Tangier Disease: Causes, Symptoms and Risks

Tangier Disease is a rare genetic disorder characterized by extremely low levels of high-density lipoprotein (HDL) cholesterol, also known as “good cholesterol.” It is caused by mutations in the ABCA1 gene, which impair the body’s ability to transport cholesterol out of cells. This leads to cholesterol buildup in tissues such as the liver, spleen, tonsils, and lymph nodes. The condition was first discovered on Tangier Island, near the coast of Virginia, but cases have since been identified worldwide.¹Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839
Only a few cases of this rare disease have been reported worldwide, with approximately 100 individuals diagnosed since 1961.²Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: epidemiology, pathophysiology, and management. Am J Cardiovasc Drugs. 2012 Oct 01;12(5):303-11.

Symptoms of Tangier Disease

Symptoms of Tangier disease differ from person to person, depending on where the fatty deposits settle or which organs are involved and the severity of those manifestations. Swollen, yellow or orange tonsils are one of the classic symptoms of Tangier disease. Other symptoms include enlarged lymph nodes, liver (hepatomegaly), spleen (splenomegaly), or tonsils. Tangier disease may also be associated with an increased risk of cardiovascular disease, mild triglyceride elevation (hypertriglyceridemia) and nervous system abnormalities (neuropathy).³Raj, S. R., Chen, W., Sheldon, R. S., Shah, A. N., Kantharia, B. K., Salzer, U., … Kempf, W. (2009). Tangier Disease. Springer EBooks, 2022–2024. https://doi.org/10.1007/978-3-540-29676-8_1712 In rare cases, corneal clouding occurs, but it is generally mild and does not cause vision impairment.⁴Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839

Other Signs & Symptoms:

• Abdominal pain or nausea
• Atherosclerosis (plaque buildup in arteries)
• Peripheral neuropathy (fat deposits in nerves leading to numbness or sensory disturbances)
• Chronic dry skin
• Type 2 diabetes
• Persistent lymph node swelling unrelated to infection
• Ectropion (eyelid turning outward)
• Anemia
• Muscle weakness in the arms, legs, hands, or feet
• Discoloration in parts of the digestive tract (rectum and large intestine)

Symptoms can appear at any time from shortly after birth to age 65.⁵PMC, E. (2019). Europe PMC. Retrieved September 23, 2023, from europepmc.org website: https://europepmc.org/article/nbk/nbk549920⁶Geller, A. S., Polisecki, E. Y., Diffenderfer, M. R., Asztalos, B. F., Karathanasis, S. K., Hegele, R. A., & Schaefer, E. J. (2018). Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. Journal of Lipid Research, 59(12), 2421–2435. https://doi.org/10.1194/jlr.m088203

What Causes Tangier Disease?

Mutations in the ABCA1 gene (9q31), which codes for the ATP-binding cassette transporter A1 (ABCA1), cause Tangier disease. This gene provides instructions for a protein that helps cells release cholesterol and phospholipids. They are utilized in the production of HDL (high-density lipoprotein), which carries them to the liver. ABCA1 gene mutations prevent the release of phospholipids and cholesterol from cells. Due to the accumulation of these compounds within cells, certain bodily tissues enlarge, and the tonsils acquire a yellowish-orange color. Excess cholesterol can be toxic to cells, leading to cellular damage or death.⁷Geller, A. S., Polisecki, E. Y., Diffenderfer, M. R., Asztalos, B. F., Karathanasis, S. K., Hegele, R. A., & Schaefer, E. J. (2018). Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. Journal of Lipid Research, 59(12), 2421–2435. https://doi.org/10.1194/jlr.m088203

Furthermore, the inability to transport phospholipids and cholesterol out of the cells leads to extremely low HDL (high-density lipoprotein) levels, which increases the risk of cardiovascular (heart) disease.⁸Mercan, M., Yayla, V., Altinay, S., & Seyhan, S. (2018). Peripheral neuropathy in Tangier disease: A literature review and assessment. Journal of the Peripheral Nervous System, 23(2), 88–98. https://doi.org/10.1111/jns.12265

How is Tangier Disease Inherited?

Tangier disease is inherited in an autosomal recessive manner. This means that an affected individual must inherit two mutated copies of the ABCA1 gene, one from each parent. Carriers—individuals with only one mutated copy—typically do not show signs or symptoms of the disease.

