Tangier Disease

What is Tangier Disease?

Tangier disease is a condition people are born with. It was first identified in two siblings living on Tangier Island, Virginia, in the Chesapeake Bay in 1961. The disease got its name from the island. In people with Tangier disease, there’s a significant decrease in HDL, also known as “good cholesterol,” and an increase of a type of cholesterol called cholesterol esters in many parts of the body, especially the reticuloendothelial systems (a group of cells in your immune system). This makes organs appear yellow-orange and larger than usual. This is why people with this disease are at a higher risk of experiencing heart and blood vessel diseases at a younger age than most people.

From a medical standpoint, Tangier disease leads to an enlargement of the liver, spleen, lymph nodes, and tonsils. It’s also associated with peripheral neuropathy, a condition that affects the nerves in the body that can lead to pain, numbness, or difficulty controlling muscles, often seen in children and adolescents with Tangier disease.

What Causes Tangier Disease?

Tangier disease is a condition that depends on the genes you inherit from your parents. If you get a certain pair of genes from both of your parents, your body will have very low levels of a substance called HDL, a type of “good” cholesterol. If you get just one of these genes, your HDL levels will be somewhat low, but you won’t necessarily show signs of the disease.

If two parents that both carry the gene have children, their children have a 25% chance of inheriting the disease, a 50% chance of being a carrier of the disease, and a 25% chance of being completely free of the disease. If a person with the disease has children with a person who does not have the disease, their children will all be carriers of the disease.

The disease is caused by a mutation, or change, in a gene located on a part of our DNA known as chromosome 9q31. This gene controls the creation of a certain protein that helps move cholesterol from inside our cells to the liver. When there’s a problem with this gene, cholesterol builds up inside our cells, which can harm them and eventually lead to their death.

Risk Factors and Frequency for Tangier Disease

This disease is considered rare, with a prevalence of 1 in 1,000,000 people. There have only been roughly 100 documented cases since 1961, showing that it’s not common and it can affect individuals of all races. It’s observed that marriages between relatives can increase the risk of the next generation developing this disease. However, there have been cases where children from unrelated families have also contracted the disease.

Signs and Symptoms of Tangier Disease

Patients with one altered gene (heterozygous) for Tangier’s disease usually have low levels of good cholesterol (HDL) but don’t get cholesterol deposits within body organs. If a person inherits two altered genes (recessive), they will show signs of cholesterol deposits and have extremely low HDL levels.

Here’s what might appear in different parts of the body as a result of Tangier’s disease:

Mouth: Tonsils can have yellow or orange cholesterol deposits. This is often the first sign doctors notice, especially in children and young adults.
Heart and blood vessels: Individuals may develop early-onset heart disease and strokes. Sometimes the heart valves could also be damaged.
Nervous system: Cholesterol can deposit in the peripheral nerves, causing varied symptoms like loss of pain and temperature sensitivity in arms, multifocal sensory and motor neuropathy (an unpredictable pattern of symptoms), and a type of damage known as distal symmetric polyneuropathy.
Eyes: The cornea (the transparent front part of the eye) can become clouded, but this doesn’t typically cause vision loss.
Internal organs: Cholesterol can build up in the liver, spleen, and lymph nodes, causing enlargement and sometimes lower platelet counts in the blood. It could also be deposited in the pancreas and cause diabetes.
Blood: Symptoms can include low platelet count, increased immature red blood cells (reticulocytosis), a specific type of anemia (hemolytic anemia), and abnormal red blood cells (stomatocytosis).

Tangier disease typically appears early in life, often first showing up as enlarged tonsils and clouding of the cornea. Neuropathy (nerve damage) and heart disease are the most serious complications.

