Introduction

Tangier disease (TD) is a very rare metabolic disorder with an autosomal recessive inheritance. It takes its name from Tangier Islands of Virginia in Chesapeake Bay, where the first case was reported.¹

The disease is characterised by low levels of high-density lipoprotein (HDL) cholesterol, known as “good cholesterol”, and accumulation of cholesterol esters in many organs, that will appear orange colored and larger.²

It is caused by a mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the essential gene responsible for generation of HDL particles from cellular cholesterol and phospholipids.¹

Cholesterol is an essential lipid for cell membrane structure and steroid hormone synthesis, and can also be converted into bile acids.

HDL is involved in reverse cholesterol transport (RCT), a process that induces the movement of cholesterol from the extrahepatic tissues back to the liver for its excretion through feces as bile acid.³

It has been recognized that HDL-cholesterol acts as a protective factor against coronary heart disease (CHD), and various studies have shown its anti-inflammatory and antioxidant effects and its role in reducing the risk of atherosclerosis.⁴

Tangier disease causes reverse cholesterol transport disorder, resulting in cholesterol accumulation in peripheral tissue cells, which leads to a series of conditions such as dyslipidemia and early onset of atherosclerosis.⁵

High-Density Lipoprotein (HDL) and its role

Cholesterol is necessary in all mammalian cells, and its homeostasis is a crucial process for normal cell function, thus it is important to keep the amount of free cholesterol within a narrow range. HDL is the key factor in this process, since it acts as the cholesterol acceptor by transporting the excess cholesterol through the plasma from peripheral tissues to the liver, where it can be metabolized into bile acids and then be excreted in the feces. This mechanism is known as reverse cholesterol transport (RCT).⁶

The HDL particle is made up of lipids and apolipoproteins, with Apo-A1 being the principal surface protein component. It has been shown that HDL-cholesterol (HDL-C) and Apo-A1 are essential for mediating reverse cholesterol transport, which plays an important role in the atheroprotective mechanism of HDL.⁴

This is particularly relevant as cardiovascular disease (CVD), with atherosclerosis as the major underlying factor, is the primary cause of death worldwide. The cholesterol ester-enriched foam cells are the hallmark of atherosclerotic plaques, which means that enhancing foam cell cholesterol efflux by HDL particles - the first step of RCT - is a promising antiatherogenic strategy. In the 1960s, the Framingham Heart Study first reported the inverse associations between cardiovascular risk and HDL-C, meaning that high levels of HDL cholesterol (HDL-C) reduce the cardiovascular risk. This discovery inspired the researchers to investigate how HDL protects against atherosclerosis, and they attributed the cardiovascular protective effects to its ability to accept cholesterol from cells and act as its carrier in the RCT pathway.⁶

Tangier disease: Genetic and molecular basis

Tangier disease is an autosomal recessive disease caused by variations in both alleles of the ATP-binding cassette transporter A1 (ABCA1) gene, which encodes the membrane transporter ABCA1.⁷

The principal clinical signs are yellow-orange tonsils, hepatosplenomegaly and very low HDL-C levels (<5 mg/dL). In fact, people affected by TD have a severe deficiency of circulating HDL particles and accumulation of cholesteryl-esters in cells all over the body, particularly in the reticuloendothelial system.

ABCA1 is a protein widely expressed in many tissues with different functions, but its most studied role is in cholesterol homeostasis, where it is a key molecule.⁸

It helps release free cholesterol and phospholipids from cells, transferring them to apolipoprotein AI, which then generates nascent high-density lipoprotein (HDL). Thus, ABCA1 is strictly necessary for the cellular biogenesis of HDL from Apo-A1.⁹

In patients with Tangier disease (TD), macrophages and other cells accumulate too much cholesterol, forming so-called "foam cells". This happens because the transport of free cholesterol and phospholipids to Apo-A1, mediated by ABCA1, does not function properly.

These foam cells are the cause of atherosclerosis and coronary heart disease (CHD). Therefore, given the importance of ABCA1, it is clear that mutations in its gene have significant consequences, such as Tangier disease.⁸

TD is extremely rare, with a prevalence of 1 in1,000,000. Only approximately 100 cases have been reported worldwide since 1961, but more cases are likely undiagnosed. It has an autosomal recessive inheritance pattern and consanguineous marriages increase the risk in the following generation, but cases have also been found in unrelated families.²

Clinical manifestations of Tangier disease

The clinical expression of TD is variable, with some affected individuals only showing biochemical perturbation such as low levels of plasma HDL-C. However, the principal clinical signs of TD are:

• Enlarged tonsils, that appear yellow/orange in children and young adults, usually with no symptoms, even if sometimes there may be difficulty breathing or swallowing
• Peripheral neuropathy, with a clinical course commonly benign, but it can be relapsing-remitting or chronic progressive with sensory abnormalities
• Hepatosplenomegaly (enlargement of the liver and spleen), common particularly in adulthood

Other possible manifestations include brown focal deposits of the intestinal and rectal, usually with no symptoms; corneal opacities that is generally mild and do not affect vision; premature coronary artery disease that occur typically in the 50s-60s; and hematological disorders such as thrombocytopenia, reticulocytosis, hemolytic anemia.¹⁰

Other clinical signs that affected people can show are abdominal pain, chronic noninfectious lymphadenopathy, dry skin, nail dystrophy, and facial diplegia.