Individuals inherit Tangier disease (TD) when they receive two defective copies of the ABCA1 gene, one from each parent. The ABCA1 gene is responsible for producing a protein that helps transport cholesterol out of cells and into high-density lipoprotein (HDL). HDL is responsible for carrying cholesterol to the liver for removal. When this gene is mutated, the body is unable to effectively transport cholesterol, leading to cholesterol buildup in tissues and extremely low HDL levels.⁹Fasano, T., Zanoni, P., Rabacchi, C., Pisciotta, L., Favari, E., Adorni, M. P., … Calandra, S. (2012). Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency. Molecular Genetics and Metabolism, 107(3), 534–541. https://doi.org/10.1016/j.ymgme.2012.08.005

Role of Genetics

• If both parents carry one mutated copy of the ABCA1 gene, there is a 25% chance (1 in 4) that their child will inherit both mutated copies and develop Tangier disease.
• There is a 50% chance (2 in 4) that the child will inherit only one mutated copy of the ABCA1 gene, making them a carrier like their parents but without symptoms.
• Lastly, there is a 25% chance (1 in 4) that the child will inherit two normal copies of the ABCA1 gene and be completely unaffected.
• These probabilities remain the same for each pregnancy, regardless of the baby’s sex.¹⁰Hooper, A. J., Hegele, R. A., & Burnett, J. R. (2020). Tangier disease. Current Opinion in Lipidology, 31(2), 80–84. https://doi.org/10.1097/mol.0000000000000669

How to diagnose Tangier Disease?

Diagnosis of Tangier disease is achieved through clinical evaluation and can be confirmed through genetic testing involving the sequencing of the abnormal ABCA1 gene. The primary diagnostic criteria include extremely low levels of HDL-C (high-density lipoprotein cholesterol) and apolipoprotein A1 (ApoA1).¹¹Koseki, M., Yamashita, S., Ogura, M., Ishigaki, Y., Ono, K., Tsukamoto, K., … Harada-Shiba, M. (2021). Current Diagnosis and Management of Tangier Disease. Journal of Atherosclerosis and Thrombosis, 28(8), 802–810. https://doi.org/10.5551/jat.rv17053
After a physical examination and blood tests measuring HDL-C levels, a doctor can determine if Tangier disease (TD) is likely. The diagnosis is confirmed by genetic testing. If genetic testing is unavailable, a tissue biopsy may be taken from different parts of the body to assess cholesterol buildup.

Additional Investigations

Tests that may help diagnose or monitor Tangier disease include:

• Abdominal ultrasound to check for organ enlargement
• CT angiogram to assess heart health
• Eye examination to detect corneal abnormalities
• Nerve and muscle studies (electromyograms) for neuropathy assessment
• Echocardiogram to evaluate heart function
• Carotid artery ultrasound to check for atherosclerosis
• Exercise stress test to assess cardiovascular risk

Treatment of Tangier Disease

There are no known specific treatments for this disease. Treatment of Tangier disease is supportive and based on specific disease manifestations in a given individual. Medications that typically raise HDL levels, such as estrogens, statins, nicotinic acid, or phenytoin, do not work in Tangier disease patients. To lower the risk of cardiovascular disease, individuals with TD should adopt a low-saturated-fat diet and a healthy lifestyle.

Cardiovascular risk factors include:¹²Low HDL Cholesterol (Hypoalphalipoproteinemia) Treatment & Management: Medical Care, Surgical Care, Consultations. (2023). EMedicine. Retrieved from https://emedicine.medscape.com/article/127943-treatment#showall

• Smoking
• High blood pressure
• Diabetes
• Obesity
• High levels of triglycerides or homocysteine in the blood

These should receive prompt treatment. Triglyceride levels can be reduced with fibrates. Despite trials of omega-3 fatty acids, antioxidants, and vitamin E, there is currently no treatment to stop disease progression. Patients may benefit from referrals to specialized lipid clinics for advanced care.¹³Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839

Surgical removal of the spleen, tonsils, or other enlarged tissues may be necessary for some patients. Regular cardiovascular, neurological, and ophthalmological evaluations are recommended. Genetic counseling can help families understand the inheritance pattern and risks.¹⁴Low HDL Cholesterol (Hypoalphalipoproteinemia) Treatment & Management: Medical Care, Surgical Care, Consultations. (2023). EMedicine. Retrieved from https://emedicine.medscape.com/article/127943-treatment#showall

Medications used to help with Tangier Disease

Your doctor may prescribe cholesterol lowering drugs.
Doctors may also suggest lifestyle changes to improve your HDL( good cholesterol) level, such as:

• Not using tobacco products.
• Exercising often.
• Eating monounsaturated fat instead of the saturated type.
• Staying at a healthy weight¹⁵Tabacco, J., & Turgeon, L. (2023). Interpreting New Thoughts on HDL Through the Lens of Chesapeake Bay’s Tangier Disease. Journal of Community Hospital Internal Medicine Perspectives, 13(5). https://doi.org/10.55729/2000-9666.1243

What are the Side Effects of Treatment?

