What causes ttr amyloidosis

Overview

Transthyretin (TTR) amyloidosis is a serious and often progressive condition characterized by the abnormal buildup of transthyretin protein in various organs and tissues throughout the body. The transthyretin protein, normally produced in the liver and choroid plexus in the brain, plays a role in transporting thyroid hormone and retinol (vitamin A). In TTR amyloidosis, this protein misfolds, breaks apart, and forms amyloid fibrils. These amyloid fibrils are sticky and can accumulate in the heart, nerves, kidneys, and other organs, leading to damage and dysfunction. The severity and specific organs affected depend on the type of TTR amyloidosis and individual factors.

What is Transthyretin (TTR)?

Transthyretin (TTR) is a protein that is primarily synthesized in the liver, with smaller amounts produced in the brain by the choroid plexus. Its main functions are to transport thyroxine (a thyroid hormone) and retinol (vitamin A) throughout the bloodstream. TTR circulates in the blood and cerebrospinal fluid as a tetramer, a complex of four identical protein subunits. In its normal state, TTR is a stable protein.

The Misfolding and Aggregation Process

The root cause of TTR amyloidosis lies in the misfolding of the TTR protein. For reasons not fully understood, the tetrameric structure of TTR can become unstable and break apart into individual subunits. These subunits then misfold into an abnormal shape that causes them to aggregate, or clump together, forming insoluble amyloid fibrils. These fibrils are rigid, rod-like structures that are resistant to breakdown by the body's normal cellular processes. Over time, these amyloid deposits accumulate in the extracellular spaces of various tissues and organs. The deposition of these amyloid fibrils disrupts the normal architecture and function of the affected organs, leading to the clinical manifestations of the disease.

Types of TTR Amyloidosis

TTR amyloidosis is broadly categorized into two main types:

1. Hereditary Transthyretin Amyloidosis (ATTRv)

Also known as familial amyloid polyneuropathy (FAP), ATTRv is an inherited disorder caused by specific genetic mutations in the TTR gene. These mutations lead to a less stable TTR protein that is prone to misfolding and forming amyloid deposits. ATTRv is an autosomal dominant condition, meaning that if one parent carries a mutated TTR gene, each child has a 50% chance of inheriting the mutation and developing the disease. There are over 120 known mutations in the TTR gene, each potentially leading to different clinical presentations, severity, and organ involvement. Common mutations include V30M, V122I, and L55P. ATTRv typically affects the peripheral nerves, causing progressive sensory and motor neuropathy, and can also affect the autonomic nervous system, heart (cardiomyopathy), and other organs.

2. Wild-Type Transthyretin Amyloidosis (ATTRwt)

Also known as senile systemic amyloidosis, ATTRwt is not caused by a genetic mutation but rather by the normal TTR protein that becomes unstable with age. As individuals age, particularly after 60, the TTR protein can naturally become more prone to misfolding and aggregation, even without a genetic predisposition. ATTRwt is more common in men and predominantly affects the heart, leading to a restrictive cardiomyopathy. This amyloid buildup stiffens the heart muscle, impairing its ability to fill and pump blood effectively. While ATTRwt primarily affects the heart, it can also involve other organs to a lesser extent.

Factors Contributing to Disease Onset and Progression

While the underlying cause is protein misfolding, several factors can influence the development and progression of TTR amyloidosis:

• Genetic Predisposition: For ATTRv, the specific mutation inherited from parents is the primary determinant of disease risk and characteristics. Some mutations are associated with earlier onset and more aggressive disease.
• Age: Age is a significant factor, especially for ATTRwt, where the risk increases substantially in older adults. Even in ATTRv, symptoms may not manifest until adulthood.
• Sex: ATTRwt is more prevalent in men, while ATTRv can affect both sexes, though presentation might differ.
• Environmental Factors: While less understood, ongoing research explores potential environmental triggers or co-factors that might influence TTR protein stability or amyloid formation.
• Other Medical Conditions: Certain co-existing conditions might influence disease severity or progression, although direct causal links are still being investigated.

Understanding the causes of TTR amyloidosis is crucial for accurate diagnosis, effective management, and the development of targeted therapies. Research continues to shed light on the complex mechanisms involved, offering hope for improved treatments and outcomes for affected individuals.