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Hereditary Amyloidosis — An Overview

Posted on April 01, 2021
Medically reviewed by
Todd Gersten, M.D.
Article written by
Maureen McNulty

Hereditary amyloidosis, also called familial amyloidosis, is a rare disease caused by a gene mutation 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 in about 1 out of 100,000 white people within the United States. However, not everyone with the gene mutation develops the disease.

Experts estimate that about 50,000 people are currently living with hATTR amyloidosis around the world. The other type of hereditary amyloidosis, non-TTR amyloidosis, is even less common.

Causes of Hereditary Amyloidosis

Hereditary 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 hereditary amyloidosis, a gene mutation causes an abnormal protein to form. This protein, called an amyloid protein, 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 hereditary amyloidosis, their parents, children, and siblings each have a 50 percent chance of also having the same gene mutation. When one person in a family is diagnosed with hereditary amyloidosis, it can be helpful for other family members to talk to a genetic counselor to find out about their own risk of disease.

Types of Hereditary Amyloidosis

Multiple gene mutations can lead to hereditary amyloidosis. The disease is divided into two main types (hATTR and non-TTR) based on which gene is affected. The two types of hereditary amyloidosis affect different organs, lead to different sets of symptoms, and have different treatment options.

Hereditary ATTR Amyloidosis

Some people with amyloidosis have a mutation in the transthyretin (TTR) gene, which leads to hereditary ATTR 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 hereditary 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. hATTR that affects the nerves may be known 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 other genes. Scientists currently know of at least 60 gene mutations that can cause non-TTR amyloidosis. Some of the genes that may be mutated in non-TTR amyloidosis are:

  • Apolipoprotein A1
  • Apolipoprotein A2
  • Gelsolin
  • LECT2
  • Cystatin C
  • Fibrinogen A alpha chain

Hereditary Amyloidosis Symptoms

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

Non-TTR amyloidosis affects different organs based on which genetic mutation is involved. For example:

  • Apolipoprotein A1 mutations tend to cause symptoms in the kidneys, liver, nerves, heart, skin, and larynx (voice box).
  • Apolipoprotein A2 mutations lead to kidney problems.
  • Fibrinogen A alpha-chain mutations cause amyloid proteins to build up in the kidneys and nerves.
  • Gelsolin mutations may involve the nerves or eyes.
  • Cystatin C mutation leads to brain hemorrhage (bleeding).

Heart Symptoms

Amyloid fibrils can build up in the heart muscle, the heart valves, or the blood vessels. Often, the walls of the heart become thick, and the heart has a difficult time pumping blood. Eventually, hereditary amyloidosis can cause heart failure.

Nerve Symptoms

Nerve symptoms in hereditary 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 is known as neuropathy.

Other Symptoms

Other organs may also be affected. Additional symptoms of hereditary amyloidosis include:

  • Tiredness
  • Dizziness
  • Nausea
  • Diarrhea
  • Constipation
  • Feeling full after only eating a little
  • Weight loss
  • Insomnia
  • Breathing difficulties
  • Glaucoma (damage to the nerve connecting the eye to the brain)
  • Swollen eyelids
  • Edema (swelling in the legs or ankles)
  • Orthostatic hypotension (a decrease in blood pressure when you stand up)
  • Erectile dysfunction
  • Carpal tunnel syndrome (feelings of pain, tingling, or numbness in the wrist)

Diagnosis of 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.

Biopsy

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 detect 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. Biopsies of rectal tissue are better for diagnosing certain types of hereditary amyloidosis, including 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.

Identifying Your Type of Amyloidosis

If your doctor finds amyloid deposits in your tissues, the next step is determining whether you have hereditary amyloidosis or another type.

When making a diagnosis, your doctor will ask you about your family history. Hereditary amyloidosis runs in families. Often, several different people within the same family will have this condition. If your doctor finds that you have amyloidosis, knowing whether 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. A TcPYP scan can confirm whether you have ATTR amyloidosis or AL amyloidosis, another common type of amyloidosis that is not hereditary.

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

Treatments for Hereditary Amyloidosis

Hereditary amyloidosis treatment often has two goals. 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.

Treatment for hATTR Amyloidosis

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 a couple of different categories of medication that may help. One type of medication blocks the TTR gene from making amyloid protein. Two 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: Onpattro (patisiran) and Tegsedi (inotersen).

A second type of medication stabilizes the TTR protein, preventing it from making amyloid fibrils. Vyndamax (tafamidis) is FDA-approved to treat people with hATTR amyloidosis who have heart symptoms. Another stabilizer drug, Dolobid (diflunisal), is not officially approved to treat amyloidosis but may be used off-label. 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:

  • Vibramycin (doxycycline), an antibiotic that may be able to help break up amyloid fibrils
  • Green tea extract, a supplement that could also play a role in removing amyloid proteins
  • PRX-004, an antibody that may be able to remove abnormal TTR proteins

Non-TTR Amyloidosis Treatments

Occasionally, liver transplantation may help treat non-TTR amyloidosis. Amyloid proteins caused by fibrinogen mutations are made in the liver, so a transplant may help people with this form of amyloidosis. However, in other types of non-TTR amyloidosis, amyloid proteins are often made by other tissues. A liver transplant won’t help in these cases.

Because non-TTR amyloidosis is so rare, it is more difficult to study than hATTR amyloidosis. Researchers have not developed as many treatments for non-TTR amyloidosis. If you are diagnosed with this condition, it is a good idea to be treated by an amyloidosis specialist who can help you understand which treatments may be best for your specific genetic mutation.

Treating Amyloidosis Symptoms

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 are experiencing amyloidosis symptoms, 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.

Hereditary Amyloidosis Outlook

People live for an average of seven to 12 years after being diagnosed with hATTR amyloidosis. Your outlook may be different. Several factors can affect your prognosis, including which gene mutation you have, which organs are affected, and whether the amyloidosis is caught early. Many of the medications that are now used to treat hATTR amyloidosis are relatively new. Some of these treatments may lead to a better outlook for people with this condition.

The prognosis for non-TTR amyloidosis varies based on the specific gene affected. For example, people with amyloidosis caused by fibrinogen mutations often live for more than 15 years. And amyloidosis with gelsolin mutations may not shorten a person’s life span at all.

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.

Are you living with hereditary amyloidosis? Share your experiences in the comments below, or start a conversation by posting on MyAmyloidosisTeam.

All updates must be accompanied by text or a picture.
Todd Gersten, M.D. is a hematologist-oncologist at the Florida Cancer Specialists & Research Institute in Wellington, Florida. Review provided by VeriMed Healthcare Network. 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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