Side effects of medicines that lower your cholesterol (LDL) may include:

• Headache
• Constipation
• Muscle soreness
• Upset stomach

Dietary Modification for Tangier Disease

Certain foods may help increase HDL (good cholesterol) while lowering LDL (bad cholesterol):

• Avocados
• Beans
• Fruits that have a lot of fiber
• Whole grains
• Fatty fish
• Olive oil
• Nuts
• Chia seeds and flax seeds

Tangier Disease Prognosis

The prognosis is usually good and is mostly dependent on the presence of peripheral neuropathy and cardiovascular disease. Patients with severely low HDL cholesterol (<20 mg/dL) are at higher risk of coronary artery disease in adulthood and should undergo regular cardiovascular and neurological monitoring.¹⁶Liang, Z., Li, W., Yang, S., Liu, Z., Sun, X., Gao, X., & Yu, G. (2018). Tangier disease may cause early onset of atherosclerotic cerebral infarction. Medicine, 97(39), e12472. https://doi.org/10.1097/md.0000000000012472¹⁷Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839

How long does Tangier’s Disease last?

This disease is genetic. Therefore, you’ll have it for the rest of your life. Early detection and regular examinations can help you manage this disease.

Bottom lines

This disease is a rare genetic disorder. It can affect various parts of your body (tonsils, spleen, or liver) or cause heart diseases. Therefore, it’s important to receive regular checkups. Currently, there is no specific treatment for TD, and management focuses on addressing symptoms through lifestyle changes. Keep taking any medications your doctor has prescribed for you, and try your best to make food and exercise work for you.

Refrences

• 1
  Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839
• 2
  Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: epidemiology, pathophysiology, and management. Am J Cardiovasc Drugs. 2012 Oct 01;12(5):303-11.
• 3
  Raj, S. R., Chen, W., Sheldon, R. S., Shah, A. N., Kantharia, B. K., Salzer, U., … Kempf, W. (2009). Tangier Disease. Springer EBooks, 2022–2024. https://doi.org/10.1007/978-3-540-29676-8_1712
• 4
  Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839
• 5
  PMC, E. (2019). Europe PMC. Retrieved September 23, 2023, from europepmc.org website: https://europepmc.org/article/nbk/nbk549920
• 6
  Geller, A. S., Polisecki, E. Y., Diffenderfer, M. R., Asztalos, B. F., Karathanasis, S. K., Hegele, R. A., & Schaefer, E. J. (2018). Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. Journal of Lipid Research, 59(12), 2421–2435. https://doi.org/10.1194/jlr.m088203
• 7
  Geller, A. S., Polisecki, E. Y., Diffenderfer, M. R., Asztalos, B. F., Karathanasis, S. K., Hegele, R. A., & Schaefer, E. J. (2018). Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. Journal of Lipid Research, 59(12), 2421–2435. https://doi.org/10.1194/jlr.m088203
• 8
  Mercan, M., Yayla, V., Altinay, S., & Seyhan, S. (2018). Peripheral neuropathy in Tangier disease: A literature review and assessment. Journal of the Peripheral Nervous System, 23(2), 88–98. https://doi.org/10.1111/jns.12265
• 9
  Fasano, T., Zanoni, P., Rabacchi, C., Pisciotta, L., Favari, E., Adorni, M. P., … Calandra, S. (2012). Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency. Molecular Genetics and Metabolism, 107(3), 534–541. https://doi.org/10.1016/j.ymgme.2012.08.005
• 10
  Hooper, A. J., Hegele, R. A., & Burnett, J. R. (2020). Tangier disease. Current Opinion in Lipidology, 31(2), 80–84. https://doi.org/10.1097/mol.0000000000000669
• 11
  Koseki, M., Yamashita, S., Ogura, M., Ishigaki, Y., Ono, K., Tsukamoto, K., … Harada-Shiba, M. (2021). Current Diagnosis and Management of Tangier Disease. Journal of Atherosclerosis and Thrombosis, 28(8), 802–810. https://doi.org/10.5551/jat.rv17053
• 12
  Low HDL Cholesterol (Hypoalphalipoproteinemia) Treatment & Management: Medical Care, Surgical Care, Consultations. (2023). EMedicine. Retrieved from https://emedicine.medscape.com/article/127943-treatment#showall
• 13
  Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839
• 14
  Low HDL Cholesterol (Hypoalphalipoproteinemia) Treatment & Management: Medical Care, Surgical Care, Consultations. (2023). EMedicine. Retrieved from https://emedicine.medscape.com/article/127943-treatment#showall
• 15
  Tabacco, J., & Turgeon, L. (2023). Interpreting New Thoughts on HDL Through the Lens of Chesapeake Bay’s Tangier Disease. Journal of Community Hospital Internal Medicine Perspectives, 13(5). https://doi.org/10.55729/2000-9666.1243
• 16
  Liang, Z., Li, W., Yang, S., Liu, Z., Sun, X., Gao, X., & Yu, G. (2018). Tangier disease may cause early onset of atherosclerotic cerebral infarction. Medicine, 97(39), e12472. https://doi.org/10.1097/md.0000000000012472
• 17
  Puntoni, M., Sbrana, F., Bigazzi, F., & Sampietro, T. (2012). Tangier Disease. American Journal of Cardiovascular Drugs, 12(5), 303–311. https://doi.org/10.1007/BF03261839