hATTR Amyloidosis Overview

Amyloid as a cause of pain.

Amyloidosis is a disorder resulting in an abnormal protein, amyloid, depositing in different organs throughout the body. The defective protein may build up in these organs and cause them to function improperly. It can be localized to one organ, or present systemically, affecting multiple regions of the body. There are three known amyloid syndromes: arthritis, neuropathy, and headache.

The disease is classified into several types. Here, we focus on hereditary ATTR amyloidosis (hATTR amyloidosis), a rare subtype of the disease that results from inherited mutations in the transthyretin (TTR) gene. This gene is responsible for the formation of TTR, a protein formed in the liver that transports the hormones thyroxine and retinol (vitamin A) throughout the body. To date, there are more than 120 different known mutations in the TTR gene. Each mutation is inherited in an autosomal dominant pattern, that is, only one parent must possess the mutated gene for a child to be affected.

“hATTR amyloidosis is a genetically transmitted disease and can affect 50% of family members,” said Vaishali Sanchorawala, MD, director of the Amyloidosis Center at Boston University School of Medicine and Boston Medical Center. “It is a devastating disease [that has had] a paucity of definitive treatments for many decades, but now the future is bright with many available treatments. There are many clinical trials available … to find the right treatment and combinations of treatment.”

The National Institutes of Health (NIH) classifies amyloidosis as a rare disease, meaning it affects less than 200,000 individuals in the US. The number of people living with hATTR amyloidosis is even more uncommon. However, efforts to build awareness are underway to improve the identification, management, and outlook of this chronic and painful condition.

hATTR amyloidosis is a genetic chronic disease that affects multiple organs and body systems, such as the heart, nervous system, gastrointestinal tract, and kidneys. (Source: 123RF)

hATTR Symptoms

Every patient with hATTR amyloidosis presents differently. Symptoms depend on many factors, including the specific gene mutation, the organs affected, and the extent of organ damage. Symptoms usually begin in adulthood and may worsen over time. As described below, the cardiovascular, nervous, and digestive systems are most commonly affected by hATTR amyloidosis. The kidneys, eyes, and carpal ligament may also be involved. Note that hATTR amyloidosis may present alongside other disorders, such as multiple myeloma, rheumatoid arthritis, and familial Mediterranean fever.

Patients may develop a heart condition called cardiomyopathy, or stiffening of the heart. This condition may result in chest pain, irregular heartbeat, difficulty breathing, ankle swelling, fatigue, and fainting.

Peripheral neuropathy, or nerve damage, affects different nerves throughout the body, resulting in numbness, tingling sensations and/or a loss of motion and weakness that starts in the feet and moves through the legs to the upper extremities.

Sometimes a condition called autonomic neuropathy, affecting the nerves that assist in organ function, may also develop. Symptoms of autonomic neuropathy can include lightheadedness from standing (postural hypotension), bladder and/or bowel problems, as well as erectile dysfunction in men.

Problems with the digestive system may result in nausea, diarrhea, constipation, weight loss, and poor appetite. Dysfunction in the kidneys, responsible for filtering toxins and proteins, may result in swelling, or edema, and possible renal failure. Carpal tunnel syndrome may result when amyloid deposits on the carpal ligaments irritate the surrounding nerves.

Diagnosis

hATTR amyloidosis requires early identification by a primary care doctor, with a referral to a specialist required for management. Without appropriate management, symptoms can worsen rapidly, causing disability, decreased life quality, and sometimes death.

A doctor will begin the evaluation by taking your detailed medical history. If amyloidosis is suspected, he or she will biopsy the abdominal fat pad and/or involved organ. Upon confirmation of amyloidosis, further evaluation may be needed to determine if any other organs have been impacted. These may include additional biopsies, as well as blood, nerve, and muscle tests.

To confirm the subtype of hATTR amyloidosis specifically, your doctor will likely request a blood sample. A genetic test will be performed on the blood sample to look for mutations in the TTR gene. Sometimes, other family members may choose to be tested as well.

Treatment

Patients usually benefit most from an individualized treatment plan developed in collaboration by an amyloidosis specialist and other healthcare professionals.

Liver transplantation is the most common method of treatment in hATTR amyloidosis, as the liver is the main source of abnormal TTR production. This procedure is most effective in patients who are in the early stages of the disease.

In addition, medications may be beneficial for symptom management. Only a few have been approved for this disease indication in the US, and each drug has a different purpose or mode of action, such as stabilization of the TTR protein, preventing the production of the TTR protein, or removing amyloid deposits. In 2018, FDA approved Patisiran (Alnylam Pharmaceuticals, Cambridge, MA) to help treat hATTR peripheral neuropathy. It acts as a “gene silencer,” acting directly to suppress the gene that produces TTR protein.

Supportive treatments geared toward alleviating bothersome symptoms can help to improve quality of life and decrease disability. Patients and family members may opt for genetic counseling as well.

According to Dr. Sanchorawala, patients with amyloidosis should “focus on definitive treatment as well as supportive treatment to improve quality of life.” She also recommends that patients “attend support group meetings and talk to others affected with the disease.”

To learn more, visit the Amyloidosis Research Consortium or the Amyloidosis Foundation.

Updated on: 03/04/19
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