What is Tangier disease?

Tangier disease is a rare genetic disorder with approximately 100 cases identified around the globe. Put simply, a genetic disorder is a disease passed down from generation to generation through a mutated gene or multiple genes. 

In the case of Tangier disease, the mutation is found in the ABCA1 gene. This gene usually codes for a type of transporter or “fancy vehicle” which helps in moving cholesterol out of the cells into the blood and then on to be removed from the body. This vehicle is called high-density lipoprotein (HDL), and when it is not being produced as usual, due to the defect in the gene, this shuts down the entire “cholesterol conveyance system.” A very low level of HDL, commonly referred to as “good cholesterol,” means that cholesteryl esters or “bad cholesterols” are not removed from the body, leading to accumulation in different organs of the body. This can give rise to a plethora of complications such as premature atherosclerosis.

Tangier disease follows an autosomal recessive pattern which means that both birth parents each need to contribute a defective gene to their baby, for the baby to be affected. If a person only receives one defective gene from either birth parent, the person may develop only mild symptoms or no symptoms. However, they will still be a carrier of the disease, meaning they can still pass it on to their children. 

Symptoms of Tangier disease

Enlarged tonsils

Nearly all children affected by Tangier disease present with large, yellowish-orange tonsils. However, this can also be present in young adults. This occurs due to the deposition of cholesterol in the tonsils, as it is unable to be transported elsewhere in the blood.

Peripheral neuropathy

Most adults with Tangier disease complain of peripheral neuropathy. Peripheral neuropathy is a condition in which the nerves that supply the arms, hands, feet and lower legs are damaged. Patients may complain of numbness, tingling, muscle weakness and pain. Some may even complain of the loss of sensations to pain or temperature. In Tangier disease, peripheral nerves are damaged due to cholesterol deposition in the nerves. 

Orange discolouration

Deposition of cholesterol under the skin often gives off an orange hue. 

Complications of Tangier disease

In addition to the key symptoms mentioned above, there are some other clinical manifestations often associated with this disease that occur due to deposition of cholesterol in a variety of systems within the body.

Clouded cornea

The cornea is the transparent layer in the front part of the eye. This part of the eye can become cloudy in appearance due to the deposition of cholesterol throughout the cornea; however, this is rare and when it does occur, is unlikely to have only a mild impact on vision.

Diabetes

Diabetes may develop due to deposition of cholesterol in the cells of the pancreas where insulin is produced. This means insulin cannot be produced as will result in poor blood sugar control.

Premature atherosclerosis

Atherosclerosis is the deposition of fatty plaques typically made of cholesterol in the walls of the arteries, thus making it hard for blood to pass through and supply the organs, especially the heart. This usually happens in older patients. However, in patients with Tangier disease, this may manifest at a very young age, and they are at much higher risk of suffering a heart attack or stroke.

Hepatosplenomegaly

“Hepato” refers to the liver, “spleno” refers to the spleen and “megaly” refers to abnormal enlargement. So, as the term hepatosplenomegaly might suggest, a person may develop an abnormally enlarged liver and spleen due to deposition of cholesterol in these organs. It is also quite common for lymph nodes to be enlarged due to the same process.

Less common symptoms

Some other not-so-common symptoms include:

• Stomach pain
• Dry skin
• Deformed/ thickened/ discoloured nails

Who’s at risk?

Since Tangier disease is a condition that is inherited genetically, relatives of individuals who either have Tangier disease, or are carriers of the disease are at risk. Therefore, blood lipid tests may be offered to relatives of patients to identify those at risk as early as possible.

Diagnosis

Tangier disease may be first suspected when a patient comes in with any of the symptoms above. However, given how rare the disease is, it may take several investigations to reach a diagnosis. The first step towards diagnosis is a blood test that will measure cholesterol levels, including levels of both high- and low-density lipoproteins (HDL’s and LDL’s).

A test results showing unusually low levels of HDL cholesterol will flag to your health provider that there is likely something more specific underlying your symptoms. Your healthcare provider may also measure your ApoA-1 levels, which are a protein component of HDL cholesterol. This is likely to be extremely low, in combination with very low HDL levels, if you have Tangier disease.

The most accurate method of testing is a genetic test, looking for the mutation in the ABCA1 gene. However, if for any reason this test cannot be performed, a tissue biopsy may also be done. A tissue biopsy is a procedure in which a small piece of an organ is taken out for a closer look under the microscope. A tissue biopsy of an individual with the disease would show large cholesterol deposits, helping to confirm the disease.

What happens following diagnosis?

Once diagnosed it is important to assess other organs for evidence of complications. Generally, eye examinations are done to check for any opacities, and ultrasound scans are done to check for enlargement of the liver or spleen. Nerve studies can be done to look for peripheral neuropathy, and angiography (tracing the blood vessels of the heart) may be arranged to monitor for potential blockages in the arteries.

Treatment

Unfortunately, there has been no specific treatment discovered for Tangier disease. Patients will be given advice to maintain a healthy lifestyle which can help to improve symptoms. Some of the suggested lifestyle modifications you can make are:

• Regular aerobic exercise
• Cessation of smoking
• Maintaining a healthy weight 

Specific treatments can be given to manage individual symptoms. For example, individuals complaining of difficulty breathing or swallowing due to enlarged tonsils may be offered surgery to remove them. Patients with clouding of the cornea causing blurred vision may be offered corneal replacement surgery.

Managing risk

Much of the focus for patients with Tangier disease will be on managing their risk of developing further complications. For example, those with an enlarged spleen may be advised to refrain from contact sports or high-intensity physical activities because they are at a higher risk of spleen rupture.

Since patients with Tangier disease are also at a higher risk of developing atherosclerosis, and therefore have a higher chance of developing a heart attack or stroke, their heart health will be regularly monitored. It is also crucial to detect and manage other risk factors of atherosclerosis such as high blood pressure, high blood sugar, and high LDL cholesterol (“bad cholesterol”) levels, and provide treatment where needed.

Summary 

Tangier disease is a rare, inherited genetic disorder characterised by mutations in the ABCA1 gene, leading to impaired cholesterol transport. This results in very low levels of HDL ("good") cholesterol and the accumulation of bad cholesterol in various body tissues. Key symptoms include enlarged, yellowish-orange tonsils, peripheral neuropathy (muscle weakness, pain and tingling), and an orange discolouration of the skin due to deposition of cholesterol.

Other complications can include clouded corneas, diabetes, premature atherosclerosis (leading to increased risk of heart attacks and strokes), and hepatosplenomegaly (enlarged liver and spleen). Diagnosis involves blood tests to measure HDL cholesterol and ApoA-1 levels, and genetic testing for the ABCA1 gene mutation. Tissue biopsies can also confirm the diagnosis.

There is no specific treatment for Tangier disease. Management focuses on lifestyle modifications like regular exercise, smoking cessation, and maintaining a healthy weight. Symptomatic treatments, such as tonsil removal or corneal replacement surgery may be provided when needed. 

Careful monitoring for heart complications is also essential, so early detection and management of other atherosclerosis risk factors is fundamental. Direct relatives of individuals with Tangier disease are at higher risk due to the genetic inheritance and may undergo blood lipid tests for early identification.