Other potential symptoms of Tangier’s disease include:

Abdominal pain
Chronic, non-infectious swollen lymph nodes
Dry skin
Unhealthy nails
Facial muscle weakness

Testing for Tangier Disease

Tangier disease is a condition that can be challenging to diagnose, as symptoms may appear early or later in life. The primary way to diagnose this illness is through blood tests. Key indicators of Tangier disease include low levels of “good cholesterol” (HDL), cholesterol-binding protein (Apo-a1), and total cholesterol (usually less than 150mg/dl). Additionally, triglyceride levels may be normal or high, while LDL cholesterol (“bad cholesterol”) levels may be decreased. Another sign may be thrombocytopenia, which is a low platelet count, the cell component that helps your blood clot.

The most definitive way to confirm Tangier disease is through genetic testing, specifically of the ABCA1 gene. If genetic testing isn’t available, doctors can also perform a tissue biopsy in various parts of the body, like the bone marrow, jejunum (part of the small intestine), liver, or rectum. These biopsies often show large collections of cells full of cholesterol.

Doctors may also conduct other tests to examine damage to different parts of the body. These can include nerve conduction studies and electromyography (EMG) to look for signs of nerve damage, eye exams to look for clouding of the cornea, ultrasound of the abdomen to check for an enlarged liver or spleen, tests for possible plaque build-up in the carotid arteries (carotid duplex), and CT angiography to look for hardened arteries (atherosclerosis) in the heart.

People at high risk of Tangier disease, like relatives of someone with a confirmed diagnosis, should get tested for the presence of the mutated ABCA1 gene. Doctors can also check their cholesterol levels and apo A-I concentration. People who are carriers of one copy of the mutated gene usually don’t show symptoms but tend to have half the normal serum levels of HDL cholesterol.

It’s also possible to diagnose Tangier disease before birth, though this is unusual.

Treatment Options for Tangier Disease

Tangier disease currently doesn’t have a specific treatment. However, there are ways to help increase ‘good cholesterol’ known as HDL, which can help manage the disease. Some of these methods include regular physical exercise, maintaining a healthy weight, quitting smoking, and changing your diet to include more monounsaturated fats instead of saturated fats. Although these steps might not cure the disease, they could help reduce some of its symptoms, especially problems with the nerves in the arms and legs, known as peripheral neuropathies.

While there are no solid proofs that drug therapy can specifically target low HDL (good cholesterol) levels, doctors might prescribe cholesterol-lowering drugs such as statins, niacin, or fibrates. These medications can be taken individually or in combination, depending on the patient’s needs.

Additional treatments can be given depending on the symptoms that the patient is experiencing. For instance, if the tonsils are enlarged causing breathing problems, a tonsillectomy might be performed, which is a surgical procedure to remove the tonsils. If the disease affects the eyes leading to the clouding of the cornea, a corneal transplant may be required. For those who are struggling with peripheral neuropathy, temporary usage of leg braces and exercise might be recommended. Furthermore, if the patient has an enlarged spleen, termed splenomegaly, they should avoid high-impact sports or activities to prevent possible rupture of the spleen.

Future treatments could potentially involve gene therapy to specifically target and alter certain parts of the body’s cells. This could involve either increasing the uptake of cholesterol by liver cells or slowing down the metabolism of HDL, ‘good cholesterol’. This is done by increasing expression of a gene known as ABC1, which leads to more cholesterol being taken up by the cells.

There are several inherited diseases that may show up with symptoms of low HDL level and peripheral neuropathy. These include:

Familial HDL deficiency – an inherited disorder associated with very low serum HDL concentrations and premature cardiovascular heart disease. Unlike Tangier disease, it doesn’t show any systemic findings.
Abetalipoproteinemia – this rare hereditary disorder is characterized by defective assembly and secretion of certain lipoproteins. It manifests symptoms like failure to thrive and fat malabsorption, and in later stages, issues such as retinal decay, peripheral neuropathy, and loss of coordination.
Niemann-Pick disease – it’s an inherited disorder where abnormal metabolic products pile up in the body. Symptoms often include a larger than normal liver and spleen (much more than in Tangier disease), progressive neurodegeneration, and red spots on the macula of the eye.
LCAT deficiency – this disease results from a shortage of the Lecithin cholesterol acyltransferase enzyme. It can lead to ring-shaped corneal opacity and progressive kidney disease with protein in urine.
Fish-Eye disease – it results from a partial deficiency of LCAT. Symptoms include corneal opacity with normal kidney function.
Charcot-Marie-Tooth Disease – it’s an inherited neurological disorder which results in peripheral neuropathy and various types of foot deformities.
Besides these, having low HDL levels can be caused by certain medications like beta-blockers, benzodiazepines, and anabolic steroids, as well as acute infections like HIV, inflammation, or conditions like multiple myeloma.

