathic complications. Reconstituted HDL cholesterol (rHDL) therapy has had positive results in the treatment of cardiovascular disease and could be effective in the treatment of Tangier disease.

Preventative approaches to disease control should also be employed. LDL-lowering drugs may be required in patients with cardiovascular disease or carotid atherosclerosis. Low-fat diets can reduce the complications of Tangier disease including liver enlargement and atherosclerosis. Patients should not smoke cigarettes as smoking lowers HDL levels and encourages the production of a hormone that increases triglycerides and LDL cholesterol. 

In extreme circumstances, surgery may be required to remove or repair organs compromised by Tangier disease. Many patients undergo tonsillectomies in adolescence, long before the disease is properly diagnosed. The spleen may also have to be removed if it is enlarged. Heart surgery may sometimes be required. Severe aortic stenosis may require valve replacement. Patients with atherosclerosis may have to have coronary angioplasties to open blocked arteries. 

Prevention & Prophylaxis

With the advent of affordable genetic testing, genetic counseling is increasingly integrated into standard medical practice and could be especially effective in the control of hereditary diseases.

There is some evidence that gene-diet interactions modulate plasma lipids and thus affect the expression of diseases. However, much more research needs to be conducted before any conclusions regarding nutrigenetic correlations in Tangier disease can be made.