Hereditary amyloidosis, also called familial amyloidosis, is a rare disease caused by a gene mutation (change in DNA) in the transthyretin (TTR) gene. This gene produces a protein that carries thyroid hormone and vitamin A through the blood. The mutation can be passed down through families and may lead to problems in various parts of the body.

The most common type of hereditary amyloidosis, hATTR amyloidosis, is linked to the TTR gene. In the United States, around 4 percent of the African American population and about 1 out of 100,000 white individuals have the gene mutation that causes hATTR amyloidosis, according to the National Organization for Rare Disorders (NORD). However, having the gene mutation does not guarantee someone will develop the disease.

Globally, around 50,000 people are living with hATTR amyloidosis. Read on to learn more about causes, symptoms, outlook, and other key topics related to hATTR amyloidosis.

1. Genetic Changes Cause hATTR Amyloidosis

Hereditary ATTR amyloidosis happens because of a gene change that you inherit from your parents. Normally, genes produce proteins that perform important tasks in the body. In hATTR amyloidosis, a gene mutation causes a protein called transthyretin to misfold, meaning it isn’t shaped correctly and can’t do its usual job. These misfolded proteins clump together to form amyloid fibrils or amyloid deposits, which can build up in different organs and tissues, leading to damage.

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

If someone develops hATTR amyloidosis, their parents, children, and siblings each have a 50 percent chance of having the same gene mutation. Because of this, if one family member is diagnosed with hATTR amyloidosis, it’s a good idea for other relatives to speak with a genetic counselor to learn more about their own risk.

2. There Are Two Main Types of hATTR Amyloidosis

Multiple gene mutations can lead to hATTR 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. Scientists know of 136 different TTR mutations that can cause ATTR amyloidosis, and more may be discovered in the future. Some mutations are more common in people of certain ethnicities or living 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.

The TTR gene directs the liver to produce a protein called transthyretin, which carries thyroid hormone and vitamin A in the blood. In hATTR amyloidosis, TTR protein misfolds, creating amyloid deposits that spread throughout the body. These deposits can cause problems with the heart, nerves, or both.

When hATTR amyloidosis affects the heart, it is sometimes called familial amyloid cardiomyopathy. When it affects the nerves, it is occasionally referred to as familial amyloid polyneuropathy. However, these terms are older and are now rarely used.

Non-TTR Amyloidosis

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

3. Symptoms of hATTR Amyloidosis Vary by Type

Symptoms for hATTR amyloidosis vary based on which type of condition you have. The condition most often causes problems with the heart (cardiac amyloidosis) and nervous system. It can also affect the gastrointestinal (digestive) system, kidneys, eyes, and wrists.

Heart Symptoms

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 cardiac amyloidosis may also develop arrhythmias (irregular heart rhythms). Over time, these issues can lead to heart failure.

Nerve Symptoms

Nerve symptoms in hATTR amyloidosis, known as neuropathy, 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 the condition progresses, it may become harder to move the legs. Eventually, nerves in the arms and fingers can also be affected.

Other Symptoms

Other organs may also be affected, and additional symptoms of hATTR amyloidosis include:

• Fatigue (tiredness that does not improve with rest)
• Dizziness
• Nausea, diarrhea, or constipation
• Early satiety (feeling full quickly while eating)
• Weight loss
• Insomnia (difficulty sleeping)
• Shortness of breath
• Eye problems such as glaucoma (damage to the nerve connecting the eye to the brain) or swollen eyelids
• Edema (swelling in the legs or ankles)
• Orthostatic hypotension (a drop in blood pressure while standing)
• Erectile dysfunction (difficulty maintaining an erection)
• Carpal tunnel syndrome (feelings of pain, tingling, or numbness in the wrist)
• Peripheral neuropathy (tingling or numbness in the hands or feet)

4. Biopsies Help Diagnose hATTR Amyloidosis by Detecting Amyloid Deposits

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. It 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 is showing symptoms or from an area like the abdominal fat pad (fat in your belly). Sometimes, a rectal biopsy is used as a diagnostic tool for hATTR amyloidosis.

Once a tissue sample is collected, it is sent to a lab for analysis. Lab technicians will 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 your doctor finds amyloid deposits in your tissues, the next step is determining whether you have hATTR amyloidosis or another type.

When making a diagnosis, your doctor will ask you about your family history, as hATTR amyloidosis is inherited and tends to affect multiple family members. Knowing whether relatives have been diagnosed with amyloidosis can help point to a hereditary form of the disease.

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

Your doctor may recommend getting a bone scan called a technetium pyrophosphate (TcPYP) scan. This test can show whether amyloid fibrils are in your heart. An echocardiogram may also be performed to check your heart function. A TcPYP scan can confirm whether you have ATTR amyloidosis, which can be hereditary, or AL amyloidosis — the most common type of amyloidosis in the United States, also called amyloid light chain or primary amyloidosis — which is not hereditary. It can alone provide the diagnosis of ATTR, sometimes even without biopsy. In the case of AL, further tests may be necessary.

Genetic testing of a blood sample can also help doctors diagnose hATTR amyloidosis. Genetic tests can read genes and find any mutations that may be present.

5. Several Treatments Are Available for hATTR Amyloidosis

There are two goals in treating hATTR amyloidosis: to reduce the production of amyloid proteins and to manage symptoms and repair organ damage.

Traditionally, hATTR amyloidosis was treated with a liver transplant. The liver is the organ that makes most of the abnormal TTR protein, so getting a new, healthy liver lowers the levels of amyloid proteins. However, liver transplants are now less common thanks to new medications.

There are two categories of medication for hATTR amyloidosis. One type of medication 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. Acoramidis (Attruby), tafamidis (Vyndamax), and tafamidis meglumine (Vyndaqel) are FDA-approved to treat people with hATTR amyloidosis who have heart symptoms.

Another stabilizer drug, diflunisal, is not officially approved to treat amyloidosis, but it is sometimes prescribed off-label. (When a drug is used off-label, it means that it is being used in a way that is different from what is indicated on the drug’s label or approved by regulatory authorities.) Other drugs are also being studied.

Treating Amyloidosis Symptoms and Organ Damage

Medication may help treat symptoms like nerve pain and digestive symptoms. Additionally, if an organ such as the kidney or heart becomes too damaged, you may need a transplant.

hATTR amyloidosis most often causes problems with the heart and nervous system.

If you’re experiencing amyloidosis symptoms or side effects of treatments, talk to your healthcare team about how to manage them. There may be ways to make you more comfortable and enhance your quality of life.

6. The Outlook for hATTR Amyloidosis Has Improved in Recent Years

Because symptoms of hATTR amyloidosis vary and range in severity, your outlook can also vary. Historically, untreated hATTR amyloidosis had a median survival of 4.7 years after diagnosis. This means that 4.7 years after diagnosis, half of the study participants were still alive. However, new treatments are significantly improving life expectancy with hATTR amyloidosis, with some people living over a decade or longer following diagnosis.

Several factors can affect your prognosis (outcome of your condition), including:

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

Medications for heart-related symptoms and nerve involvement can slow disease progression and improve survival. 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 and better-quality lives.

Talk With Others Who Understand

MyAmyloidosisTeam is the social network for people with amyloidosis and their loved ones. On MyAmyloidosisTeam, members come together to ask questions, give advice, and share their stories with others who understand life with amyloidosis.

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