Hereditary amyloidosis is a group of rare diseases caused by gene mutations (changes) that can be passed down through families. The most common form is hereditary transthyretin amyloidosis (hATTR amyloidosis), which is caused by an inherited mutation in the transthyretin (TTR) gene.

Changes in this gene can lead to a buildup of abnormal protein deposits in different parts of the body, affecting organs and nerves. However, inheriting a TTR gene mutation doesn’t always mean someone will develop symptoms.

Read on to learn more about the causes, symptoms, outlook, and other key details about hATTR amyloidosis.

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Hereditary ATTR amyloidosis happens because of a TTR gene change passed down from a parent. The mutation causes a protein called transthyretin to misfold. The misfolded TTR proteins form amyloid fibrils, which can build up as amyloid deposits in different organs and tissues and cause damage.

If someone has a TTR gene that causes hATTR amyloidosis, each of their children has a 50 percent chance of inheriting that mutation. Because of this, family members may want to talk with a genetic counselor to learn more about their own risk.

Multiple gene mutations can cause hereditary amyloidosis. These diseases can be divided into two main types — hereditary ATTR amyloidosis and non-TTR amyloidosis — based on the gene involved. These types can affect different organs, cause different symptoms, and have different treatment options.

ATTR Amyloidosis

Hereditary ATTR amyloidosis is caused by mutations in the TTR gene. So far, scientists have identified more than 100 TTR mutations associated with ATTR amyloidosis. Some mutations are more common in people with certain ethnicities or from certain parts of the world.

According to the Amyloidosis Research Consortium:

• The V30M variant is most often found in people from Portugal, Spain, France, Sweden, and Japan and their descendants.
• The V122I mutation is most often found in African Americans.
• The T60A mutation is most often seen in people of Irish ancestry and is the most common variant in the United Kingdom.

These TTR mutations can lead to a range of health problems. Amyloid deposits may affect the heart, nerves, or both, depending in part on the specific gene variant.

Non-TTR Amyloidosis

Non-TTR amyloidosis is caused by mutations in genes other than TTR. Scientists know of at least 60 mutations linked to these forms of amyloidosis, which are rarer than hATTR amyloidosis.

Symptoms of hATTR amyloidosis vary based on which organs and tissues are affected by amyloid deposits. The condition most often causes problems with the heart (cardiac amyloidosis), peripheral nerves, or both.

Heart Symptoms

People with hATTR amyloidosis can develop transthyretin amyloid cardiomyopathy (ATTR-CM). Amyloid fibrils can build up in the heart muscle and other parts of the heart. This buildup can cause the walls of the heart to stiffen, making it harder for the heart to fill with and pump blood.

People with ATTR-CM may also develop arrhythmias (irregular heart rhythms). Over time, heart damage can lead to heart failure (when the heart doesn’t pump blood well enough to meet the body’s needs).

Nerve Symptoms

Some people with hATTR amyloidosis develop polyneuropathy (ATTR-PN), a type of neuropathy that affects nerves throughout the body. Symptoms often start gradually with pain, tingling, or numbness in the feet and may spread up the legs.

As ATTR-PN progresses, it may become harder to move the legs. Eventually, nerves in the arms and fingers can also be affected.

Nerve damage in hATTR amyloidosis can have widespread effects, including:

• Nausea, diarrhea, or constipation
• Weight loss
• Orthostatic hypotension (a drop in blood pressure when standing up)
• Sexual dysfunction
• Carpal tunnel syndrome (pain, tingling, or numbness in the hand and wrist)

V122I is the most common variant associated with hereditary ATTR amyloidosis in the United States and is primarily associated with heart involvement. The V122I variant linked to hATTR amyloidosis is carried by about 3 percent to 4 percent of African Americans, according to the Amyloidosis Research Consortium.

Also called Val122Ile, V122I is linked to an increased risk of transthyretin amyloid cardiomyopathy (ATTR-CM). Heart-related symptoms associated with this variant often develop late in life. If you have a family member with this variant, genetic testing and genetic counseling can help you learn whether you carry the same variant.

Your doctor may use different types of tests to diagnose amyloidosis. Some tests look for amyloid proteins, and others determine which type of amyloidosis you have.

Biopsy

A biopsy may be used to diagnose amyloidosis. This procedure involves removing a small piece of tissue to check for amyloid deposits.

Your doctor may take a biopsy from an affected organ or from an area such as the abdominal fat pad (fat in your belly). The tissue sample is then sent to a lab for analysis.

Identifying Your Type of Amyloidosis

If amyloid deposits are found, the next step is to determine which type of amyloidosis you have. Your doctor will ask about your family history because hATTR amyloidosis is inherited. Sharing whether anyone in your family has been diagnosed with amyloidosis can help guide testing.

If ATTR amyloidosis is suspected, genetic testing of a blood sample can identify a TTR gene mutation and help determine whether you have hereditary ATTR amyloidosis.

Treatment for hATTR amyloidosis focuses on two goals — slowing the disease and managing symptoms or organ damage.

Two medication categories can be used for hATTR amyloidosis. One type, called a gene silencer, reduces the liver’s production of TTR protein. TTR silencers approved by the U.S. Food and Drug Administration (FDA) for treating hATTR amyloidosis with polyneuropathy include:

• Eplontersen (Wainua)
• Patisiran (Onpattro)
• Vutrisiran (Amvuttra), which is also approved for ATTR cardiomyopathy

A second type of medication stabilizes the TTR protein, helping prevent it from breaking down and forming amyloid fibrils. Acoramidis (Attruby) and tafamidis (Vyndamax) are FDA-approved TTR stabilizers for ATTR cardiomyopathy, including hATTR with heart involvement.

Another stabilizer, diflunisal, is sometimes prescribed off-label, meaning it’s not FDA-approved for amyloidosis but may be used under a doctor’s guidance. Additional medications are being studied in clinical trials.

Treating Amyloidosis Symptoms and Organ Damage

Medications can also help manage symptoms such as nerve pain and gastrointestinal (digestive system) problems. For some people with severe organ damage, transplantation may be considered.

If you’re experiencing symptoms or side effects from treatment, talk with your healthcare team. There may be ways to make you more comfortable and improve your quality of life.

Because hATTR amyloidosis can affect people differently, each person’s prognosis (outlook) can vary. Historically, people with hATTR amyloidosis had a median survival of 4.7 years after diagnosis (meaning half lived longer than 4.7 years and half lived less than that), but survival varies widely.

Newer treatments can slow disease progression and may help people live longer. Early diagnosis can help people start appropriate treatment sooner. However, life expectancy with hATTR amyloidosis varies widely depending on the person and the course of the disease.

Several factors can influence your prognosis, including:

• The gene mutation involved
• The organs that are affected
• The extent of disease at diagnosis
• The severity of symptoms
• The type and timing of your treatment

Treatments for heart or nerve involvement can slow disease progression and improve quality of life. Liver transplantation may also be considered for certain people with hATTR amyloidosis.

As treatments continue to advance, people with hATTR amyloidosis have more options for slowing the disease and managing its effects.

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