What Is Tangier Disease

Overview

Tangier Disease was named after Tangier Island in Virginia, where it was first discovered. It is a rare genetic disease where the body has very little to none “good cholesterol” known as high-density lipoprotein (HDL). HDL is important because it helps carry “bad cholesterol” called low-density lipoprotein (LDL) and fats from the body tissues to the liver to get rid of them. The reduced HDL in Tangier disease happens because of a defective gene called ATP-binding cassette transporter A1 (ABCA1), which is responsible for the removal of cholesterol and phospholipids from cells. This results in very low HDL levels and an increased risk of heart disease. This genetic condition is inherited from both parents each passing on a defective gene  (autosomal recessive disorder).¹

This rare genetic disease has two main features:

• A low level of a “good cholesterol” high-density lipoprotein (HDL)
• Enlargement of the liver, spleen, lymph nodes, and tonsils, along with anomalies in various body parts like nerves, eyes, skin, nails, and sometimes the heart²

Causes and inheritance

Tangier Disease is inherited in an autosomal recessive manner, meaning that an individual must inherit two copies of the defective gene (one from each parent) to develop the disease. If only one defective gene is inherited, the individual becomes a carrier and may have lower levels of HDL, but may not show clinical manifestations of the disease.³

Individuals  have a:

• 25% chance of being unaffected by Tangier Disease
• 50% chance of being carriers
• 25% chance of being unaffected without inheriting the gene from either parent⁴

The ATP-Binding Cassette Transporter A1 (ABCA1) gene is responsible for producing a protein that plays a crucial role in the formation of HDL. Mutations in this gene disrupt the normal function of the protein, leading to the accumulation of LDL “bad cholesterol” in various tissues and the absence of functional HDL.^3,5
Cholesterol is a soft, waxy stuff in our blood and cells. It's important for making the body's cell walls, hormones, and other substances the body needs. Cholesterol and other fats need special carriers called lipoproteins to move around in the blood. The key ones are low-density lipoprotein (LDL) called the "bad cholesterol" and high-density lipoprotein called the "good cholesterol". In Tangier disease, there is a reduced level of HDL. With less HDL to clear artery clogs, there's a higher risk of fat building up in organs like the liver, brain, heart, spleen, and lymph nodes.

Clinical Features

There are varying clinical features of Tangier Disease.

•  Enlargement of organs like the liver (hepatomegaly), spleen (splenomegaly), and discoloured tonsils¹
• Neuropathy, which involves dysfunction of nerves⁶
• Atherosclerosis, which is the buildup of fatty deposits in artery walls⁴

Symptoms of tangier disease

Tangier Disease have a range of symptoms, depending on where the fatty deposits build up. These symptoms may include:

• Stomach pain or nausea⁷
• Plaque buildup in the arteries (atherosclerosis)
• Dry skin
• Eyelid turning inside out (ectropion)
• Anaemia⁴
• Muscle weakness in the arms, legs, hands, or feet
• Persistent lymph node swelling unrelated to infections⁷

Symptoms can manifest at any age, from early infancy to 65 years old. 

Diagnosis of tangier disease

Diagnosis of Tangier Disease involves a combination of clinical evaluation, laboratory tests, and genetic analysis. Blood tests can reveal low levels of HDL, apolipoprotein A1 (ApoA1), and cholesterol, while genetic testing can confirm the presence of mutations in the ABCA1 gene.

• Physical examination and blood tests⁴
• ABCA1 gene sequencing⁷(gold standard)
• Nerve and muscle tests (electromyograms)
• Eye examination
• Abdominal ultrasound
• Carotid artery ultrasound
• Heart CT angiogram
• Echocardiogram
• Exercise stress test Genetic testing⁴

Complications and associated conditions

• Tangier Disease increases the risk of cardiovascular complications , especially premature coronary artery disease⁴
• It can lead to atherosclerosis and artery narrowing resulting from reduced  HDL and abnormal fat processing⁴
• Tangier Disease can lead to complications like Cloudy eyes (corneal opacities), enlarged spleen ( splenomegaly), and  nerve disorders (peripheral neuropathy)¹

These complications can greatly affect a person's life and need suitable care.

