Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive condition that affects multiple organ systems. It is a type of amyloidosis, characterized by the buildup of an abnormal protein deposit called amyloid. This systemic disease is inherited, resulting from a mutation in a specific gene that leads to the production of unstable proteins. The progressive accumulation of these deposits impairs the normal function of tissues and organs.
How TTR Protein Causes Amyloid Deposits
The condition stems from a mutation in the TTR gene, which provides instructions for making the transthyretin (TTR) protein. TTR is primarily produced in the liver, where its normal function is to transport the thyroid hormone thyroxine and vitamin A (retinol). Four TTR protein units must bind together to form a stable structure known as a tetramer. The inherited genetic mutation alters the TTR protein structure, making the tetramer unstable and prone to dissociation.
Once the tetramer separates, the individual TTR protein units, called monomers, misfold into an incorrect shape. These misfolded proteins then stick together, aggregating into insoluble strands known as amyloid fibrils. This accumulation occurs outside of cells and gradually infiltrates various tissues and organs, disrupting their normal architecture and function. The extent and location of these amyloid deposits determine the specific manifestations of hATTR amyloidosis.
Common Symptoms and Organ Involvement
hATTR amyloidosis frequently presents with symptoms related to nerve damage and heart disease. The infiltration of amyloid fibrils into the peripheral nervous system causes a condition called polyneuropathy. This nerve damage often begins in the extremities, resulting in sensations like numbness, tingling, or pain, typically starting in the feet and lower legs.
The autonomic nervous system is also commonly affected. Damage here can lead to gastrointestinal issues such as alternating bouts of diarrhea and constipation, or early satiety. Patients may also experience orthostatic hypotension—a sudden drop in blood pressure upon standing that causes dizziness or lightheadedness.
When amyloid deposits accumulate in the heart muscle, they cause a thickening and stiffening of the walls, known as restrictive cardiomyopathy. This stiffening prevents the heart from properly relaxing and filling with blood between beats, leading to heart failure. Symptoms of cardiac involvement include shortness of breath, fatigue, and fluid retention leading to swelling in the legs and ankles. Abnormal heart rhythms, such as atrial fibrillation, can also occur.
Other organs can be involved, such as the eyes, where amyloid deposition can cause vision changes like floaters. The kidneys may be affected, leading to protein in the urine (proteinuria) and swelling. Carpal tunnel syndrome is also frequently an early or associated sign of hATTR amyloidosis.
The Diagnostic Process
Diagnosing hATTR amyloidosis requires combining clinical findings with specific laboratory and imaging tests, especially because its symptoms can mimic other conditions. Initial suspicion often arises when a person presents with unexplained, progressive nerve damage or heart failure, particularly if there is a family history of similar issues.
A tissue biopsy is a conventional step to confirm the presence of amyloid deposits in the body. A small sample of tissue, often from the abdominal fat pad, is stained with Congo red dye, which shows the characteristic amyloid under a microscope. Once amyloid is confirmed, the next procedure is to determine the specific protein responsible for the deposits.
Genetic testing, typically performed via a blood test, is necessary to confirm the hereditary form of the disease. This test identifies a mutation in the TTR gene, which confirms the diagnosis of hATTR amyloidosis. Specialized cardiac imaging, such as a technetium-labeled cardiac scintigraphy, may also be used to specifically identify TTR amyloid in the heart.
Treating hATTR Amyloidosis
Treatment strategies for hATTR amyloidosis focus on two main approaches: disease-modifying therapies to slow disease progression and supportive care to manage symptoms. The goal of disease-modifying treatment is to reduce the amount of abnormal TTR protein being produced or to prevent it from misfolding.
One category of medication involves TTR stabilizers, such as tafamidis, which bind to the TTR protein tetramer. By stabilizing the tetramer structure, these drugs prevent it from dissociating and misfolding into amyloid fibrils. Another strategy uses gene silencers (e.g., patisiran and inotersen), which target the messenger RNA (mRNA) that carries instructions from the mutated TTR gene. These drugs use RNA interference to reduce the production of the TTR protein by the liver, decreasing the supply of unstable protein. Liver transplantation was historically performed to replace the organ producing abnormal TTR, though newer drug therapies are often preferred.
Supportive care addresses the organ damage and symptoms that have already occurred. This may involve the use of pacemakers to regulate irregular heart rhythms or medications to manage pain associated with nerve damage. Addressing gastrointestinal issues, orthostatic hypotension, and heart failure with appropriate symptomatic treatments remains an ongoing component of comprehensive care for hATTR amyloidosis.