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Hereditary amyloidosis, also called familial amyloidosis, is a rare disease caused by a gene mutation (change) that is passed down within families. Hereditary amyloidosis can affect several different parts of the body.
The most common type of hereditary amyloidosis is called hereditary ATTR (hATTR) amyloidosis. The gene mutations that cause hATTR amyloidosis are found in as much as 4 percent of the Black population and about 1 out of 100,000 (0.001 percent) white people within the United States. However, not everyone with the gene mutation develops the disease.
About 50,000 people are currently living with hATTR amyloidosis around the world. Read on to learn more about causes, symptoms, outlook, and other key topics related to hATTR amyloidosis.
Hereditary ATTR amyloidosis is caused by a gene change that you inherit from your parents. Normal genes produce proteins that carry out multiple roles within a cell. In hATTR amyloidosis, a gene mutation causes an abnormal protein to form. This protein called an amyloid protein misfolds and is not shaped correctly. It can’t perform its usual tasks. Amyloid proteins tend to attach and form clumps called amyloid fibrils or amyloid deposits. The clumps can collect in different organs and tissues, causing damage.
If someone develops hATTR amyloidosis, their parents, children, and siblings each have a 50 percent chance of having the same gene mutation. When one person in a family is diagnosed with hATTR amyloidosis, it can be helpful for other family members to talk to a genetic counselor to find out about their own risk of the disease.
Multiple gene mutations can lead to hATTR amyloidosis. The disease is divided into two main types (hATTR and non-TTR) based on which gene is affected. The two types of hATTR amyloidosis affect different organs, lead to different sets of symptoms, and have different treatment options.
Some people with amyloidosis have a mutation in the transthyretin (TTR) gene, which leads to hATTR amyloidosis. 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. For instance, the V30M variant is most often found in people from Portugal, Spain, France, Sweden, and Japan. The V122I mutation is most common in the Black population, and T60A is most often seen in people from the United Kingdom and Ireland.
The liver uses the TTR gene to make a protein also called TTR. In people with hATTR amyloidosis, the liver makes misfolded amyloid TTR, which spreads throughout the body. TTR mutations may cause problems with the heart, nerves, or both. When hATTR amyloidosis affects the heart, it may be called familial amyloid cardiomyopathy. When hATTR amyloidosis affects the nerves, it may be known as familial amyloid polyneuropathy. However, these terms are older and are now rarely used.
Non-TTR amyloidosis is caused by mutations in other genes. Scientists currently know of at least 60 gene mutations that can cause non-TTR amyloidosis. Non-TTR amyloidosis is even less common than hATTR amyloidosis.
Symptoms vary based on which type of hATTR amyloidosis 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.
Amyloid fibrils can build up in the heart muscle, heart valves, or blood vessels. Often, the walls of the heart become thick, the heart has a difficult time pumping blood, and arrhythmias (problems with heart rhythm) develop. Eventually, hATTR amyloidosis can cause heart failure.
Nerve symptoms in hATTR amyloidosis often start small and then gradually worsen and spread. Many people first notice pain or numbness in the toes. Later, the ankles and then lower legs may become numb. If amyloidosis progresses, people may eventually have trouble moving their legs. Eventually, nerves in the arms and fingers can be affected. When nerve damage causes symptoms like pain and numbness, it’s known as neuropathy.
Other organs may also be affected, and additional symptoms of hATTR amyloidosis include:
Read more about which symptoms to watch for in hATTR amyloidosis.
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.
If your doctor suspects you have amyloidosis, they will look for amyloid proteins in your body with a biopsy. Biopsies are used to look for amyloid deposits in organs and can also determine whether an organ is damaged. During a biopsy, a doctor will remove a small piece of tissue. A doctor may take a biopsy of an organ that is causing symptoms, or they may biopsy the abdominal fat pad (belly fat). Alternatively, you may need to get a biopsy of your rectum. In some cases, a rectal biopsy may be a useful diagnostic tool for hATTR amyloidosis.
After your doctor takes a tissue sample, they will send it to a lab to be analyzed. There, technicians will stain the tissue with a dye called Congo red. If amyloid proteins are present, they will appear green under a microscope.
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, because hATTR amyloidosis runs in families. Often, several people within the same family will have this condition. If your doctor finds that you have amyloidosis, knowing if other people in your family have the condition can provide a clue as to whether your amyloidosis is hereditary.
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 or AL amyloidosis, another common type of amyloidosis that is not hereditary. AL amyloidosis is also called amyloid light chain or primary amyloidosis and is the most common type of amyloidosis in the United States.
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.
There are two goals in treating hATTR amyloidosis. One is to help the body stop making so much amyloid protein. The other is to reduce the symptoms of amyloidosis and heal 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.
Now, hATTR amyloidosis can be treated with medication. There are two categories of medication that may help. 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) to treat people with hATTR amyloidosis who have nerve problems:
A second type of medication stabilizes the TTR protein, preventing it from making amyloid fibrils. Tafamidis (Vyndamax) is FDA approved to treat people with hATTR amyloidosis who have heart symptoms. Another stabilizer drug, diflunisal, is not officially approved to treat amyloidosis but 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.) AG10 is an additional stabilizer drug that is being studied in clinical trials.
Other drugs are also in the process of being studied. It’s not yet clear if these medications may help treat hATTR amyloidosis:
Read more about the safety and effectiveness of hATTR amyloidosis treatments.
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. If you’re experiencing amyloidosis symptoms or side effects of treatments, talk to your health care team about how to manage them. There may be ways to make you more comfortable and increase your quality of life.
Because symptoms of hATTR amyloidosis vary and range in severity, your outlook can also vary. On average, people live for three to 15 years after being diagnosed with hATTR amyloidosis. Several factors can affect your prognosis (outcome of your condition), including which gene mutation you have, which organs are affected, and whether you had an early diagnosis. Many of the medications that are now used to treat hATTR amyloidosis are relatively new. Some of these treatments may slow disease progression and improve the outlook for people with this potentially life-threatening condition.
Read more about life expectancy with hATTR amyloidosis.
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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Manuel Penton, M.D. is a medical editor at MyHealthTeam. Learn more about him here.
Maureen McNulty studied molecular genetics and English at Ohio State University. Learn more about her here.
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