Epidemiology

Tangier Disease is a rare disorder, with about 100 cases reported worldwide since its discovery. The prevalence of the disease is estimated to be 1 in 1,000,000. While Tangier Disease has been reported in individuals of different ethnic backgrounds, consanguinity marriages have been associated with an increased risk of developing the disease in subsequent generations.⁴

Treatment and management

At present, Tangier Disease has no cure, so the treatment is symptom management and risk reduction.

• Lifestyle changes such as maintaining a healthy diet, regular exercise, and avoiding smoking are essential for managing cardiovascular risk factors
• Medications might be recommended in certain instances to address complications or related conditions. For instance, lipid-lowering drugs can help regulate high triglyceride levels, and symptomatic relief may be offered for neuropathy or other associated symptoms. Although limited evidence is available for drug therapy effectiveness
• Tonsillectomy for enlarged tonsils¹
• Corneal transplantation for corneal opacities
• Bracing and exercise for peripheral neuropathy
• Caution to avoid high-impact activities to prevent splenic rupture if there's splenomegaly¹

Researchers are working to uncover how Tangier Disease works and find ways to treat it. They're looking into ways to improve cholesterol and HDL metabolism. Also, progress in genetic testing and understanding the genetics behind Tangier Disease may lead to better ways to diagnose and provide genetic advice for those affected and their families.^{7, 4}

Differential diagnosis of Tangier Disease

There are other inherited diseases characterized by low HDL and peripheral neuropathy,  similar to Tangier disease. These include:

• Familial HDL deficiency 
• Abetalipoproteinemia Niemann-Pick disease 
• Familial lecithin-cholesterol acyltransferase deficiency
• Fish-eye diseaseCharcot-Marie-Tooth Disease^7,6

FAQ

How common is Tangier disease?

Tangier disease is a rare condition, with roughly 100 cases worldwide, however there may be more undiagnosed cases. The name comes from an island near Virginia, where the first affected individuals were discovered.

How to prevent Tangier disease?

Tangier disease can be prevented by eating low-fat diets, and genetic testing in cases of known history in the family.⁴

How long does one live with Tangier Disease?

Tangier disease is a lifelong condition since it's inherited. Early diagnosis and regular checkups can assist in its management.

When is it important to visit your healthcare provider?

Regular appointments are vital to ensure the prompt detection and management of any deteriorating symptoms. During these check-ups, your healthcare provider will routinely assess your nervous system, heart, and eyes.

What can I eat with Tangier Disease?

Patients with Tangier disease can benefit from foods that contain omega-3 fatty acids. These foods can help raise the good cholesterol (HDL) and lower the bad cholesterol (LDL). Some good options include olive oil, whole grains, beans, fruits with high fibre, fatty fish, flax and chia seeds, nuts, and avocados.⁷

Summary

Tangier Disease is a rare genetic disorder characterized by abnormally low levels of high-density lipoprotein (HDL), often referred to as "good cholesterol." This condition is caused by mutations in the ABCA1 gene, which affects the body's ability to remove cholesterol and fats. Individuals with Tangier Disease are at increased risk of developing cardiovascular complications, including premature coronary artery disease, due to atherosclerosis.

Symptoms of Tangier Disease can vary and may include peripheral neuropathy, corneal opacities, enlarged organs (hepatomegaly, splenomegaly), and other health disorders. Management involves lifestyle modifications, such as exercise and a low-fat diet, as well as potential medication to address specific symptoms and complications. Genetic counselling is important for families affected by Tangier Disease, and ongoing research aims to improve understanding, diagnosis, and potential treatments for this rare condition. Support groups and patient organizations offer valuable resources and community for those affected by Tangier Disease.