Introduction

Tangier disease is a rare genetic condition inherited through parental genetic mutations. It can be defined by the alarmingly low levels of high-density lipoprotein (HDL), otherwise known as good cholesterol. This causes enlarged organs due to a build-up of cholesterol esters. A person can become at risk for several complications throughout the body, such as cardiovascular disease and nerve and cornea damage. Hence, it is essential to understand this disorder to ensure early diagnosis and treatment. This article will explore the genetic mutations and their subsequent inheritance patterns.¹

What is tangier disease?

In our diet, we have good and bad cholesterol. HDL is known as good cholesterol, as it is responsible for removing bad cholesterol from the blood. Low-density lipoprotein (LDL) is the bad cholesterol that builds up in blood vessels, leading to heart disease or stroke. Tangier disease lowers HDL levels and causes the accumulation of LDL in the vital organs.

This has several symptoms and clinical manifestations: 

• The outer layer of the eye (the cornea) may become cloudy
• Tonsils are enlarged and appear yellow-orange
• Liver enlargement
• Spleen enlargement
• Lymph nodes swell up
• Nerve damage causing numbness, tingling or weakness
• Risk of heart disease/ stroke
• Mild hypertriglyceridemia - elevated levels of fat in the blood
• Type 2 diabetes¹

Tangier disease is a rare occurrence with approximately 100 cases since 1961. There has been little evidence showing race has any impact. Some instances showed that married couples with blood relations showed an increased likelihood of their offspring developing Tangier disease. Despite the lack of knowledge, we know this condition is passed by genetic mutation from parents to the child.²

Inheritance pattern of tangier disease

Patients with Tangier disease inherit both mutated recessive genes from their parents. This is an autosomal recessive condition; two copies of the mutated gene are required for the disease to take place.

Autosomal tells us the location of the gene affected is not on sex chromosomes. It is found within one of the 46 chromosomes we inherit from our parents: 23 chromosomes from each parent's sperm and egg. Autosomal recessive conditions can pass through families for years undetected, as carriers show no symptoms.  Unaffected parents are carriers. They have one mutated and one normal copy of the gene.

If both parents are carriers, there is a 25% chance that the offspring will inherit two copies of the mutated gene, therefore developing Tangier disease. There is a 50% chance that the child will be a carrier with only one copy of the mutated gene. Or a 25% chance of inheriting two normal copies of the gene. These statistics show a 75% chance of no disease manifestation. This makes Tangier disease a rare occurrence.³

Genetic mutations leading to tangier disease

Patients with the two recessive genes of Tangier disease exhibit low HDL levels. The 9q31 chromosome holds the ATP-binding cassette transporter (ABCA-1) gene, which controls the cellular pathway of cholesterol and phospholipids. It does so by moving excess cholesterol to the cell surface. Then, the liver eliminates the bad cholesterol. Furthermore, ABCA-1 is crucial for forming new HDL particles, which can lower the risk of cardiovascular disease.⁴

The mutation of ABCA-1 occurs in the non-coding region of the gene, the introns. The mutation at position intron 12 activated the splicing site on exon 13, the coding region of ABCA-1. This produced a mutated ABCA-1 with 22 fewer amino acids and a premature stop codon. The gene becomes dysfunctional, resulting in low HDL levels.

Mutations prevent the removal of cholesterol within the reticuloendothelial cells. These specific cells are found in the tonsils, lymph nodes, spleen, liver, neurons, and smooth muscle cells. Thus causing Tangier disease.⁵

Pathophysiology and molecular mechanisms

HDL’s life begins with a small beta HDL molecule. The ABCA transporter helps the small HDL pick up free cholesterol. The new HDL molecule matures through esterification. Mature HDL assists in the transfer of cholesterol esters to LDL. The rest is used in the liver or recycled into the HDL cycle. Defects in this stage of the molecular mechanism cause Tangier disease.

Excess plaque, as a result,  poses several threats throughout the body. 

