Transthyretin amyloidosis is a progressive condition characterized by the buildup of abnormal protein deposits called amyloids (amyloidosis) in the body's organs and tissues. These protein deposits most frequently occur in the peripheral nervous system, which is made up of nerves that connect the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves result in a loss of sensation or in muscle weakness in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis. In some cases, the brain and spinal cord (central nervous system) are affected. Other areas of amyloidosis include the heart, kidneys, eyes, and gastrointestinal tract. The age at which symptoms begin to develop varies widely among individuals with this condition, typically ranging from age 20 to 70.

There are two major forms of transthyretin amyloidosis, which are distinguished by their symptoms and the body systems they affect.

The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions. Impairments to bodily functions can include sexual impotence, diarrhea, constipation, problems with urination, and a sharp drop in blood pressure upon standing (orthostatic hypotension). Some people experience heart and kidney problems as well. Various eye problems may occur, such as cloudiness of the clear gel that fills the eyeball (vitreous opacity), dry eyes, increased pressure in the eyes (glaucoma), or pupils with an irregular or "scalloped" appearance. Some people with this form of transthyretin amyloidosis develop carpal tunnel syndrome, which is characterized by numbness, tingling, and weakness in the hands and fingers.

The cardiac form of transthyretin amyloidosis affects the heart. People with cardiac amyloidosis may have an abnormal heartbeat (arrhythmia), an enlarged heart (cardiomegaly), or orthostatic hypertension. These abnormalities can lead to progressive heart failure and death. Occasionally, people with the cardiac form of transthyretin amyloidosis have mild peripheral neuropathy.

A less common form of transthyretin amyloidosis, called the leptomeningeal form, primarily affects the central nervous system. In people with this form, amyloidosis occurs in the leptomeninges, which are two thin layers of tissue that cover the brain and spinal cord. A buildup of proteins in this tissue can cause stroke and bleeding in the brain, an accumulation of fluid in the brain (hydrocephalus), difficulty coordinating movements (ataxia), muscle stiffness and weakness (spastic paralysis), seizures, and loss of intellectual function (dementia). Eye problems similar to those seen in the neuropathic form of transthyretin amyloidosis may also occur; people with leptomeningeal transthyretin amyloidosis who have these eye problems are said to have the oculoleptomeningeal form.

Variants (also called mutations) in the TTR gene cause transthyretin amyloidosis. The TTR gene provides instructions for making a protein called transthyretin. Transthyretin transports vitamin A (retinol) and a hormone called thyroxine throughout the body. To transport retinol and thyroxine, four transthyretin proteins must attach (bind) to each other to form a four-protein unit (tetramer).

The TTR gene variants that cause transthyretin amyloidosis alter the structure of transthyretin, impairing its ability to form tetramers. As a result, the tetramers break down into individual transthyretin proteins, which attach to each other in strands called fibrils. The fibrils clump together and form amyloid deposits in certain tissues, leading to the signs and symptoms of transthyretin amyloidosis.

Normal Function

The TTR gene provides instructions for making a protein called transthyretin. This protein transports vitamin A (retinol) and a hormone called thyroxine throughout the body. To transport thyroxine, four transthyretin proteins must attach (bind) to each other to form a four-protein unit (tetramer). To transport retinol, transthyretin must form a tetramer and bind to another protein called retinol-binding protein. Transthyretin is produced primarily in the liver, and a small amount of this protein is produced in an area of the brain called the choroid plexus and in the light-sensitive tissue that lines the back of the eye (the retina).

Health Conditions Related to Genetic Changes

Transthyretin amyloidosis

Variants (also called mutations) in the TTR gene cause transthyretin amyloidosis. Nearly all of these variants change one protein building block (amino acid) in the transthyretin protein. The most common variant found in people with transthyretin amyloidosis replaces the amino acid valine with the amino acid methionine at position 50 in the transthyretin protein (written as Val50Met or V50M). This variant is seen most commonly in the Portuguese and Swedish populations, although it is found in affected people worldwide. Another common variant replaces the amino acid valine with the amino acid isoleucine at position 142 in the transthyretin protein (written as Val142Ile or V142I). It is estimated that 3 percent to 3.9 percent of African Americans and 5 percent of some West African populations have this variant.

Most of the TTR gene variants that cause transthyretin amyloidosis alter the structure of transthyretin, impairing its ability to form tetramers. As a result, the tetramers break down into individual transthyretin proteins, which attach to each other to form strands called fibrils. The fibrils clump together and form amyloid deposits in certain tissues, leading to the signs and symptoms of transthyretin amyloidosis.

