Introduction

Overview of Tangier disease

Tangier disease is a rare genetic disorder, characterised by a severe deficiency or complete absence of a type of cholesterol (which is a waxy, fat-like substance) known as ‘high-density lipoprotein’ (HDL). HDL, also referred to as ‘good’ cholesterol, helps to remove low-density lipoprotein (LDL), which is the ‘bad’ cholesterol. Excess amounts of bad cholesterol are problematic as LDL can clog arteries, increasing your risk of developing health complications such as heart attack or stroke. In Tangier disease, the absence of HDL allows LDL to build up in parts of your body, resulting in the symptoms of Tangier disease.^1,5 

In this article, we will be discussing the prognosis of Tangier Disease by looking at outcomes of Tangier disease and predicting how your condition is likely to unfold over time. We will also look at how living with Tangier Disease may affect quality of life by seeing how it may affect patients' physical health and overall well-being. 

Understanding Tangier disease

Pathophysiology (causes and consequences) of Tangier disease

Tangier disease arises when you have certain ‘mutations’ (which are changes to the DNA code) in the ‘ATP-Binding cassette transporter’ (ABCA-1) gene. A gene is a sequence of DNA that encodes a specific protein. The normal, unmutated ABCA-1 gene encodes the ABCA-1 protein ABCA-1 protein, which normally functions to transmit types of lipid (fats) like cholesterol and phospholipids from inside cells to the liver. Hence, in individuals with Tangier disease that lack functional transporters, cholesterol accumulates in cells, which eventually limits cell function and leads to cell death. Individuals with Tangier disease have very low amounts of HDL; this is because its precursor normally picks up free cholesterol from cells using an ABCA transporter. Defects in the transporter mean this process cannot occur, resulting in no HDL production and therefore Tangier disease. The role of mature HDL is to help mediate the transfer of cholesterol and other lipids out of the bloodstream to the liver for removal. Without HDL and therefore without cholesterol transfer, cholesterol is not taken to the liver for removal, leading to cholesterol deposition in organs, resulting in the clinical manifestations of Tangier disease.^1,2 

Symptoms 

Tangier disease symptoms vary between individuals as they depend on where fatty deposits occur in the body. Initial presentation may be enlargement of the tonsils and clouding of the cornea. While later development of neuropathy and cardiovascular disease are the most severe complications of Tangier disease.¹ 

Possible clinical findings of Tangier disease include:¹  

• Cholesterol deposits in the tonsils: deposits appear yellow in colour and tonsils may be enlarged
• Premature atherosclerosis: (narrowing of arteries due to fatty plaque formation), meaning individuals are more prone to coronary artery disease and stroke earlier in life than the normal population
• Deposition of cholesterol in peripheral nerves leads to the development of peripheral neuropathy⁴ 
• Clouding of the cornea, although this is usually mild and without loss of vision
• Hepatosplenomegaly (simultaneous swelling of the spleen and liver beyond their normal size)
• Diabetes if cholesterol deposits in alpha cells of the pancreas
• Abnormal blood findings: thrombocytopenia (low platelet count) that can lead to blood clotting problems, reticulocytosis (elevated number of reticulocytes, which are immature red blood cells), haemolytic anaemia (low red blood cell count) 
• Other clinical signs: abdominal pain, swelling of lymph nodes, dry skin, nail dystrophy, facial diplegia (bilateral facial paralysis) 

Long-term outcomes/prognosis

The prognosis of Tangier disease is usually good, but depends on how symptoms progress. Variable disease progression means that some individuals will experience only mild symptoms while others have more severe symptoms and will face greater health challenges.

While there is currently no cure for Tangier disease, new developments in gene therapy may help in the future to eliminate symptoms of the disease. Since it is a genetic condition, Tangier disease will last a lifetime, but it can be managed with treatment. Prognosis can worsen following the development of conditions such as peripheral neuropathies and atherosclerosis. To avoid developing these conditions and therefore improve the prognosis, prompt diagnosis and adequate treatment/management are important.¹ As Tangier disease is rare, there is insufficient data to accurately determine life expectancy for individuals with the disease.¹ 

Possible health complications

Cardiovascular risks 

Individuals with Tangier disease have an increased likelihood of developing atherosclerosis compared to the normal population. Having atherosclerosis increases the risk of developing atherosclerotic complications like stroke and cardiovascular diseases (such as coronary heart disease, which refers specifically to atherosclerosis in the arteries that supply the heart with blood).^1,3

Atherosclerosis is the dangerous accumulation of fat-laden deposits or ‘plaques’ in arteries, initially described as a simple ‘plumbing problem’ in which fatty plaques blocked arteries impeding blood flow. It is now understood that inflammation fuels the development and progression of atherosclerosis.³ Excess LDL in the blood can trigger arterial inflammation thus driving atherosclerosis development. Furthermore, inflammation can cause plaques to rupture, leading to blood clots forming over ruptured plaques, which can block arteries. This can result in atherosclerotic complications such as heart attack and stroke.³

