Hereditary amyloidosis, also called familial amyloidosis, is a rare disease caused by a gene mutation (change) passed down through families. In most cases, the mutation affects the transthyretin (TTR) gene, which provides instructions for making a protein that carries thyroid hormone and vitamin A in the blood. Changes in this gene can lead to a buildup of abnormal protein deposits in different parts of the body, affecting organs and nerves.

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The most common form is hereditary transthyretin amyloidosis (hATTR amyloidosis). This condition is more common among African-Americans in the United States, where about 4 percent have the related TTR gene variant, according to the National Organization for Rare Disorders (NORD). Among people of European descent in the U.S., about 1 in 100,000 carry the mutation. However, having the gene mutation doesn’t always mean someone will develop the disease.

Globally, around 50,000 people are living with hATTR amyloidosis, although many cases likely go undiagnosed. Read on to learn more about causes, symptoms, outlook, and other key details about hATTR amyloidosis.

Globally, around 50,000 people are living with hATTR amyloidosis.

1. Genetic Changes Cause hATTR Amyloidosis

Hereditary ATTR amyloidosis happens because of a gene change passed down from a parent. Normally, genes produce proteins that help the body function properly. In hATTR amyloidosis, a mutation in the TTR gene causes a protein called transthyretin to misfold. These misfolded proteins clump together and form amyloid fibrils or amyloid deposits, which can build up in different organs and tissues, leading to damage.

If someone has hATTR amyloidosis, each of their children has a 50 percent chance of inheriting the same gene mutation. Because of this, it’s a good idea for family members to talk with a genetic counselor to learn more about their own risk.

2. There Are 2 Main Types of Hereditary Amyloidosis

Multiple gene mutations can lead to hereditary amyloidosis. The disease is divided into two main types — ATTR amyloidosis and non-TTR amyloidosis — based on the gene involved. These types can affect different organs, lead to unique symptoms, and have distinct treatment options.

ATTR Amyloidosis

Most cases of hereditary ATTR amyloidosis are caused by mutations in the TTR gene. So far, scientists know of 136 TTR mutations that can cause ATTR amyloidosis. Some mutations are more common in people of certain ethnicities or who live in certain parts of the world.

According to the Amyloidosis Research Consortium:

• The V30M variant is most often found in people from Portugal, Spain, France, Sweden, and Japan and their descendants.
• The V122I mutation is most often found in African Americans.
• The T60A mutation is most often seen in people of Irish descent and is the most common variant in the United Kingdom.

These TTR mutations can lead to a range of health problems. The buildup of amyloid deposits may affect the heart, nerves, or both, depending on the specific gene variant.

Non-TTR Amyloidosis

Non-TTR amyloidosis is caused by mutations in genes other than TTR. Scientists currently know of at least 60 mutations linked to this condition, which is even rarer than ATTR amyloidosis.

3. Symptoms of hATTR Amyloidosis Vary by Type

Symptoms of hATTR amyloidosis vary based on which organs and tissues are affected by the amyloid deposits. The condition most often causes problems with the heart (cardiac amyloidosis) and nervous system.

Heart Symptoms

People with hATTR can develop transthyretin amyloid cardiomyopathy (ATTR-CM). Amyloid fibrils can build up in the heart muscle, heart valves, or blood vessels. This often causes the walls of the heart to thicken, making it harder for the heart to pump blood. People with ATTR-CM may also develop arrhythmias (irregular heart rhythms). Over time, these issues can lead to heart failure (when the heart doesn’t pump blood well enough to meet the body’s needs).

Nerve Symptoms

Nerve symptoms in hATTR amyloidosis — hATTR with polyneuropathy (ATTR-PN) — often start gradually and worsen over time. Many people first feel pain or numbness in their toes, which may spread to the ankles and then the lower legs. As ATTR-PN progresses, it may become harder to move the legs. Eventually, nerves in the arms and fingers can also be affected.

