Role of Genes in hATTR Amyloidosis

Hereditary ATTR amyloidosis (hATTR amyloidosis) is a rare, debilitating disease that runs in families. It's caused by inheriting a faulty transthyretin gene, which leads to the harmful buildup of abnormal protein clumps within different organs in the body.

This article reviews the role of genetics in developing hATTR amyloidosis. An overview of the symptoms, diagnosis, treatment, and outlook of hATTR amyloidosis will also be discussed.

Hereditary ATTR Amyloidosis and Genetic Risk Factors

Genes are composed of DNA, which is the blueprint for a person's appearance and how their body works. A child inherits half of their genes from one biological parent and half from the other.

Most genes code for proteins, which are molecules that carry out vital functions in the body. If a gene is faulty or mutated, the coded protein can be structurally and functionally abnormal, leading to disease.

Hereditary ATTR amyloidosis is caused by inheriting a mutated transthyretin gene, which produces an unstable, misshapen protein.

In hereditary ATTR amyloidosis, the abnormal transthyretin protein forms clumps called "amyloid fibrils," which deposit themselves within different tissues and organs throughout the body, causing harm and toxicity.

Hereditary ATTR amyloidosis is autosomal dominantly inherited, meaning if either parent has the disease, their child has a 50% risk of inheriting the faulty TTR gene.

That said, it's important to understand that inheriting a TTR gene mutation does not always mean a person will develop symptoms or that the disease will severely affect them.

Currently, over 130 TTR gene mutations are linked to hereditary ATTR amyloidosis. Symptoms and disease impact vary depending on the TTR gene mutation inherited.

hATTR Amyloidosis and Life Expectancy

Symptoms of hATTR amyloidosis begin in adulthood and are progressive, meaning they worsen over time. If not treated, hATTR amyloidosis has an irreversible course and, on average, becomes fatal seven to 10 years after the onset of symptoms.

Progressive hATTR Amyloidosis Symptoms

Symptoms of hATTR amyloidosis arise from the buildup of abnormal protein within various organs throughout the body. The protein buildup damages the organs, interfering with their normal functioning.

The most common sites of amyloid deposition are the peripheral nervous system and the heart. Other organs, namely the gut, kidneys, eyes, and brain, may also be involved.

Peripheral Nervous System

The peripheral nervous system consists of nerves that communicate information between a person's brain and spinal cord and the rest of their body (e.g., their limbs and internal organs).

Damage or inflammation of peripheral nerves (peripheral neuropathy) from amyloid deposits may cause prickling or burning pain, reduced temperature sensitivity, and tingling and numbness (paresthesia), often starting in the feet and lower limbs.

As the disease advances, symptoms, including muscle weakness, progress to the arms and trunk, and walking becomes impaired.

The autonomic nervous system (ANS), which regulates body functions out of a person's control (e.g., heartbeat and digestion), is also part of the peripheral nervous system and is commonly affected in hereditary ATTR amyloidosis.

Symptoms and signs of autonomic nervous system dysfunction include:

• Erectile dysfunction
• Orthostatic hypotension (lightheadedness when standing up)
• Reduced sweating
• Dry eye
• Urinary retention or incontinence

Heart

Amyloid deposits in the heart are mainly associated with palpitations and abnormal heart rhythms (arrhythmias), especially atrial fibrillation.

Restrictive cardiomyopathy—stiffening of the heart due to amyloid fibrils infiltrating the heart muscle—is also common in hereditary amyloidosis.

Amyloid cardiomyopathy can eventually lead to heart failure, causing symptoms like:

• Trouble breathing with activity and when lying down
• Unusual fatigue
• Lightheadedness and fainting
• Swelling (edema) in the feet, ankles, and legs

Other Organs

Other potential symptoms of hereditary ATTR amyloidosis based on organ involvement include:

• Digestive tract: Unintended weight loss, stomach pain, nausea, diarrhea, constipation, and early satiety (feeling full after eating only a small amount of food)
• Kidneys: Swelling, especially of the legs and ankles, and foamy urine due to protein in the urine (proteinuria)
• Eyes: Eye floaters or blurry vision
• Brain: Headaches, seizures, or stroke-like episodes

hATTR Amyloidosis Testing and Diagnosis

Several tests are performed to diagnose hATTR.

First, urine and/or blood tests are often ordered to check for amyloid protein.

Next, an abdominal fat pad biopsy is usually performed to confirm the presence of amyloid deposits.

Imaging or other diagnostic tests may also support the diagnosis of hATTR amyloidosis and evaluate for specific organ involvement. Examples of such tests include:

• Heart or kidney biopsy (a tissue sample is obtained and analyzed in the lab)
• Cardiac magnetic resonance imaging (MRI)
• Echocardiogram
• Nerve conduction tests
• Eye exam

Lastly, a genetic blood test is performed to analyze the DNA sequence of the mutated TTR gene. The specific TTR gene mutation provides vital clues about which organs will likely be affected and, in some cases, how well a person may respond to a particular therapy.

