Hereditary Transthyretin Amyloidosis (hATTR) With Polyneuropathy

Medically Reviewed by Melinda Ratini, MS, DO on May 17, 2023
9 min read

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy is a rare disorder passed down in families that gets worse over time. It’s a result of a change in a gene, also called a mutation. The mutated TTR gene in the liver makes abnormal shapes of a protein called transthyretin. These abnormal transthyretin proteins clump together in various organs and nerves to form deposits called amyloids. The deposits of amyloid damage organs and tissues. hATTR can cause serious complications and death. But symptoms can be managed through drugs and therapies. 

Your doctor might also use the word "amyloidosis" when talking about the condition. That's because hATTR is one of a group of diseases also known by that name.

When you have hATTR, you may have a variety of symptoms when too much amyloid protein starts to collect in the nerves that branch out from your brain and spinal cord. This can affect your senses. For instance, you may be less likely to feel pain or heat, or you might have trouble walking. Or it could affect your hearing or vision.

The protein also gathers in the nerves that control important actions in your body, like blood pressure, heart rate, and digestion. You may have trouble going to the bathroom or having sex, or you may sweat too much. Your heart may beat too fast or too slowly.

Serious symptoms that can be life-threatening include an enlarged heart and an irregular heartbeat.

hATTR can affect people of almost any age, usually between their 30s and 70s.

Because hATTR can affect a number of organs and systems in your body, it can have a lot of symptoms. The most serious problems include heart enlargement and irregular heartbeats, the cause of death in many people with hATTR.

You might have numbness, tingling, and swelling in your hands and feet. Or you could have problems like diarrhea, constipation, feeling full soon after you start eating, and trouble peeing. You might also feel very tired.

Some eye problems you could get include:

  • Cloudiness
  • Dry eyes
  • Increased pressure in the eye (glaucoma)

As the name suggests, hereditary transthyretin amyloidosis (hATTR) with polyneuropathy runs in families. If you have it, you got it from genes one or both of your parents passed to you.

How common is it?

The exact number of people who have hATTR isn’t known. In parts of Brazil, Japan, Portugal, and Sweden, the disease is considered endemic. That means it’s around all the time in certain areas. In northern Portugal, for instance, hATTR is common, with one in 538 diagnosed. 

In the U.S., an estimated 6,400 people have hATTR. Americans of European descent are more likely to have it, with one in 100,000 people diagnosed. Black and Irish Americans more commonly get it, but it can impact all ethnic groups. Men and women are equally affected. 

It’s likely that there are many more hATTR cases than reported. Because its symptoms are similar to those of other conditions, it’s often misdiagnosed. 

If you know hATTR runs in your family, your doctor will probably suggest you get a DNA test to see if you have the gene that causes it. They check a sample of your blood, cheek cells, or skin.

It can be tough to diagnose hATTR. Your doctor will ask you about your health history to get clues, including:

  • Have you or anyone in your family had heart failure or thickening of the heart muscle?
  • Do you feel numbness or tingling in your hands or feet?
  • Do you have digestive problems such as diarrhea or constipation?
  • Are you having trouble controlling your bladder?
  • Do you get dizzy when standing up or stretching?
  • Have you had any eye or vision problems?

Your doctor may want to do tests related to symptoms you have, too, especially for your nerves and heart.

Blood and urine tests. These simple lab tests will sometimes show if there's too much protein in your body.

Tissue biopsy. Your doctor may suggest a tissue biopsy if hATTR is suspected. They will take a little bit of tissue from your body, often a small piece of fat from your belly or side. This is quick and does not need a hospital stay. The doctor numbs the skin and then uses a needle to pull out some of the fat cells. Then a lab runs tests on these cells. A type of bone scan called scintigraphy may be done first, and if it detects amyloid deposits in the heart, a heart muscle biopsy may not be needed.

hATTR amyloidosis genetic testing

If tests find amyloid, genetic testing will help figure out whether you have hereditary ATTR amyloidosis (hATTR) or non-hereditary, which is commonly called wild-type ATTR amyloidosis. Knowing which one you have is important because it affects treatment plans and prognosis. But tests cannot predict when symptoms will start, how serious they’ll be, or how soon the disease will get worse. 

You may want to get a second opinion once you’re diagnosed since hATTR is rare and not every doctor has experience with the disease. 

  • Will my symptoms keep getting worse?
  • What treatments are best for me now? Is there a clinical trial that I should think about?
  • Do these treatments have side effects? What can I do about them?
  • How do we check on my progress? Are there new symptoms I should watch for?
  • How often should I see you?
  • Should I add my name to a transplant or disease registry?

Treatment of hATTR depends on your symptoms and how far your condition has developed. The goal of some treatment is to ease the symptoms that are caused when too much amyloid gathers in your organs.

For instance, if you're having problems with your heart or kidneys, you may have a buildup of fluid in your body. Your doctor may prescribe a pill that helps you get rid of extra fluid.

There are also medications you can take if you have digestive problems such as diarrhea or an early feeling of fullness.

Researchers are also looking at the drugs anakinra and tocilizumab as possible treatments for hATTR.

Treatment plan

There are options to treat hATTR with polyneuropathy. The goal of these treatments is to lower the number of misfolded proteins. You can: 

Use gene silencer drugs. Some FDA-approved drugs act as a gene silencer. They stop the creation of TTR protein. They include: 

  • Inotersen. This drug is mostly used in stage I or II of hATTR. It is offered only through a specific, limited program because it can cause serious bleeding and kidney disease. You give yourself a shot from a prefilled syringe once a week. 
  • Patisiran. This drug is used in stage I or II. You get this in an 80-minute intravenous infusion at a clinic once every 3 weeks.
  • Vutrisiran. It's an injection into the skin every 3 months to treat hATTR polyneuropathy.