Nerve symptoms in hATTR can have widespread effects, including:

• Nausea, diarrhea, or constipation
• Early satiety (feeling full quickly while eating)
• Weight loss
• Orthostatic hypotension (a drop in blood pressure while standing)
• Sexual impotence
• Carpal tunnel syndrome (feelings of pain, tingling, or numbness in the wrist)

4. Biopsies Detect Amyloid Deposits and Aid Diagnosis

Your doctor may use different types of tests to diagnose amyloidosis. Some tests look for amyloid proteins, and others help you find out which type of amyloidosis you have.

Biopsy

A biopsy is a key test for diagnosing amyloidosis. This procedure involves removing a small piece of tissue to check for amyloid deposits and determine if an organ is damaged. Your doctor may take a biopsy from an organ that’s showing symptoms or from an area like the abdominal fat pad (fat in your belly).

The tissue sample is then sent to a lab for analysis. Lab technicians stain the sample with a dye called Congo red, which makes amyloid proteins show up as green under polarized light when viewed through a microscope.

Identifying Your Type of Amyloidosis

If amyloid deposits are found, the next step is to determine which type of amyloidosis you have — such as hATTR amyloidosis or another form.

Your doctor will ask about your family history, since hATTR amyloidosis is inherited and may affect multiple family members. Sharing whether anyone in your family has been diagnosed with amyloidosis can help guide testing.

Your doctor may order an echocardiogram to check your heart function and may also recommend a nuclear imaging test called a technetium pyrophosphate scan. This scan can help tell the difference between ATTR amyloidosis and amyloid light chain (AL) amyloidosis — also called primary amyloidosis — which is the most common type in the U.S. AL amyloidosis is not hereditary.

If ATTR amyloidosis is suspected, genetic testing of a blood sample can confirm whether you have the hereditary form by identifying changes in the TTR gene.

5. Several Treatments Are Available for hATTR Amyloidosis

Treatment for hATTR amyloidosis focuses on two goals — reducing the production of amyloid proteins and managing symptoms or organ damage.

In the past, the main treatment was a liver transplant, since the liver makes most of the abnormal TTR protein. Replacing it with a healthy liver could slow progression. However, liver transplants are now less common thanks to new medications that target the disease earlier and more effectively.

There are two categories of medication for hATTR amyloidosis. One type blocks the TTR gene from making amyloid protein. Three drugs in this category have been approved by the U.S. Food and Drug Administration (FDA) for treating hATTR amyloidosis with nerve involvement:

• Eplontersen (Wainua)
• Patisiran (Onpattro)
• Vutrisiran (Amvuttra)

A second type of medication stabilizes the TTR protein, preventing it from making amyloid fibrils. The FDA has approved these medications to treat hATTR with heart involvement:

• Acoramidis (Attruby)
• Tafamidis (Vyndamax)
• Tafamidis meglumine (Vyndaqel)
• Vutrisiran (approved for both nerve and heart symptoms)

Another stabilizer, diflunisal, is sometimes prescribed off-label, meaning it’s not FDA-approved for amyloidosis but may be used under a doctor’s guidance. Additional medications are being studied in clinical trials.

Treating Amyloidosis Symptoms and Organ Damage

Medications can also help manage symptoms such as nerve pain and digestive issues. If amyloid has severely damaged an organ, such as the heart or kidneys, an organ transplant may be considered.

If you’re experiencing symptoms or side effects from treatment, talk with your healthcare team. There may be ways to make you more comfortable and enhance your quality of life.

6. The Outlook for hATTR Amyloidosis Is Improving

Because symptoms of hATTR amyloidosis vary and range in severity, each person’s prognosis (outlook) can differ. In the past, people with untreated hATTR amyloidosis had a median survival of 4.7 years after diagnosis — meaning half lived longer and half lived less. Today, new treatments are significantly improving life expectancy with hATTR amyloidosis, with some people living over a decade or longer following diagnosis.

New treatments are significantly improving life expectancy with hATTR amyloidosis, with some people living over a decade or longer following diagnosis.

Several factors can influence your prognosis, including:

• Which gene mutation you have
• Which organs are affected
• Whether you had an early diagnosis

Medications that treat heart-related symptoms and nerve involvement can slow disease progression and improve quality of life. Liver transplantation also remains a life-extending option for certain cases.

With ongoing advances in treatment and earlier diagnoses, the outlook for people with hATTR amyloidosis continues to improve, offering hope for longer, healthier lives.

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