Common Gene Mutation Can Cause ATTR and Early Death

Researchers are learning more about a genetic mutation in many Black Americans that can cause a serious, often misdiagnosed disease. The amyloidogenic V142I variant of the transthyretin (TTR) gene affects 3% to 4% of people with West African heritage. It increases the risk of developing transthyretin amyloidosis (ATTR), a disease that can cause problems throughout the body, including the heart.

Recent research shows that carriers of this mutation are more likely to develop heart failure and to die up to two-and-a-half years earlier than people without the mutation.

“Given our estimations, there are about 500,000 Black Americans who live with this mutation. It’s potentially one of the most common genetic diseases of people of African descent,” says Scott D. Solomon, MD, a Mass General Brigham cardiologist.

Dr. Solomon and the Cardiac Amyloidosis Program want more people to understand their risk, the symptoms, and the unique treatment options for ATTR. The information can help prevent misdiagnosis and it can direct patients and clinicians toward more targeted, effective treatment.

Understanding transthyretin amyloidosis

Amyloidosis is a condition that causes proteins in the blood to fold up on themselves. These misfolded proteins form clumps called amyloid fibrils, which can deposit in organs throughout the body.

Transthyretin amyloidosis is a particular type of amyloidosis that involves misfolding of the transthyretin protein. This protein is produced in the liver and normally carries thyroxine, a thyroid hormone, throughout the body.

There are two types of transthyretin amyloidosis. One mostly affects the nervous system, and it affects bodily sensations such as touch, pain, heat, and sound, as well as involuntary bodily functions such as blood pressure, heart rate, and digestion.

The other type is a cardiac amyloidosis, which occurs when the misfolded proteins clump up and deposit in the heart. This makes the heart walls stiff, and the heart loses its ability to properly relax and fill with blood. This is called amyloid cardiomyopathy.

“What happens with this disease is that, ultimately, enough of these amyloid fibrils get deposited in the heart that the heart becomes stiff and it can’t pump as well. These people develop heart failure and then are at high risk for hospitalizations and death,” Dr. Solomon explains.

One of the most common causes of ATTR is a genetic mutation that affects the transthyretin protein or the DNA that tells the body to make the protein.

Symptoms of ATTR

ATTR symptoms can be subtle, and they can be the same as the symptoms of other heart conditions. Therefore, the condition is often missed or misdiagnosed.

Heart symptoms may include:

• Difficulty breathing, especially while lying down
• Excessive peeing, especially at night
• Fatigue for no apparent reason 
• Heart palpitations
• Lightheadedness
• Shortness of breath 
• Swelling in the belly, arms, hands, legs, or feet

Amyloid deposits can also deposit in other areas of the body. This may cause other seemingly unrelated symptoms, such as:

• Carpal tunnel syndrome, which causes pain and stiffness in the wrists
• Eye floaters (black or grey specks in your vision)
• Peripheral neuropathy, which may cause numbness, tingling, and problems with balance or coordination
• Spinal stenosis, which can cause pain, numbness, cramping, or tingling in the lower back, butt, and legs

Genetic testing for transthyretin amyloidosis

Having the genetic variant doesn’t guarantee that a person will develop transthyretin amyloidosis and heart failure. So Dr. Solomon doesn’t recommend that all people of West African descent have genetic testing to screen for the mutation.

But people who have several risk factors may want to consider genetic testing. Knowing whether you have the mutation can help with more accurate diagnosis and treatment options to help control this specific type of disease.

Risk factors include:

• Age: Most carriers of the genetic mutation who develop the disease do so later in life. Dr. Solomon’s research, published in JAMA, indicates that risk increased by about age 63, and mortality significantly increased at age 72.
• Family history: If a relative has had heart failure, especially at a younger age, tell your doctor. It may indicate a mutation that can be inherited in your family.
• West African descent: The genetic mutation is present almost exclusively in people whose families originated in countries of West Africa. This is the area of Africa where most Black Americans have their heritage. The variant is “almost unheard of” in people who aren’t of African descent.

Tafamidis treatment for transthyretin amyloidosis

Dr. Solomon wants people to be more aware of this mutation and this specific type of amyloidosis. These factors make a difference in your treatment options.

“We treat this differently than we treat generic heart failure. There are therapies that are coming on the market that are designed specifically for transthyretin amyloidosis and can dramatically improve outcomes,” he says.

The U.S. Food and Drug Administration (FDA) has approved tafamidis (brand names Vyndaqel® and Vyndamax®) for adults with transthyretin amyloidosis. The medication binds to transthyretin (TTR) protein to prevent it from breaking apart.

Several other medications are currently being tested. These include “silencers,” which lower the amount of transthyretin in the blood and medications that remove amyloid from the heart. In addition, scientists are exploring new technology that can edit the TTR gene to decrease production of this protein.

People with ATTR who develop heart failure may eventually require other medications, such as diuretics, or surgery, such as heart transplantation.

Mass General Brigham has a dedicated program to treat patients with ATTR and conducts research into risk factors and potential treatments. “If you put together our incredibly strong patient care with our deep commitment to the research in both understanding the disease and exploring potential therapies for the disease, it makes us a unique center that deeply understand this disease,” Dr. Solomon says.