What to expect with Tangier Disease

Tangier disease is a rare condition and it is currently unclear how it might affect an individual’s lifespan. Although most people with the disease have good outlooks, this can depend on the progression of atherosclerosis (a disease where plaque builds up inside your arteries) and peripheral neuropathies (damage to the nerves that transmit signals between the body and the brain).

Additionally, those who inherited the specific genes for Tangier disease might have “good” cholesterol or HDL levels lower than 5 mg/dL, which increases their risk of coronary artery disease, a condition affecting the blood vessels supplying the heart. Therefore, regular check-ups with doctors are important for these individuals.

Possible Complications When Diagnosed with Tangier Disease

Even though many studies suggest that there’s a likely link between the risk of heart disease and the levels of ‘good cholesterol’, or HDL cholesterol, it hasn’t been proven that low levels of this good cholesterol directly cause heart disease or lead to a condition called atherosclerosis (which is the hardening of the arteries due to plaque build-up).

One of the key risks to consider is the deposit of cholesterol which could lead to premature heart events in patients with a condition called Tangier disease. These issues usually only occur after the age of 40. People with this condition could also suffer from an enlarged spleen over time, and if engaging in intense physical activities or sports, it could potentially rupture.

People with excessive cholesterol deposits in the pancreas could potentially develop diabetes. Other problems could include blockages in the airways or other related symptoms if the tonsils become considerably enlarged. Some people could also encounter aggressive and recurring peripheral neuropathies (a condition that leads to weakness, numbness, and pain from nerve damage), which could affect any part of the nervous system. Lastly, some degree of visual impairment has also been reported in such cases.

Common issues related to cholesterol deposits:

Premature heart events after the age of 40
Potential spleen rupture if engaging in intense physical activities
Possible development of diabetes due to cholesterol in the pancreas
Airway blockages due to enlarged tonsils
Aggressive and recurring peripheral neuropathies affecting any part of the nervous system
Mild to moderate visual impairment

Preventing Tangier Disease

Good cholesterol, or HDL, is crucial for preventing heart diseases. HDL works by collecting cholesterol from body tissues and carrying it to the liver for expulsion. Apart from this, HDL has other functions:

* It works as a protector against harmful substances that can cause swelling and damage to the body’s cells.
* HDL helps in reducing blood clot formation.
* It supports the healing of inner lining of the blood vessels and aids the growth of new blood vessels.
* It assists people with diabetes in managing their illness better.

In order to keep a healthy lifestyle and to maintain balanced fat levels in your body, you are advised to do regular aerobic exercise, maintain a healthy weight, quit smoking, and switch to healthier fats. For upping the good cholesterol, increase intake of foods rich in omega-3 fatty acids like olive oil, whole grains, beans, legumes, fruits high in fiber, fatty fish, flax and chia seeds, nuts, and avocado. These not only increase HDL levels but also reduce the bad cholesterol.

Certain medicines like beta-blockers, benzodiazepines, and androgens, might lower good cholesterol levels. However, if such medicines are necessary for treating other health conditions, they will not be stopped. Also, medicines that may cause damage to the nerves such as vincristine or taxols (paclitaxel) should be used with caution.

Frequently asked questions

Tangier Disease is a condition that causes a significant decrease in HDL (good cholesterol) and an increase in cholesterol esters in the body, leading to yellow-orange organs and an increased risk of heart and blood vessel diseases at a younger age. It is also associated with enlargement of the liver, spleen, lymph nodes, and tonsils, as well as peripheral neuropathy.

Tangier Disease is considered rare, with a prevalence of 1 in 1,000,000 people.

