Tangier disease: Overview

The first documented cases of Tangier Disease (TD) occurred in 1961 on the island of Tangier in the state of Virginia, hence the name.¹ TD is a genetic condition characterised by a severe deficiency of high-density lipoproteins (HDL), also known as ‘good cholesterol’, which helps move and break down other fats. Without ample HDL, it results in the buildup of cholesterol throughout the body, including internal organs.² This can cause yellowish discolouration and abnormal size of various organs and tissues, such as the tonsils and liver. 

TD is caused by a mutation in the ABCA1 gene, a gene responsible for a protein found in the membrane of your cells that helps transport molecules across the cellular membrane. Therefore, a mutation in this gene prevents this movement, causing cholesterol and other fats like triglycerides to accumulate in cells throughout the body. This creates a dysfunctional cellular environment whereby tissues and organs slowly deteriorate until they eventually die.¹

Diagnosing TD 

TD is extremely rare, as there have been only 150 reported cases worldwide since first discovered in 1961. However, scientists predict that TD’s prevalence is more likely around 1 in 640,000 people when considering the allele frequency (likelihood of the faulty ABCA1 gene occurring) in a given population.³

The lack of clinical diagnoses in TD emphasises the need to improve our understanding of the condition. Enabling us to enhance diagnosis and successfully treat the condition. 

The clinical features of TD are listed below: 

• Large, yellow-orange tonsils 
• Hepatosplenomegaly - An abnormally large liver and spleen
• Peripheral neuropathy
• Very low HDL levels in the blood

Diagnosing TD can prove difficult due to the large number of other lipid disorders that present with similar symptoms, including a deficiency of HDL in blood test results. Ultimately, diagnosis of TD requires genetic analysis of the ABCA1 gene sequence in the individual.⁴ However, this is a time-consuming and costly process; hence, simpler tests have been developed to help in the diagnosis of this condition. These include investigating how efficiently cells allow cholesterol to pass through their membranes (cholesterol efflux assay) and determining which specific HDL particles are present within the blood, as people with TD will have a majority of pre-beta HDL, rather than alpha-HDL.⁴

The low number of confirmed TD cases makes it hard to discuss the epidemiology (how it is spread, controlled, and prevented) of this condition. So far, no conclusions can be made as to whether TD affects one gender more than the other, or if particular ages or ethnicities are more susceptible. 

Additionally, there is currently no specific treatment for TD, and most work on the symptoms, not the root cause of the condition. Approaches to treating TD are aimed at reducing the buildup of cholesterol in the body by encouraging regular exercise, a healthy diet that is very low in fat, and discouraging smoking in those affected.⁵ For example, maintaining a low-fat diet in TD is thought to reduce the chances of developing fatty liver disease.⁴ Overall, the treatment for TD is more focused on tackling and monitoring the long-term consequences of TD, such as a fatty liver and heart disease.⁵

Overview of other major lipid disorders

Many other known conditions affect lipid production and function around the body. These conditions can be hard to differentiate from each other and TD due to symptoms overlapping and them sharing similar long-term implications. However, there are subtle characteristics that set them apart. 

The differences used by clinicians to distinguish them from each other are described below;

Familial Hypercholesterolemia (FHC)

This condition affects 1 in 250 people, making it more common than TD. FHC is caused by a genetic mutation that prevents the liver from removing low-density lipoprotein (LDL), which is known as ‘bad cholesterol’.⁶ The level of LDL in the blood, therefore, gradually increases, causing it to accumulate in arterial walls, slowing the flow of blood and increasing the risk of blood clots and heart disease. FHC is caused by a mutation in one gene that has been linked to the low-density lipoprotein receptor (LDLR). 

The accumulation of LDL starts from birth due to these mutations, and this can cause a major increase in the risk of coronary heart disease, strokes, and peripheral vascular disease.⁸ Clinical indications of FHC include swelling of the knuckles, achilles tendon, or swelling of the knees (tendon xanthomata), small yellow lumps around the eye (xanthelasmas), and a white ring around the iris (corneal arcus).⁶

Familial Combined Hyperlipidemia (FCHL)

FCHL causes high levels of total cholesterol, triglycerides, and LDL, and unfortunately, low levels of HDL.⁹ It is one of the most common lipid disorders, affecting around 1 in 100 people.¹⁰ The genetic basis behind this disease is not yet fully understood, as it has a complex inheritance pattern with variable physical presentations (phenotypes).⁹

Unlike other lipid disorders, few physical signs can be observed in those with FCHL, with swelling of the tendons being a rarely found symptom. Despite this, the abnormal lipid levels can still cause an increased risk of cardiovascular disease, strokes, or early death.⁹ Furthermore, those affected may display chest pains, breathing difficulties, and find that their legs are painful when walking. It is important for clinicians to gain a detailed history of family members' conditions and health status when diagnosing FCHL, as well as looking out for risk factors such as diabetes and obesity. 