Consider a liver transplant. Since TTR is made in the liver, a liver transplant may slow the disease, but it won't stop it. Transplants are sometimes recommended in the first stage of the disease in certain cases. If other organs are affected, such as the heart or kidney, other transplants may be considered. But transplants are costly and have a high risk of complications. The outcome of the transplant depends on a person’s age when symptoms start and the type of mutation. 

A liver transplant is major surgery. First, you'll need to get on a waiting list for a donor. Your new liver will come from someone who recently died and has the same blood type and a similar body size as yours. When donor livers are available, they go to the sickest people on the waiting list.

You may need to stay in the hospital for up to 3 weeks after your surgery. It could take you 6 months to a year before you can return to your regular lifestyle. After your transplant, you'll need to take drugs that prevent your body from rejecting the new liver.

If you're considering a transplant, you'll need a lot of emotional support. Ask your doctor about support groups that have people facing the same concerns as you. Also ask about educational workshops that can explain what to expect before and after a transplant.

What to do if your treatment isn’t working

When approved treatments aren’t working, there are drugs that can help block the TTR gene. These drugs are considered “off-label” and are not officially approved for this particular use.

Gene stabilizer drugs. These drugs prevent the TTR proteins from misfolding and forming amyloid deposits. They include: 

  • Tafamidis. This drug binds to the TTR gene. It is taken orally and slows down the disease in stages I-III. It also helps maintain quality of life. Tafamidis is approved to treat the cardiomyopathy of hATTR.
  • Diflunisal. This is an NSAID (an anti-inflammatory). Studies of this drug show that it slowed disease progression and improved quality of life. It is taken orally twice a day. 
  • Doxycycline. This antibiotic may disrupt the amyloid fibrils (long strands of proteins that clump together) and may help relieve cardiac symptoms. More clinical trials need to be done to find out how effective it is. 

Future or innovative treatments 

Researchers are looking into new treatments to find ways to suppress or stabilize the TTR gene. One of the drugs being researched is acoramidis. Clinical trials are looking at whether it works for both polyneuropathy and cardiac patients. In addition, clinical trials are using antibodies to remove amyloid deposits. Lastly, IONIS-TTR-LRx is a medicine in clinical trials to find out whether it reduces TTR production. 

Meet the care team (who treats this condition)

Since hATTR with polyneuropathy impacts several organs and is a genetic disease, you’ll likely have to see several specialists to manage the disease. Your care team can include: 

  • Genetic counselor. This professional will help you understand how this disease affects you and your family. Genetic tests and counseling can help with early diagnosis of the disease.
  • Neurologist. Neuropathy, or nerve pain and numbness, is one of the early signs of hATTR. A neurologist will use different tools to address the disease as it gets worse. 
  • Cardiologist. Some people with hATTR may have irregular heartbeats or other heart conditions. A cardiologist can guide you on how to reduce the cardiac symptoms.
  • Nephrologist. Kidneys are often impacted by hATTR, and a nephrologist will assist in evaluating how well your kidneys work. 
  • Ophthalmologist. Some hATTR patients can have eye issues because of amyloid deposits. An ophthalmologist can help you with any impact on vision. 
  • Physical therapist. The physical therapist can help you with mobility issues and exercises that assist with walking. 

hATTR with polyneuropathy is a progressive disorder, meaning it gets worse over time. Different symptoms can come during the stages. These are the likely stages of the disease:

Stage 0

In stage 0, hATTR with polyneuropathy generally has no symptoms. It is the stage where the TTR gene mutation is found through genetic testing. 

Stage I

Mild symptoms appear in stage I. Those could include mild sensory, motor, and autonomic neuropathy in the lower limbs. Walking is generally not seriously affected. 

Stage II

As the disease progresses, walking becomes more difficult and assistance may be required for movement. Your upper and lower limbs, as well as your trunk, are moderately affected. 

Stage III

This involves serious motor, sensory, and autonomic involvement of all limbs. Most patients are bedridden and need the assistance of a wheelchair. 

Transplant surgery and medications for TTR blocking and stabilization are very expensive. People in lower socioeconomic groups may not be able to afford them. There are also issues of access as many of the treatments involved with hATTR use injectable medications, permission beforehand, specialist referrals, and shifts between medical and pharmacy benefits. 

Other baseline differences show up when considering race as a factor in hATTR. Black Americans have more heart failure complications from hATTR than White people. Some of the reasoning is related to societal factors related to access, health literacy, and poor access to care. But biological differences – such as how Black people respond to heart failure therapies, and a greater risk for high blood pressure and diabetes – also play a role in Black Americans and increased heart issues from hATTR.

Since hATTR amyloidosis affects several organs, the disease can lead to serious complications. 

Peripheral nervous system complications include carpal tunnel syndrome, trouble walking, and trouble with fine motor skills. You could be more sensitive to pain, and you may get weaker.

hATTR patients will likely have autonomic problems that affect your internal organs. Among them are passing out from not enough blood getting to your brain (syncope), lower blood pressure, urinary tract infections that keep coming back, bladder issues, sexual dysfunction, and abnormal sweating. You can also have diarrhea and constipation.

Irregular heartbeat and palpitations can happen and may need a pacemaker. Heart failure may need diuretic medicines to get extra fluid out of your body. And you may need medicine to raise your blood pressure if it becomes too low. 

Kidney failure, eye issues, and pain are also potential complications of hATTR.