Carpal tunnel syndrome

MedlinePlus Genetics provides information about Carpal tunnel syndrome

Other disorders

In some older adults, deposits of normal transthyretin proteins cause a condition called senile systemic amyloidosis. People with this condition do not have a variant in the TTR gene; for reasons that are unclear, the transthyretin protein begins to form protein deposits. The most common place for amyloidosis in people with this condition is in the heart; this causes progressive heart failure. Other sites of amyloidosis may include the lungs, blood vessels, and kidneys. It is estimated that 10 percent to 25 percent of people older than 80 have senile systemic amyloidosis.

Other Names for This Gene

• ATTR
• PALB
• prealbumin, amyloidosis type I
• TBPA
• TTHY_HUMAN

Genomic Location

Familial transthyretin amyloidosis (FTA) is inherited in families in an autosomal dominant pattern. This means only one copy of a mutatedTTR gene is needed for a person to have the condition. The mutation can be inherited from a parent or can happen by chance for the first time (de novo) in an individual.

Each child of a person with FTA has a 50% chance of inheriting the mutation. Most children who inherit a TTR mutation will develop FTA, although they could be more or less severely affected than their parent. For reasons that are unclear, some people have mutations in the TTR gene and never develop FTA.

The exact incidence of familial transthyretin amyloidosis is unknown. It is more common in certain parts of Portugal, Sweden, and Japan. The common TTR gene mutation, known as Val30Met, associated with familial transthyretin amyloidosis (FTA) occurs in about 1 in 583 people in some parts of Portugal, compared to about 1 in 100,000 people in the US. A different TTR gene mutation associated with FTA, Val122Ile, is more common in parts of West Africa. While FTA is more common in certain parts of the world, it has been found across all ethnic groups and occurs equally in males and females.

Familial transthyretin amyloidosis (FTA) is a slowly progressing, adult-onset condition. Symptoms depend on which body parts are most affected. The age symptoms begin may also vary by country. In Portugal and Japan, people with FTA usually start developing symptoms in their late 20s to 40s. In other parts of the world, people with FTA may not have symptoms until after age 50.

The most common form of FTA affects the peripheral nervous system. The peripheral nerves send messages from the brain and spinal cord to the rest of the body. Other forms of FTA can affect the brain, spinal cord, heart, and eyes.

Symptoms of FTA include

• Weakness, numbness or pain in the lower legs and feet
• Carpal tunnel syndrome in both wrists
• Sexual impotence
• Urinary problems, protein in the urine
• Diarrhea or constipation
• Unexplained weight loss
• Dry eyes, increased pressure in the eyes (glaucoma), seeing ‘floaters’
• Abnormal heart beat, enlarged heart
• Getting dizzy when moving from sitting to standing (orthostatic hypotension)
• Dry eyes and mouth

Later symptoms may include muscle weakness and stiffness, difficulty with coordination, stroke, seizures, dementia, and congestive heart failure.

Less common symptoms include skin changes, hearing loss, shortness of breath, and anemia.

There is no treatment available for familial transthyretin amyloidosis (FTA) that reverses damage caused by amyloid deposits, but there are treatments that may prevent or delay progression. Treatment depends on which tissues are affected and how far the disease has progressed.

Liver transplantation is the "gold standard" for treatment for FTA, because it replaces the main source of amyloid. It may slow or halt progression of peripheral neuropathy, but the disease often still progresses in the eyes and brain. Transplantation ideally should be done as early as possible before there are severe neurological problems.

Several medications have been developed that slow the build-up of amyloid along nerves and in other parts of the body. These include tafamidis, diflunsial, and more recently inotersen and patisiran. There are other drugs that are currently under investigation for this condition.

Additional treatments may include heart and/or kidney transplantation, replacement of the liquid part of the eye (vitrectomy) for eye involvement, and carpal tunnel surgery.

Diuretics, medications that remove excess water and salt from the body, are often used to manage congestive heart failure associated with the disease. Other symptoms of FTA are treated as they arise.

The outlook and life expectancy for each person with familial transthyretin amyloidosis (FTA) varies and depends on the TTR genemutation present, organ(s) involved, and how early a person is diagnosed and treated. Some people whose symptoms begin at a younger age may live for only a few years after diagnosis, while older patients with slowly progressive disease can live for many years. On average, people with FTA typically live for 7-12 years after they are first diagnosed.

The long-term outlook after liver transplant is also influenced by many factors, including the type of amyloid present, nutritional status, age, and how much the brain and heart are involved. Newer medications are now available that help slow the build-up of amyloid and delay symptoms and it is not yet clear how these medications will affect the long-term outlook for people with FTA. People with questions about their personal outlook should speak with their healthcare providers.

The exact incidence of transthyretin amyloidosis is unknown. In northern Portugal, the incidence of this condition is thought to be one in 538 people. Transthyretin amyloidosis is less common among Americans of European descent, where it is estimated to affect one in 100,000 people. The cardiac form of transthyretin amyloidosis is more common among people with African ancestry. It is estimated that this form affects between 3 percent and 3.9 percent of African Americans and approximately 5 percent of people in some areas of West Africa.