Overview

Tangier Disease (TD) is a rare genetic condition that throws a spanner into the works of the body's cholesterol regulation system. Those who suffer from this condition have extremely low levels of high-density lipoprotein (HDL), often referred to as "good cholesterol," which plays a pivotal role in controlling levels of cholesterol. With inadequate HDL, cholesterol builds up in tissues and contributes to a multitude of diseases.¹ Tangier Disease is the title of this tale, which began in 1960. Dr. Donald Frederickson and his team met a 5-year-old boy from Tangier Island, a small town located in the Chesapeake Bay. The boy possessed one remarkable feature, his tonsils were large and yellow-orange in colour. When the doctors visited his home, they found his sister to have the same unusual tonsils. Both of the siblings had tested positive for tonsils that were full of cholesteryl esters, a type of cholesterol, and their blood had almost zero HDL. These twins were the first acknowledged cases of what we now understand as Tangier Disease, named after the island where it was originally discovered.²

At the core of this illness is a mutation in the ABCA1 gene. The ABCA1 gene has the job of exporting cholesterol from cells and into HDL particles, which carry it to the liver for removal. When the ABCA1 gene is mutated, this function does not work, leading to cholesterol buildup in tissues and the near elimination of HDL from the blood.³

Here, we will discuss the reason why ABCA1 gene mutations cause Tangier Disease, the inheritance of the disease through genetics, and how it affects patients who have the disease. The more we know about the biology of this rare disorder, the better we can appreciate the intricacy of the disease and the potential of ongoing research.

What does ABCA1 do?

The ABCA1 protein acts as a "cholesterol delivery driver". It absorbs excess cholesterol (referred to as free cholesterol, FC) from cells, such as macrophages, and loads it onto nascent HDL particles. These particles are formed with the help of a protein called apoA-I, which forms the framework of HDL. Think of apoA-I as the "scaffold" that holds the HDL particle in position, allowing it to carry cholesterol.

Once it is loaded, the cholesterol is esterified to cholesteryl esters (CE) by the LCAT enzyme that matures the newly formed HDL. Mature HDL is taken to the liver, where it exports cholesterol for excretion into bile. The process is called reverse cholesterol transport (RCT) and keeps cholesterol in equilibrium and prevents harmful accumulation in tissues. Refer to Figure 1 for illustration.⁴

But in Tangier Disease, ABCA1 doesn't work properly. Cholesterol builds up inside cells, and immune cells called macrophages become "foam cells" and cause tissue damage and inflammation. Without functioning ABCA1, the body can't produce enough HDL, which leads to Tangier Disease symptoms.⁵

Figure: ABCA1 protein plays the most crucial role in the metabolism of HDL (good cholesterol) and reverse cholesterol transport (RCT), a process that removes excess cholesterol from tissues and delivers it to the liver to be excreted. ABCA1 specifically mediates the transport of cholesterol out of cells onto an apoA-I protein, the main protein in HDL. Certain principal players in this process are LCAT (a protein that plays the role of altering cholesterol) and SR-BI (a receptor which helps the transport of cholesterol). These two molecules deal with the management of cholesterol and the removal of the body. Adapted from Alshaikhli A. et al..⁶

Inheritance and effects of ABCA1 gene mutations

Tangier Disease follows an autosomal recessive pattern of inheritance; a person will need to inherit two faulty copies of the ABCA1 gene, one from each parent, to fall ill. People with a single faulty copy are "carriers," usually having less severe symptoms and less than normal HDL ("good cholesterol").

Faulty ABCA1 gene mutations inhibit its action in exporting cholesterol from the cells, the consequence:^7,8

• Severely low HDL cholesterol: HDL is almost absent, a characteristic of Tangier Disease
• Cholesterol storage in tissues: It causes many symptoms like damage to nerves, swelling of the liver and spleen (hepatosplenomegaly), corneal opacification, and susceptibility to heart disease
• Formation of foam cells: Immune cells, macrophages, try to eliminate the excess cholesterol but end up as foam cells, which cause premature atherosclerosis (arterial hardening) and nerve problems (peripheral neuropathy)

Understanding these genetic effects is crucial for early diagnosis and control. Carrier identification and affected individuals allow preventive measures, including lifestyle change and medical monitoring, to reduce complications.

Symptoms of tangier disease

Tangier Disease presents in several ways based on the site where cholesterol accumulates within the body. Most often, it begins early in childhood with several of the initial presenting features, including swollen yellow-orange tonsils secondary to cholesterol deposition. Here's an outline of the major features:^9,10

Oral cavity

Tonsils enlarged by cholesterol deposits, so they appear yellow-orange. The swelling in this setting is commonly among the very first presentation and presentation noticed by physicians, particularly among children.