Familial Hypertriglyceridemia (FHT)

FHT is classified by elevated triglyceride (fat) levels in the blood due to an increase in the production of LDL and less efficient clearance of these molecules. FHT is caused by a mutation in the LPL gene, which prevents the breakdown of triglycerides, leading to their buildup. It is an autosomal dominant condition, meaning that it is passed down if one parent has the faulty gene that codes for this condition.¹¹ It tends to be present in patients alongside other conditions such as obesity or having high blood sugar (hyperglycemia). In very serious cases, FHT can increase the risk of pancreatitis. 

Clinical signs of this condition include yellow raised bumps on the skin (xanthomas), which can occur anywhere on the body, as well as an enlarged liver and abnormal appearance of the veins and arteries in the retina (lipemia retinalis). A family history of FHT can help aid in the diagnosis of this condition.¹¹

Comparative analysis: Tangier disease vs. other lipid disorders

Lipoprotein profile differences

One of the most efficient ways lipid disorders can be distinguished from one another is by looking into the different concentrations of lipids present within the body.¹² This allows clinicians to determine which metabolic processes are being affected, so they can make conclusions about what type of lipid disorder is present in any one individual. Lipid disorders can cause levels of total cholesterol, HDL, LDL, or triglycerides to be abnormal. This can be due to overproduction, underproduction, or a disruption of the processes involved in clearing these molecules from the body. Below outlines the distinguishing changes in lipid concentrations for the lipid disorders discussed in this article;

• TD - Low HDL
• FHC - High LDL
• FCHL - High total cholesterol, triglycerides & LDL. Low HDL.
• FHT - High triglycerides & LDL.

Genetic basis

Some lipid disorders have been linked to certain genetic mutations, making them easier to diagnose and therefore treat effectively. This is done by carefully mapping the genomes of those with lipid disorders and comparing them to healthy individuals' genomes to identify he specific genes associated with each condition.

Since 2021, a genetic therapy called Inclisiran has been used to treat FHC by preventing the production of the faulty enzyme PCSK9.¹³ However, no similar treatment has been developed for TD, even though the faulty gene (ABCA1) has been identified. Due to the lack of documentation of TD and its rarity, little effort has been put into developing gene therapies, but new genetic variants of the condition have been discovered more recently.¹⁴ This helps scientists gain a more comprehensive understanding of the exact ways in which the ABCA1 mutation affects the body.

Clinical presentation

The varying clinical presentations that arise as a result of abnormal lipid concentrations can be useful in determining which disorder is present. If there is too much cholesterol within the body, it accumulates and forms fat deposits. This happens specifically in the tonsils in TD, whereas in other lipid disorders it occurs in less localised regions (commonly around the eyes and the joints). The eyes can also be affected by lipid disorder, with FHT affecting the vascular systems, and FHC affecting the appearance of the iris. These are other useful, unique indicators that can help with diagnosis. Another clinical presentation specific to TD is peripheral neuropathy, whereby the extremities are damaged and lose feeling. 

Treatment and management of lipid disorders

Treatment of lipid disorders involves a multifactorial approach. Lifestyle changes, medications, and close monitoring are required.¹² The most commonly used medications that help reduce the risk of heart failure and strokes are called statins. These drugs are useful in lowering LDL and can also be helpful in lowering triglycerides. However, these drugs are not useful in the context of TD, as this is characterised by low HDL levels, which statins do not affect. 

Improving diet and exercise has also been linked to improved outcomes for those suffering from lipid disorders. Increasing the amount of exercise and lowering intake of saturated fats can reduce obesity and help with lowering cholesterol levels.

Summary

The presence of yellow tonsils, low HDL concentrations, and a specific mutation in the ABCA1 gene all indicate TD. If abnormal levels of LDL and triglycerides are present, this likely indicates an alternative lipid disorder. Early diagnosis and a tailored treatment plan, including an emphasis on diet and lifestyle changes, are all key in the successful management of TD as well as other lipid disorders. 

Common lipid disorders are well documented and understood, and advancements in gene therapies and medications are improving the quality of life for those affected. For rarer lipid disorders such as TD, better diagnoses and awareness of this disorder are required, as advancements in treatment options are slow.