Hereditary ATTR (hATTR) Amyloidosis Prognosis: What to Know

Hereditary transthyretin (hATTR) amyloidosis is a rare inherited disease. It is caused by a variant, or change, in the transthyretin (TTR) gene. This protein transports thyroid hormone and vitamin A to your body tissues.

With hATTR amyloidosis, variants change the TTR structure so that it clusters as amyloid deposits (proteins) in certain tissues. The disease commonly affects the nerves and heart. Over time, hATTR often becomes more severe and causes more extreme damage.

While hATTR amyloidosis is viewed as a progressive and fatal disease when untreated, many factors impact its effects and outcomes. Finding the disease early can help you start treatment to delay how fast the disease progresses.

This article describes hATTR amyloidosis, its prognosis, factors that affect its progress, and treatments.

Statistical Prognosis of hATTR Amyloidosis

The rare disease hATTR amyloidosis affects your entire system. While it's common in certain parts of Portugal, Brazil, Sweden, and Japan, it is less common in the United States. About 6,400 Americans have been diagnosed with hATTR.

In the United States, hATTR amyloidosis is most common among Americans of European descent. It affects about 1 in 100,000 people in this group. However, its exact incidence is unknown because it is considered significantly misdiagnosed.

The condition hATTR amyloidosis is inherited in an autosomal dominant manner. If one of your parents is affected or known to have the TTR variant, you have a 50% chance of inheriting the mutation. While most people who inherit the TTR mutation develop hATTR amyloidosis, some may never have the disease.

Most people affected with hATTR amyloidosis present with polyneuropathy (simultaneous damage to many nerves in different parts of your body). Cardiac, ocular, and kidney damage is also common. Cardiomyopathy (a disease affecting the heart muscle) can be identified in at least 50% of people with hATTR amyloidosis.

Since the clinical presentation and course of hATTR amyloidosis vary widely, data regarding the average prognosis (probable course of the disease) is also variable. Research indicates that the disease leads to death in an average of six to 12 years after diagnosis.

However, onset and survival vary widely based on the genetic mutation and the disease phenotype (hATTR cardiac amyloidosis, hATTR amyloidosis polyneuropathy, or combined). Death is often related to cardiac issues.

It's important to note that some data on the prognosis of hATTR amyloidosis may not have been based on the effects of very recent advances in disease treatment. Depending on individual disease factors, new and forthcoming treatments may impact your prognosis and help extend your life span.

Factors Influencing hATTR Amyloidosis Prognosis

Several factors can influence your hATTR amyloidosis prognosis. Disease progression can be unpredictable even among members of the same family. The following factors can impact your prognosis:

Type of Mutation

There are more than 120 mutations known to cause hATTR amyloidosis that are passed from parents to children. The most common variants in the United States include:

• Val122Ile: This variant is linked with cardiomyopathy. In the United States, it is more common in people with West African. Research indicates about 3.2% of African Americans have this mutation.
• Thr60Ala: This variant is found in people of Irish ancestry. It commonly affects both the heart and the peripheral nervous system.
• Val30Met: This variant primarily causes neuropathy and nerve-related symptoms. It is the most common mutation globally.

The mutation you inherit affects whether you may develop the disease. When symptoms occur, they can start as early as 30 years of age, though most types of hATTR amyloidosis occur later in life, typically by age 70.

Origin of the Inherited Mutation

The sex assigned at birth of the parent from whom the mutation is inherited seems to impact the age of onset for hATTR amyloidosis.

The signs and symptoms of hATTR amyloidosis occur more severely and at an earlier age as the disorder is passed from one generation to the next, a phenomenon called anticipation when the TRR mutation is passed from mother to son. However, inheritance from father to daughter protects female offspring from this.

Age of Onset

The age of onset can influence the clinical course and type of hATTR amyloidosis.

Early-onset disease (occurring before age 50) usually involves the following:

• Progressive sensorimotor (sensory and motor) and autonomic neuropathy (nerve damage to the nerves that control bodily functions) causing issues such as constipation, diarrhea, nausea, and vomiting, bladder and erectile dysfunction, among others
• Unspecific symptoms such as fatigue or unintentional weight loss are the initial disease manifestations
• Discomfort defined by numbness and neuropathic pain in the feet
• Cardiac arrhythmia (irregular heartbeat)
• Expected survival rate of about 10–20 years from onset

In late-onset disease (age 50 or older), disease progression is usually more rapid and severe. It typically involves the following:

• Cardiac involvement, including symptoms of congestive heart failure and ventricular hypertrophy (thickening of the heart's wall)
• Variable sensory or sensorimotor symptoms, starting in all four limbs, or exclusively in either lower or upper limbs, similar to carpal tunnel syndrome
• Ocular problems ranging from dry eye syndrome to glaucoma
• Central nervous system impairment leading to issues such as stroke, seizures, and dementia
• A survival rate of about seven years from disease onset
  

Role of hATTR Amyloidosis Treatment in Prognosis

Treatment strategies for hATTR amyloidosis can relieve symptoms. They can also manage the impact of the illness affecting your heart, nervous system, and kidneys based on the conditions that occur.

While no treatments can cure the disease or reverse the harm caused by amyloid deposits, new therapies can prevent or slow the progression of hATTR amyloidosis. The goal of therapy is to reduce the amount of abnormal TTR proteins circulating in your bloodstream.

Current treatments for hATTR amyloidosis involve the following:

Disease-Modifying Therapies

The following therapies work to prevent the production of TTR protein. People using the following treatments experience slowed disease progression and significant improvement in quality of life and neuropathic symptoms:

• Wainua (eplontersen) injection
• Tegesedi (inotersen) injection
• Onpattro (patisiran) intravenous (IV) infusion
• Amvuttra (vutrisiran) injection
• Vyndaquel/Vyndamax (tafamidis)
• Liver transplant: replacement of abnormal liver (the major source of TTR)
• Heart or other organ transplant due to damage from the disease

Off-Label and Alternative Treatments

The following drugs or treatments were originally created and approved for the treatment of other conditions and then found to have benefits for people with hATTR amyloidosis (called off-label use). These treatments include the following:

• Diflunisal (diflunisal) oral nonsteroidal anti-inflammatory drug (NSAID): This works as a TTR stabilizer to slow disease progression and preserve the quality of life.
• Doxycycline: This oral antibiotic can relieve symptoms in people with advanced cardiac diseases.
• Doxycycline plus TUDCA: This oral antibiotic plus bile acid can slow disease progression.
• Tasmar (tolcopone): This oral Parkinson's disease drug that helps with TTR stabilization.
• EGCG (green tea): This oral over-the-counter drug that can reduce the thickness of the heart wall and slow disease progression.
  

Summary

A diagnosis of hATTR amyloidosis can have a profound physical and emotional impact. Symptoms can impact your quality of life, such as problems with moving, walking, and freely using your upper limbs. It can also affect your mental health, making you feel low and alone.

Early diagnosis can help you take advantage of early treatments that can slow disease progression. It is also easier to control and relieve symptoms of pain before your disease worsens.

If just one parent has an hATTR amyloidosis mutation, contact your healthcare provider to discuss your disease risk. Genetic testing can help define your risk so you can track changes that may be early signs of the disease.