Heart and blood vessels

• Early Heart Disease: People with Tangier Disease are at risk of heart attacks, strokes, and other heart diseases at a young age
• Heart Valve Complications: In some cases, cholesterol deposits in the heart valves cause further complications

Nervous system

Neurological Damage: Cholesterol deposition in nerve cells results in:

• Loss of Sensation: Mainly in the arms and hands
• Tingling and Numbness: Usually in the hands and feet
• Muscle Weakness: Making it harder to get around

Eyes

• Cloudy Corneas: Slight clouding of the cornea that usually does not affect vision
• Eyelid Problems: The eyelids may turn outward (ectropion), causing discomfort

Liver and spleen

• Enlarged Liver and Spleen: Cholesterol deposits cause these organs to swell, resulting in abdominal pain
• Low Platelets: Swelling of the spleen can lead to a low platelet count, making it harder to stop bleeding

Pancreas

Diabetes: Pancreatic fatty deposits may interfere with insulin production and lead to diabetes.

Blood problems

• Anaemia: Red blood cells may degenerate early, leading to fatigue.
• Abnormal Red Blood Cells: Some red blood cells can be abnormally shaped (stomatocytosis).

Other symptoms

• Abdominal Pain: Typically due to an enlarged liver or spleen
• Skin and Nail Changes: Dry skin and brittle nails
• Facial Weakness: Some people have weakness or paralysis of facial muscles

Diagnostic methods

Diagnosis of Tangier Disease starts with some key pointers in the blood. Doctors look for:^11,12

• Extremely low HDL cholesterol: Typically less than 5 mg/dL (normal is far higher)
• Low total cholesterol: Typically less than 150 mg/dL
• Normal or slightly higher triglycerides: In contrast to other lipid diseases, triglycerides are not usually high in Tangier Disease
• Decreased apoA-I and apoA-II levels: They are crucial to the HDL structure, and they are at very low levels in Tangier Disease

These findings on their own, however, are not enough to make the diagnosis. To confirm, doctors need to look elsewhere.

Genetic testing: The gold standard

The most absolute way to diagnose Tangier Disease is through genetic testing to search for mutations in the ABCA1 gene, which carries cholesterol. Because the ABCA1 gene is large and complex, this is hard and expensive testing, but it's the best way to definitely diagnose the disease.

Other tests to rule it out

To help with the diagnosis, doctors may use two specialised tests:

1. Two-dimensional electrophoresis: This is a blood test that separates proteins to look for abnormal HDL particles. In Tangier Disease, only one type of HDL particle (preβ1-HDL) exists, unlike in normal individuals
2. Cholesterol efflux assay: A measurement of the efficiency with which fibroblasts (skin cells) export cholesterol. In Tangier Disease, this pathway is impaired. But it may also be impaired in other conditions, like Niemann-Pick Type C disease, so this measurement is not Tangier Disease specific

Briefly, Tangier Disease diagnosis involves a combination of blood tests, gene testing, and speciality laboratory tests to detect ABCA1 gene mutations and the typical cholesterol transport issues of the illness.

How is tangier disease treated?

There is no cure for Tangier Disease yet, but treatment focuses on managing symptoms and reducing complications. Here's what doctors typically recommend:

Lifestyle changes

• Daily Exercise: Mild exercises like walking, swimming, or cycling will boost overall well-being and HDL
• Eat Heart-Healthy Diet: Replace saturated fats (butter) with more beneficial counterparts (olive oil) and focus on whole grains, fruit, and vegetables
• Quit Smoking: Cigarette smoking lowers HDL levels, so quitting smoking will thereby enhance the balance of cholesterol
• Healthy Weight: Losing weight can decrease the burden on your heart and improve cholesterol levels

These modifications can also alleviate symptoms such as peripheral neuropathy (nerve damage), making everyday life more manageable.

Medications

No medication directly addresses low HDL levels, but physicians can prescribe medications to treat cholesterol and minimise complications, such as statins, Niacin and Fibrates. These medications are often given together, depending on the patient.

Treating specific symptoms

• Tonsillectomy: When tonsils are large and there is breathing trouble, tonsillectomy may be done
• Corneal Transplant: When severe corneal clouding blurs vision, a transplant may be done
• Braiding and Physical Therapy: For peripheral neuropathy (nerve damage), these may help improve mobility and reduce pain
• High-Impact Activity Avoidance: If the spleen is enlarged, not engaging in sports that can damage it (contact sports) is required to prevent rupture

The big picture

Although Tangier Disease can't be cured yet, these interventions can reduce symptoms and enhance the quality of life. Scientists also look for novel treatments, such as gene therapy, which in the future will provide more precise solutions.⁹

Summary

Tangier Disease, due to mutations in the ABCA1 gene, is a severe and uncommon disease that disrupts cholesterol balance, leading to presentations like orange tonsils of enlarged size, nerve damage, and enhanced risk for heart disease. Though a cure is yet to be found, recent advances in genetic testing, lifestyle modification, and experimental interventions like gene therapy hold promise for better control and future evolution.

Early awareness and detection are critical. Education about the genetic causes of Tangier Disease and supporting research will improve lives and advance towards better treatments. We must keep sharing awareness and pleading for early detection.