• The accumulation of cholesterol esters in the tonsils causes them to become enlarged. This risks airway obstruction.
• The build-up of cholesterol forms plaques in the blood vessels, particularly the coronary arteries. A person can be predisposed to coronary artery disease or stroke in their early years.
• In the nervous system, Schwann cells are crucial in nerve signal transmission. They form the myelin sheath, which insulates and supports nerve cells, ensuring fast signal transmission. When cholesterol deposits in these cells, it causes the loss of the myelin sheath. As a result, a person can lose the ability to detect temperature sensations or pain.
• The cornea becomes cloudy due to excessive cholesterol in the body
• Liver and spleen enlargement are common consequences of a surplus of cholesterol. A compromised spleen may also lead to thrombocytopenia, in which platelet levels decrease
• The lymph nodes are a part of the immune system that extends throughout the body. They function as a drainage and delivery system for immune cells to fight infection. Cholesterol deposition blocks this filtering pathway that leads to swelling
• Alpha cells of the pancreas are crucial in regulating the body’s glucose levels. They secrete glucagon, which is then broken down into glucose to increase glucose levels in the bloodstream. Cholesterol accumulation inside the Alpha cells was the origin of diabetes²

Diagnosis and genetic testing

A doctor may diagnose Tangier disease through its multiple clinical manifestations. However, genetic testing is the principal diagnostic technique for Tangier disease. The ABCA1 gene is sequenced to detect any mutations. A specific variant is looked for: biallelic pathogenic variants. Alternatively, tissue biopsies can be examined to detect HDL levels. The organ systems are assessed to ensure they are functioning as expected. Additional blood tests are taken.

These tests show significantly low levels of HDL, which are key in cholesterol transportation. Due to the nature of this condition, family history is also evaluated to confirm the diagnosis or to rule out any other similar diseases. Many inherited diseases show low HDL levels; therefore, a holistic approach should be taken during diagnosis.²

Current and future research

Currently, there is no precise protocol to follow to treat Tangier disease. Lifestyle modifications are encouraged to raise HDL levels:

• Aerobic exercise
• Healthy weight maintenance
• Quitting smoking
• Replacing monounsaturated fatty acids with saturated fatty acids

These changes have been shown to alleviate some symptoms.²

Drug therapies do not show any beneficial effects. Companies have attempted to target low HDL cholesterol and optimise LDL levels through lipid-lowering agents, such as:

• Statin 
• Niacin 
• Fibrates⁶

Treatments are based on the manifested symptoms:

• Removal of any enlarged organs, if necessary 
• Corneal transplantation, if the cornea becomes cloudy
• Avoiding high-impact sports to prevent spleen rupture⁶

These generalised methods do not target the main factor, the ABCA1 gene. Future therapeutic approaches are focusing on controlling the expression of the ABCA1 gene. By overexpressing the gene, we can reduce the metabolism of HDL and increase its uptake in liver cells. As a result, we can achieve elevated levels of HDL, hence an increase in cholesterol ester pick up within cells.²

Gene editing using CRISPR-like technology is a direct intervention on a genetic level. CRISPR-like technology is used to edit the gene sequence to correct mutations. The cells are collected and treated outside of the body. Then, they are reintroduced into the body where they can carry out proper functions. This can be used to fix the faulty ABCA1 gene and target Tangier disease from its origin. While these modifications are small, they have potential global effects on the body.⁷

These potential treatments hold great promise; however, they must proceed with caution. When tampering with genes, it is vital to ensure that the expression of other genes is not affected, and if it is, what are the consequences? The future of gene therapy has a complex development process.

Summary

Tangier disease is a rare inherited genetic disorder originating from a mutation of the ABCA1 gene. This impacts the lipid transport and reduces levels of HDL in the body. Tangier disease is an autosomal recessive disease. Early detection is crucial in managing the risks related to the cardiovascular system and neuronal complications. Conditions of this nature require extensive genetic testing and research into family history. However, there is no cure as the intricacies of the ABCA1 gene are yet to be fully explored. Prospects hold promise with advanced genetic testing and editing to target the origin of Tangier disease and create effective therapies.