Hereditary vs. Wild-Type ATTR-CM: Key Differences Explained

If you’ve recently learned that you have a heart condition called transthyretin amyloid cardiomyopathy (ATTR-CM), you’re probably wondering: What caused this?

To answer that question, your provider will run a genetic test. The results will tell them whether you have hereditary or wild-type ATTR-CM.

The differences between hereditary vs. wild-type ATTR-CM may seem small at first. But cardiologist and co-director of the Cleveland Clinic Amyloidosis Center, Mazen Hanna, MD, says knowing what type you have is crucial — not just for your health, but for your family’s, too.

How hereditary and wild-type ATTR-CM differ

Both types of ATTR-CM involve a protein produced in your liver called transthyretin (TTR).

In ATTR-CM, your TTR proteins become unstable and misfold themselves, which makes them clump together into what are called amyloid fibrils. Those amyloid fibrils deposit in your heart, causing it to get stiff. Amyloid deposits may also build up in your nerves or connective tissues.

But why does the TTR become unstable to begin with? It happens for different reasons, depending on your diagnosis.

Why it happens

If you have hereditary ATTR-CM, you inherited a change (variant) in the gene responsible for producing TTR. That coding error eventually caused the protein to misfold, forming amyloid fibrils.

“You inherited that variant from either one of your biological parents — and if you have children, each child has a 50-50 chance that they’ll inherit the same variant in the TTR gene,” Dr. Hanna explains.

So far, researchers have found more than 150 different TTR gene variants associated with ATTR amyloidosis. The most common one is p.Val142Ile, which is found in about 3.5% of people of African descent.

That’s why it’s important to share as much of your biological family’s medical history with your provider as you can.

“If someone says their parent had unexplained heart failure, neuropathy or some kind of protein disease, that raises my suspicion that they may have hereditary ATTR-CM,” Dr. Hanna adds.

Wild-type ATTR-CM is more common, and the “why” isn’t quite as clear. In wild-type, the TTR gene is normal and doesn’t have a coding error. But normal TTR protein is still misfolding, for unclear reasons.

What we do know is that it’s an age-related condition, as it most often affects people over age 60, and more commonly affects men.

“The wild-type form is not hereditary,” Dr. Hanna clarifies. “It typically happens at older ages, but we don’t yet fully understand why.”

How type affects symptoms

ATTR-CM can cause serious cardiac symptoms regardless of the type you’re living with, but the hereditary form is more likely to affect your nerves.

The “CM” in ATTR-CM stands for cardiomyopathy — a stiffening and weakening of the heart muscle that impacts its ability to effectively pump blood throughout your body. People with advanced ATTR-CM of either type are likely to have heart failure symptoms, such as:

• Shortness of breath
• Fatigue and difficulty exercising
• Swelling (edema)
• Dizziness or fainting

But TTR amyloid can build up in other parts of your body, too. For example, it’s known to contribute to problems in your peripheral nerves. It can also deposit in your ligaments, which can lead to carpal tunnel syndrome and spinal stenosis.

ATTR-CM can also affect your autonomic nervous system, which controls the things your body does automatically, from regulating your blood pressure to sweating.

While both types of ATTR-CM can affect your nervous system, Dr. Hanna says nerve issues are more common in people with the hereditary type. For some, they can be disabling.

“People with the wild-type form tend to have no neuropathy or only mild neuropathy,” he shares. “If you have significant numbness in your feet or hands that’s gradually worsening — or symptoms involving blood pressure or digestion — that may suggest hereditary disease.”

But Dr. Hanna is quick to add that you can’t know what type you have based on your symptoms.

“You can have suspicions based on symptoms or family history, but ultimately, everybody diagnosed with ATTR should undergo genetic testing,” he stresses.

How type affects treatment

While the goals of treatment are the same, the type of ATTR-CM you have may influence certain aspects of your cardiologist’s approach. That’s partly because people with hereditary ATTR-CM often have a wider range of symptoms to address, including nerve involvement.

“There are some therapies that may be favored in hereditary disease, especially when neuropathy is involved,” Dr. Hanna notes.

Gene silencing medications are a good example. These drugs slow TTR production and are U.S. Food and Drug Administration (FDA) approved to treat the neuropathy associated with hereditary ATTR amyloidosis.

Why genetic testing matters

Genetic testing doesn’t just tell you what type of ATTR-CM you have — it also helps clarify whether your family members are at risk.

“We now have therapies that can potentially prevent people from developing severe heart and nerve problems if we catch the disease early enough,” Dr. Hanna explains.

If you get an ATTR-CM diagnosis and your provider doesn’t talk to you about genetic testing, Dr. Hanna urges you to bring it up.

What your diagnosis means for your family

If it turns out that you have hereditary ATTR-CM, your provider will write up a letter you can share with your family. They often suggest that all of your first-degree relatives (including siblings and children) get tested, if possible. But the details may look a bit different, depending on your exact diagnosis.

“For some variants that don’t usually cause disease until later in life, you wouldn’t necessarily test a very young adult right away,” Dr. Hanna says.

If another member of your family tests positive for a variant that causes ATTR-CM, they’ll be notified just like you were.

For example, if you have hereditary ATTR-CM and your sister tests positive, their close relatives who haven’t already been tested (like their children) will then be offered testing. This process is called cascade testing.

But Dr. Hanna says the cascade doesn’t happen very often.

“Family members may live in different states. They may not know where to go for testing. Or they may not fully understand the importance of getting screened,” he notes. “That remains one of our biggest challenges.”

Clinical trials

Knowing if you have hereditary vs. wild-type ATTR-CM is also important because you may be eligible for clinical trials. Dr. Hanna is particularly excited about a global clinical trial for hereditary ATTR-CM called ACT EARLY.

“We’re trying to move into the next frontier,” says Dr. Hanna. “If someone carries the variant but hasn’t developed heart or nerve problems yet, could early treatment prevent it from happening at all? That’s what this trial will help us figure out.”

You may qualify if you’ve been diagnosed with hereditary ATTR-CM and you:

• Don’t have any symptoms yet
• Are expected to develop symptoms in the next 10 years

ACT EARLY is just one of many clinical trials out there helping researchers learn more about — and improve treatment options for — hereditary and wild-type ATTR-CM. Ask your provider if there are any that you’re a good fit for. They can walk you through the benefits and possible drawbacks of joining.

A path forward

Finding out you have ATTR-CM can make the future feel uncertain. But learning whether you have hereditary or wild-type is a vital first step toward clarity. No matter what the testing reveals, it can help you understand what’s happening in your body and illuminate the path forward.