However, neuropathy and cardiovascular disease remain the most devastating developments caused by Tangier's disease.²

Diagnosis and detection

Blood tests are the main way to diagnose Tangier disease. Common findings include very low HDL (less than 5 mg/dL), low Apo-A1 (below 5), and low total plasma cholesterol (less than 150 mg/dL). Patients may have normal or high triglyceride levels, reduced LDL level, and thrombocytopenia is also often detected.

The gold standard for the diagnosis of the disease is ABCA1 molecular gene sequencing, which detects possible mutations. If genetic testing cannot be performed, biopsy of tissues like the bone marrow, liver, and rectum can show accumulation of cholesterol esters.

In addition, other tests can be performed to check organ involvement, including nerve studies (EMG), eye exams for corneal opacities, abdominal ultrasound to check liver and spleen size, and CT angiography to assess for coronary atherosclerosis.

Relatives of diagnosed individuals should be tested to see if they are carriers of the mutated gene. Carriers usually don’t show symptoms but have half-normal HDL levels. For people at risk, it is suggested to regularly check their lipid profile and Apo-A1 levels through blood tests.

Moreover, Tangier disease should be distinguished from other inherited conditions that also cause low HDL and peripheral neuropathy, such as Familial HDL deficiency, Abetalipoproteinemia, Niemann-Pick disease, etc. Thus, the differential diagnosis is essential to distinguish it from other lipid disorders.²

Treatment and management

Currently there is no treatment for Tangier disease. Since, the biggest risk due to the disease is atherosclerosis, patients should follow regular check-ups, including exercise electrocardiography, echocardiography and computed tomography coronary angiography.¹

The primary focus is on increasing HDL through a healthy lifestyle by making some changes that can help improve symptoms. Regular aerobic exercise, maintaining a healthy weight, quitting smoking, and replacing saturated fats with monounsaturated fats can help raise HDL cholesterol, thus managing the atherosclerotic risk.

Drug therapy, which includes statins, niacin, and fibrates - given alone or in combination - is aimed at targeting low HDL cholesterol and optimizing LDL levels, even though there is no evidence of its benefits. Based on specific symptoms, targeted treatments are available, such as tonsillectomy for enlarged tonsils causing breathing difficulties, corneal transplant for patients with corneal opacity, exercise and the use of braces in cases of peripheral neuropathy.or patients with splenomegaly, it is recommended to avoid high-impact sports and activities to prevent spleen rupture.

A future therapeutic approach with great potential seems to be targeted gene therapy for the ABCA1 gene, which leads to the expression of the protein, consequently increasing cholesterol pick up within the cells.²

Summary

Tangier disease (TD) is a rare autosomal recessive disorder caused by mutations in the ABCA1 gene, characterized by a severe deficiency of HDL-cholesterol levels, known as “good cholesterol”. This gene encodes the transporter ABCA1, an essential protein in HDL particle biogenesis and in reverse cholesterol transport (RCT). In fact, it plays a key role in cholesterol homeostasis since it helps release free cholesterol from cells, transferring it to apolipoprotein AI, thus generating nascent HDL, the cholesterol acceptor, which transports the excess cholesterol from peripheral tissues to the liver for excretion through feces.

When ABCA1 is mutated, RCT is dysfunctional, cholesterol accumulation in peripheral cells, which increases atherosclerotic and cardiovascular risks.

The accumulation of cholesterol esters in various organs causes the typical signs of TD, such as enlarged and yellow-orange tonsils, hepatosplenomegaly, corneal opacities, and brown deposits in the intestines and rectum. TD significant complications can be peripheral neuropathy, early-onset coronary artery disease, and hematological disorders.

Diagnosis is typically based on a blood test showing low levels of HDL-C, Apo-A1, and total plasma cholesterol, but the gold standard for diagnosis is genetic testing through ABCA1 molecular gene sequencing. If genetic testing cannot be performed, tissue biopsies can show cholesterol ester accumulation.

There is no treatment for Tangier disease yet. However, it is suggested to have a healthy lifestyle in order to increase HDL levels and prevent the atherosclerotic risk.

Drug treatment involves the administration of statins, niacin, and fibrates, used to manage cholesterol levels, although their effectiveness in TD remains unclear.A promising future approach seems to be the gene therapy aimed at re-establishing ABCA1 function, potentially improving cholesterol uptake.