Signs and symptoms of Tangier Disease include: - Low levels of good cholesterol (HDL) in patients with one altered gene (heterozygous) - Cholesterol deposits in various parts of the body in individuals with two altered genes (recessive) - Yellow or orange cholesterol deposits in the tonsils, which is often the first sign noticed by doctors, especially in children and young adults - Early-onset heart disease and strokes, as well as potential damage to the heart valves and blood vessels - Cholesterol deposits in the peripheral nerves, leading to symptoms such as loss of pain and temperature sensitivity in the arms, multifocal sensory and motor neuropathy, and distal symmetric polyneuropathy - Clouding of the cornea, although this typically does not cause vision loss - Cholesterol buildup in the liver, spleen, and lymph nodes, resulting in enlargement and sometimes lower platelet counts in the blood. It can also affect the pancreas and cause diabetes. - Blood-related symptoms such as low platelet count, increased immature red blood cells, hemolytic anemia, and stomatocytosis - Other potential symptoms include abdominal pain, chronic non-infectious swollen lymph nodes, dry skin, unhealthy nails, and facial muscle weakness. Tangier Disease typically appears early in life, with enlarged tonsils and clouding of the cornea being common initial signs. Neuropathy and heart disease are the most serious complications associated with this condition.

Tangier Disease is a condition that depends on the genes you inherit from your parents. If you get a certain pair of genes from both of your parents, your body will have very low levels of a substance called HDL, a type of "good" cholesterol. If you get just one of these genes, your HDL levels will be somewhat low, but you won't necessarily show signs of the disease.

The doctor needs to rule out the following conditions when diagnosing Tangier Disease: 1. Familial HDL deficiency 2. Abetalipoproteinemia 3. Niemann-Pick disease 4. LCAT deficiency 5. Fish-Eye disease 6. Charcot-Marie-Tooth Disease 7. Medications like beta-blockers, benzodiazepines, and anabolic steroids 8. Acute infections like HIV 9. Inflammation 10. Conditions like multiple myeloma.

The types of tests needed for Tangier Disease include: - Blood tests to measure levels of HDL cholesterol, Apo-a1, total cholesterol, triglycerides, and LDL cholesterol. - Genetic testing of the ABCA1 gene to confirm the diagnosis. - Tissue biopsies in various parts of the body, such as the bone marrow, jejunum, liver, or rectum, to look for collections of cholesterol-filled cells. - Other tests to examine damage to different parts of the body, such as nerve conduction studies, electromyography, eye exams, ultrasound of the abdomen, carotid duplex, and CT angiography. - Testing for the presence of the mutated ABCA1 gene in high-risk individuals. - Cholesterol level and apo A-I concentration testing in carriers of the mutated gene. - Prenatal testing, although this is unusual.

Tangier disease currently does not have a specific treatment. However, there are ways to help manage the disease and increase "good cholesterol" known as HDL. Some methods include regular physical exercise, maintaining a healthy weight, quitting smoking, and changing the diet to include more monounsaturated fats. Cholesterol-lowering drugs such as statins, niacin, or fibrates may also be prescribed. Additional treatments may be given depending on the specific symptoms experienced by the patient, such as tonsillectomy for enlarged tonsils, corneal transplant for clouding of the cornea, and temporary usage of leg braces and exercise for peripheral neuropathy. In the future, gene therapy could potentially be used to target and alter certain parts of the body's cells.

The side effects when treating Tangier Disease can include: - Premature heart events after the age of 40 - Potential spleen rupture if engaging in intense physical activities - Possible development of diabetes due to cholesterol in the pancreas - Airway blockages due to enlarged tonsils - Aggressive and recurring peripheral neuropathies affecting any part of the nervous system - Mild to moderate visual impairment

The prognosis for Tangier Disease can vary depending on the progression of atherosclerosis and peripheral neuropathies. While most people with the disease have good outlooks, regular check-ups with doctors are important due to the increased risk of coronary artery disease. The specific impact on an individual's lifespan is currently unclear.

A geneticist or a specialist in lipid disorders.