Individuals with Tangier disease are more susceptible to developing atherosclerosis because they lack HDL, which is protective against atherosclerosis development.⁶ HDL plays a protective role against atherosclerosis because it helps remove cholesterol (LDL) from the blood, preventing plaque formation, but also prevents LDL oxidation (which is an important driver of inflammation and subsequent plaque formation). Therefore, in Tangier disease, where there is an absence of HDL, individuals lack the protection HDL provides against atherosclerosis development. The subsequent deposition of cholesterol esters acts as a major risk factor for the development of premature cardiovascular events in Tangier disease.³ 

Neurological impacts: 

Patients may develop progressive peripheral neuropathy, which significantly worsens the prognosis of Tangier disease. One study identified 54 Tangier disease patients with peripheral neuropathy reported in studies between 1960-2017. Neuropathy subtypes observed in these 54 patients included syringomyelia-like neuropathy subtype (52.4%), multifocal sensorial and motor neuropathy subtype (26.2%), focal neuropathy subtype (19.1%), and distal symmetric polyneuropathy subtype (2.4%).⁴ 

Neuropathy development in Tangier disease occurs following deposition of cholesterol in peripheral nerves inside Schwann cells that result in demyelination, which impedes nerve function. Main symptoms of peripheral neuropathy include numbness and tingling in the feet or hands, burning, stabbing or shooting pain in affected areas, loss of balance and coordination and muscle weakness. The development of neuropathy can significantly affect daily life due to associated pain.^1,4 

Hepatosplenomegaly

Hepatosplenomegaly (refers to an enlarged spleen and liver beyond normal size) occurs in around a third of Tangier disease cases due to cholesterol deposition in these organs. Blood disorders like thrombocytopenia (low platelet count) can result from an enlarged spleen. A lack of platelets can lead to slow blood clotting. Hepatosplenomegaly may present with splenic rupture when participating in aggressive contact sports, and so these should be avoided.¹

Other possible complications include: 

• Diabetes 
• Tonsillar enlargement 
• Clouding of the cornea 

Impact on quality of life

Quality of life with Tangier disease depends on the severity of symptoms, which varies between individuals. Following the development of complications of Tangier disease, such as neuropathy, quality of life may decrease due to:

Physical health challenges

• Mobility issues due to nerve damage following neuropathy development may make completing daily tasks more difficult and will require ongoing medical interventions and checkups. Quality of life may be impacted due to symptoms of neuropathy, like shooting pains and muscle weakness
• Cardiovascular disease development will require frequent checkups and continuous management and may require lifestyle changes like altering diet. Living with atherosclerosis increases the risk of heart attacks and strokes, both of which can result in lasting health complications or even death
• Development of medical conditions like diabetes or an airway obstruction from enlarged tonsils will require medical intervention and if unmanaged, could decrease quality of life following the development of complications like painful diabetic ulcers

Psychosocial effects

• Emotional and mental health challenges, such as anxiety, depression, and stress from living with a chronic, rare condition. Frequent hospital appointments for management may be stressful. Plus, increased risk of heart attacks and strokes can be a source of stress
• Social implications: Stigma and the emotional toll of managing a lifelong illness
• Visible symptoms like clubbing (nail dystrophy) could negatively impact mental health

Management and treatment

Currently, no direct or curative treatment exists. Instead, management strategies focus on increasing HDL through lifestyle modifications. These include maintaining regular exercise, maintaining a healthy weight, stopping smoking, and replacement of monounsaturated for saturated fatty acids through diet changes to raise HDL. These strategies can help manage symptoms. Lipid-lowering agents such as statins, niacin, and fibrates can be prescribed to help manage Tangier disease. Other management strategies are symptom-specific, such as tonsillectomy if enlarged tonsils lead to problems, and corneal transplantation if the cornea is cloudy, resulting in vision loss. In the future, gene therapy may help treat Tangier disease by increasing the amount of ABC1. Better management and early intervention of Tangier disease can help prevent the development of complications and therefore improve prognosis and quality of life. Future prospects of gene therapy could improve prognosis and quality of life.^1,5

Summary

In summary, for most individuals with Tangier disease, the prognosis is good and they may only experience mild symptoms and can live a fairly normal life. However, disease progression is variable, and some individuals may develop complications. Possible outcomes of Tangier disease include developing premature atherosclerosis, peripheral neuropathy, hepatosplenomegaly and swollen tonsils. Development of conditions such as atherosclerosis and peripheral neuropathy is associated with a worsened prognosis and may have a negative impact on quality of life due to increased suffering caused by disease symptoms. Early detection and proactive care will aid in preventing severe complications and help symptom management, which will improve long-term outcomes and quality of life for those living with Tangier disease. Future advancements in gene therapy could aid disease management, therefore improving the quality of life of patients.