Introduction

Tangier disease (TD) was first identified by a Navy medical doctor on the Tangier Island, located in Virginia, United States.¹ A medical doctor was assessing a 5-year-old boy who had enlarged yellow-orange tonsils, enlarged spleen and liver aka hepatosplenomegaly, as well as some signs of nerve damage that pointed towards peripheral neuropathy.² In 1961 it was first described in a paper after two siblings had it and from then it inherited the island's name.³

TD is a recessive genetic disorder caused by the deficiency or absence of good cholesterol, the more scientific term being high-density lipoproteins (HDL). This occurs when there is a mutation in the ABCA1 gene, which is a vital gene involved in creating HDL particles from phospholipids and cellular cholesterol.⁴ Although it is a rare disease where only 1 in 1,000,000 it's important to be able to identify TD to manage the consequential symptoms that occur such as chronic health issues and organ dysfunction. 

Chronic health issues

• Corneal opacities: occur as cholesterol deposits into the eyes which directly affects the light that comes into the eyes so when the corneas (the outer part of the eye) should be transparent, it would be opaque instead,⁵ therefore affecting the corneas function however it doesn't typically have a detrimental effect on vision, the build-up can also cause decreased corneal sensation and scarring of the skin or orbicularis muscle 
• Tonsillar enlargement: Tonsils are normally around the size of an olive, however when the tonsils become bigger, they are put into categories starting from grade 1 where the tonsils aren't visible to grade 4 where the tonsils are touching each other.⁶ This poses a chronic health issue as it makes it harder to breathe due to the airways being blocked which can cause snoring or stopping breathing for a short period whilst sleeping which can affect the quality of sleep⁷
• Infection susceptibility: Due to the excess deposit of cholesterol affecting multiple organs, it compromises the immune function. Abnormal amounts of fat being built up, it impairs the immune cells to respond effectively to pathogens which can cause chronic respiratory or systemic infections
  • Metabolic Complications (Defective ABCA1 protein): ABCA1 protein is created by the ABCA1 gene, its key role is to move cholesterol out of tissue cells and when there is a mutation in the gene, the cholesterol builds up in the cells as cholesterol esters and the ‘good’ cholesterol count (HDL) lowers in the blood Which affects platelets when it is observed under the microscope it would look abnormal and would produce less thromboxane A2⁸ which allows platelets to stick together to make blood clots. Not only does it cause an imbalance in cholesterol levels but it also affects how well blood clot
  • Blood disorder (thrombocytopenia): The enlargement of the spleen can cause thrombocytopenia which means that the platelet count is too low so when someone is injured it takes longer to create a protective layer around the wound which stops infections from entering the body
  • Lymphadenopathy: Lymph nodes can also swell up which affects the lymphatic system, this system is involved in filtering extra lymph from the body. Defending the body against infections is one of the roles of the lymphatic system as well as immune inspection⁹

Organ dysfunction

• Hepatosplenomegaly: As mentioned earlier, hepatomegaly was one of the first physical identifications that was linked to TD, but what is it? It's the enlargement of the spleen (lymphoid organ) and the liver caused by the defective cholesterol transport that causes an accumulation of cholesterol as there is nothing to manage the excess cholesterol causing the increase in size.¹¹ A physical examination only hits the surface as there could be closed sacs of fluids (cysts) or abnormal growth on the spleen or the liver which can only be accurately identified through imaging. The involvement of spleen can also lead to thrombocytopenia
• Neuropathy: TD is also linked to neuropathy, which consists of disorders of the nerve cells and fibers. Because of TD, cholesterol builds up in the Schwann cells which trigger neuropathy in TD.¹² Schwann Cells are a protective layer around the nerve providing insulation and nutrients to axons. Axons are thin fibers that connect to nerve cells to allow for communication, if there is no communication the body would not be able to process things that could potentially protect you, such as touching a hot stove, naturally you would flinch when you touch something hot as your nerve cells have communicated with each other and it sent a message that you hurt yourself and need to protect yourself, therefore to cause further harm you would flinch away from the stove. However, if there is something in the way of communication, you should keep your hand on the stove. The neurons have not communicated to your pain receptors, so essentially you don't feel the pain. You become desensitised. In the case of TD, it can range from loss of temperature sensation and pain, to muscle weakness or numbness and tingling¹³
• Cardiovascular complications: TD has also been linked to cardiovascular complications in some patients. When there are high levels of low-density lipoprotein (LDL) cholesterol - the bad cholesterol and low levels of HDL - the good cholesterol then there is a risk of atherosclerosis which is a buildup of cholesterol on the artery walls that can cause coronary artery disease,¹⁴ a stroke or heart attack as sufficient blood is not being pumped around the body and reaching the heart
• Gastrointestinal issues: There was a recent finding that could suggest that Tangier caused chronic diarrhea as a test on a 52-year-old man who was suffering from it and from the tests that were shown nothing was prevalent other than the fact that he was suffering from Tangier disease.¹⁵ As there is a buildup of cholesterol in the liver it can cause abdominal pains and diarrhea as the liver is no longer functioning as usual as the liver is involved in the digestion, metabolism, elimination of substances and detoxification in the body.¹⁶ The pancreas is also affected as fat is deposited inside Alpha cells of the pancreas, alpha cells secrete the hormone glucagon which increases blood glucose levels by stimulating the liver to release stored glucose however, as mentioned before the liver is not working as usual, due to the impairments it has also been reported to be linked to diabetes 

FAQs

What are the early symptoms of TD?

Early symptoms include yellow-orange tonsils, neuropathy (numbness and tingling), and an enlarged liver or spleen.

Is there a cure for TD?

No, there is currently no cure, but symptoms can be managed with proper medical care and lifestyle changes

Is TD life-threatening?

Even though it isn't necessarily life-threatening, it raises the risk of cardiovascular disease, which can be deadly if left untreated.

What lifestyle changes can help manage symptoms?

Complications can be avoided with a heart-healthy diet, consistent exercise, and careful cardiovascular health monitoring.

Summary 

The ABCA1 gene, which is essential for the production of high-density lipoproteins (HDL), or "good" cholesterol, is mutated in Tangier Disease (TD), a rare hereditary condition that was initially discovered on Tangier Island, Virginia. Lack of HDL or a sharp decline in HDL causes cholesterol to build up in different tissues and organs, which can lead to a number of chronic health problems and organ dysfunction. 

Peripheral neuropathy, hepatosplenomegaly (enlarged liver and spleen), and enlarged yellow-orange tonsils are typical symptoms. Corneal opacities, enlarged lymph nodes, immune system dysfunction that increases vulnerability to infections, metabolic problems brought on by impaired cholesterol transport, and blood diseases including thrombocytopenia are additional long-term consequences. 

Cholesterol accumulation in nerve cells causes neurological symptoms including numbness, tingling, and muscle weakness, while excessive cholesterol levels cause cardiovascular problems like an increased risk of atherosclerosis, stroke, and heart attack. Cholesterol buildup in the liver and pancreas has also been connected to gastrointestinal problems such as persistent diarrhoea, stomach pain, and even diabetes. Despite the fact that Tangier Disease only affects roughly 1 in a million people, managing its extensive and frequently worsening symptoms requires early detection.