Overall, identifying the exact TTR gene mutation is crucial in helping healthcare providers devise an individualized treatment plan.

Treatment for Neuropathy and Other hATTR Amyloidosis Symptoms 

Hereditary amyloidosis is still considered an incurable disease, although various disease-modifying therapies are available to slow or potentially stop amyloid buildup within the body.

Gene-Silencing Therapies

Gene-silencing medications block the production of the abnormal transthyretin protein in the liver, thereby reducing the amount of amyloid entering the bloodstream and accumulating within the body's tissues and organs.

Gene-silencing drugs approved by the U.S. Food and Drug Administration (FDA) to treat hATTR with polyneuropathy (peripheral nerve disease with more than one nerve involved) include:

• Amvuttra (vutrisiran) is a subcutaneous (under the skin) injection every three months.
• Onpattro (patisiran) is an intravenous (IV) infusion every three weeks.
• Tegsedi (inotersen) is a weekly subcutaneous shot.
• Wainua (eplontersen) is a monthly subcutaneous shot.

TTR Stabilizers

Vyndaqel and Vyndamax (tafamidis) are FDA-approved oral (by mouth) drugs for hATTR cardiomyopathy. TTR stabilizers bind to the transthyretin protein and block it from misfolding, so amyloid fibrils cannot be formed.

Another TTR stabilizer—acoramidis—is currently being studied for the treatment of hATTR amyloidosis-related heart and nerve disease.

Organ Transplantation

Because the liver is the primary source of amyloid production, a liver transplant is another potential (albeit less favorable) treatment for hATTR amyloidosis.

The cells of the new liver have the donor's genetic makeup without the mutated gene. Replacing a person's liver with a new one removes the source of the mutated TTR protein, allowing for a significant reduction of amyloid in the body.

A liver transplant is a significant undertaking, and studies of its benefits are mixed. Research on people with hATTR amyloidosis has found an 85% survival rate (percentage of people alive) five years after a liver transplant and 73% 10 years after a transplant.

Lastly, depending on amyloid-related damage to the heart, a heart transplant alone (or in combination with a liver) may also be considered. 

Management and Supportive Care

Besides disease-modifying therapies, there is a vast array of supportive treatments that can improve the quality of life and symptoms in individuals living with hATTR amyloidosis.

For example, nerve pain associated with hATTR amyloidosis can be eased with prescription medication, such as:

• Lyrica (pregabalin)
• Neurontin (gabapentin)
• Elavil (amitriptyline)
• Cymbalta (duloxetine)

Likewise, heart failure related to amyloidosis can be managed by a cardiologist (a doctor specializing in heart disease) with diuretics (water pills), salt and fluid restriction, and cardiac rehabilitation.

In some cases, depending on the organ involved, surgery might be considered. For instance, a vitrectomy (removal of the liquid gel that fills the eye cavity) can be performed in people with eye floaters related to amyloidosis.

Adopting specific eating patterns (e.g., avoiding fatty foods and eating small, frequent meals) can be helpful for digestive symptoms, such as diarrhea or early satiety.

Research Advancements and Future Directions

Besides gene-silencing therapies and TTR stabilizers, a therapeutic strategy being studied is using monoclonal antibodies to remove amyloid deposits. The antibodies target pre-existing amyloid deposits, potentially allowing for the recovery of the involved organ.

A gene-editing technology called CRISPR-Cas9 therapy is also being investigated and offers hope for a potential cure for hATTR amyloidosis. This complex technology targets and fixes the faulty TTR gene, thereby preventing abnormal transthyretin protein from forming in the first place.

Summary

Hereditary ATTR (hATTR) amyloidosis is a rare, progressive condition caused by a faulty or mutated transthyretin (TTR) gene. The mutated TTR gene leads to abnormal transthyretin proteins (amyloid fibrils) building up within various organs.

Amyloid fibrils mainly settle in the nervous system and heart, causing tingling and numbness, dizziness when standing up, and symptoms of heart failure. Other organs like the gut, kidney, eye, and brain can also be affected by hATTR amyloidosis.

hATTR amyloidosis is autosomal dominantly inherited, so a child has a 50% chance of inheriting the mutated TTR gene if either biological parent carries it. Besides genetic testing to detect the mutated TTR gene, tissue biopsies and urine, blood, and imaging tests can confirm the diagnosis.

Treatment of hATTR amyloidosis involves a combination of supportive therapies to manage symptoms and disease-modifying therapies to slow or stop the buildup of amyloid protein. Clinical trials of monoclonal antibodies to remove amyloid fibrils as well as gene-editing technologies to correct the faulty TTR gene are underway.